Herpes Simplex Esophagitis A Cause of Upper-Gastrointestinal Bleeding P A U L G. F I S H B E I N , MD, R A L P H T U T H I L L , MD, H E R B E R T K R E S S E L , MD, H A R V E Y F R I E D M A N , MD, and W I L L I A M J. S N A P E , JR, MD
Two patients with hemorrhagic esophagitis secondary to esophageal invasion with herpes simplex virus, type 1, are reported. Microscopic examination of the esophageal mucosa revealed multinucleated cells and intranuclear inclusions which are typical of herpes simplex infection. Herpes virus was cultured from each patient. Thus, hemorrhagic esophagitis due to esophageal invasion by herpes simplex virus may be a more frequent cause of upper-gastrointestinal bleeding than previously recognized.
Reflux of gastric acid past an incompetent lower esophageal sphincter into the esophageal squamous epithelium is the most c o m m o n cause for hemorrhagic esophagitis (1-3). Local trauma from caustic ingestion, radiotherapy, or nasogastric tubes may be less c o m m o n c a u s e s o f e r o s i v e e s o p h a g i tis (4, 5). E s o p h a g i t i s due to i n v a s i v e m i c r o organisms, such as Candida, tuberculosis, or herpes simplex virus, generally do not bleed but cause severe odynophagia and dysphagia (6, 7). An occasional case of Monilia may result in hemorrhagic esophagitis (5). At autopsy, herpetic esophagitis is a c o m m o n cause o f esophagitis and esophageal ulceration (7). However, esophagitis due to the herpes simplex virus is u n c o m m o n l y reported in living patients (811).
We report two cases of herpetic esophagitis who presented with the unusual complication of acute upper-gastrointestinal hemorrhage. CASE REPORTS Case 1 H.N. is a 68-year-old white woman who presented to the Emergency Room of the Hospital of the University of From the Gastrointestinal Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Address for reprint requests: Dr. William J. Snape, Jr., Gastrointestinal Section, Hospital of the University of Pennsylvania, 36th and Spruce Streets, Philadelphia, Pennsylvania 19104.
540
Pennsylvania on February 13, 1978, with a history of hematemesis and melena the day of admission. The vomiting was associated with chest pain, radiating to her thoracic spine. She had a history of several years of mild intermittent burning substernal chest discomfort that was typical of heartburn. The heartburn was not affected by eating, but the symptoms were exacerbated if she lay down after eating. She intermittently took antacids which relieved the heartburn. She did not complain of nausea, dysphagia, or odynophagia. There had been no weight loss. Her past medical history included chronic psychoneurosis treated with meprobamate, doxepin, and thioridazine. In the Emergency Room, she was pale, tachypneic, and in moderate distress. While lying down her blood pressure was 120/70, but it fell to 90/40 on sitting up. She had concomitant orthostatic changes in her pulse. No skin rashes, cold sores, or pharyngeal lesions were noted. Her conjuctivae were pale. She was without lymphadenopathy. She had bibasilar pulmonic tales and a grade II/VI systolic murmur at the left sternal border. Her abdomen was soft, and hyperactive bowel sounds were present. A large left lower quadrant mass, 4 x 4-cm, movable, and slightly tender, was palpated. There was no hepatosplenomegaly. Pelvic exam was negative, no mass was palpated on rectal examination, but her stool was grossly melenotic and hemoccult positive. Laboratory data on admission included: hemoglobin 5.3 g/100 cc, hematocrit 19%, WBC 18,300/mm3 with 75% neutrophils, 14% lymphocytes, 10% monocytes, 1% basophils. The platelet count was 215,000/mm a. The peripheral smear showed hypochromic and microcytic red blood cells. Her urinalysis and chest x-.rays were normal. Emergency panendoscopy was performed. The esophageal mucosa was erythematous, friable, and covered by Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
0163-2116/79/0700-0540503.00/1 ~3 1979 Digestive Disease Systems, Inc.
HERPES SIMPLEX ESOPHAGITIS
Fig 1. Air contrast barium esophogram from case 1. Multiple mucosal ulcers and nodules are present the entire length of the esophagus.
a white exudate. There was active bleeding in the distal two thirds of the esophagus. Examination of the stomach and duodenum revealed no mucosal erythema, ulceration, or other site of acute bleeding. A diagnosis of hemorrhagic, erosive esophagitis was made. Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
She was transfused 3 units of whole blood, given hourly antacids, and cimetidine 300 mg every 6 hr. On this therapy the hematemesis ceased, and her stools gradually became hemoccult negative over the next two days. Figure 1 shows her double-contrast barium esophagram. Multiple mucosal ulcers and nodules are present. The esophagus has a normal diameter. No peristalsis was present. After a week of vigorous medical therapy for reflux esophagitis, she was reendoscoped. Severe erosive esophagitis persisted throughout the distal two thirds of her esophagus. The mucosa was still friable with a whitish-yellow exudate, and diffuse ulcerations. KOH wetmount examination of the brushings and the biopsy specimens failed to demonstrate Candida. Figure 2 shows a photomicrograph of the cells obtained on cytological brushing. Multinucleated epithelial cells with groundglass change in the nuclei characteristic of herpes simplex infection were present. Viral cultures of an esophageal biopsy specimen were performed. The specimen was inoculated onto human embryonic lung fibroblast cells MRC-5 and onto primary rhesus monkey kidney cells. Viral identification was performed by immunofluorescence using a direct conjugate prepared against herpes hominis (Flow Laboratories). Herpes typing was performed by plaque morphology in chick embryo fibroblasts (12). On the second day after inoculation, typical cytopathological changes were noted. The MRC-5 isolate was identified as herpes simplex hominis virus by fluorescent antibody testing, and as type 1 virus by chick embryo plaque morphology (12). On the fourth hospital day she had a barium enema to evaluate the abdominal mass. An apple core lesion was observed in the proximal sigmoid. Ten days later, an anterior sigmoid resection was performed, and an adenocarcinoma of the colon was removed. Three out of four nodes were involved with tumor, but there was no evidence for distant metastases. She had a positive skin reaction to mumps antigen and streptokinase-streptodornase. She was discharged three weeks later, after an uneventful postoperative course. Following her surgery repeat upper-gastrointestinal exam revealed marked healing of the esophageal ulcerations. Two weeks after surgery, esophageal manometry was performed using perfused catheters. Manometry showed a lower esophageal sphincter pressure of 7 mm Hg (normal 15-30 mm Hg) with absent peristalsis in the distal 7 cm of the esophagus. Thus, she had an incompetent lower esophageal sphincter with a significant motility disorder of the lower end of the esophagus. Case 2 L.M. is a 61-year-old white woman who was transferred to the Hospital of the University of Pennsylvania on May 20, 1978, with acute renal failure. She had moderate hypertension which was treated with a-methyldopa and hydrochlorothiazide. One month prior to hospitalization a maculopapular erruption was noted. The antihypertensives were omitted and the rash resolved temporarily. Ten days prior to admission, she noted purpuric
541
FISHBEIN ET AL lesions on her legs. She was admitted to another hospital. Her BUN was 74 mg/dl, creatinine 4.0 mg/dl, LDH 2000 (IU)/titer, SGOT 600 (IU)/liter, SGPT 139 (IU)/liter, sodium was 109 rag/liter, and calcium 5.6 mg/dl. She was transferred to the Hospital of the University of Pennsylvania for dialysis. On examination, her blood pressure was 130/70 mm Hg. Her skin revealed palpable purpuric lesions on both legs to the knees, with tense hemorrhagic bullae. Her mucus membranes were not involved. Her stool was hemoccult negative. Laboratory data revealed a urinalysis with pigmented granular casts and 4-10 RBC/HPF. Her hemoglobin was 13.8 g/dl and hematocrit was 40%. The WBC was 6500/ram 3 with 66% neutrophils, 28% bands, 1% lymphocytes, and 5% monocytes. Platelets were 107,000/ram a. Her serum albumin was 2.6 g/dl and gamma globulin was 0.87 g/dl. The following laboratory tests were abnormal: BUN 99 mg/dl, bilirubin 1.02 g/dl direct and 1.73 mg/dl total, AST 328 (IU)/liter, ALT 93 (IU)/ liter, CPK 14,280 (IU)/liter. A diagnosis of allergic vasculitis with rhabdomyolysis and acute renal failure was made. Skin biopsy confirmed the presence of vasculitis with neutrophilic infiltration. She was treated with methylprednisolone 60 mg/day with clinical and biochemical improvement. However, she required hemodialysis. Odynophagia appeared on the ninth hospital day while signs of her vasculitis were resolving. Vesicular ulcerations were noted on her upper lip, tongue, and palate. KOH preparation of scrapings from the palate were negative for Monilia. The next day, an episode of hematemesis occurred. Her blood pressure was 110/75 lying and fell slightly to 100/65 standing and her pulse increased to 120/rain from 90/rain. Her hematocrit decreased to 30%. Endoscopy revealed plaque-like lesions throughout the distal two thirds of her esophagus, and one vesicle was seen. Her gastric mucosa was normal. Smears for Candida were negative, but cytologic brushings were interpreted as compatible with herpes simplex infection. The biopsy (Figure 3) revealed eosinophilic intranuclear inclusions within the epithelial cells typical of herpes simplex infection. A few budding yeast were also noted. She was treated with Diclone mouthwash, but she continued to have mild odynophagia. The vomiting ceased, but over the next 10 days her stools remained positive for occult blood. The lip and tongue lesions remained. Reendoscopy on June 9, 1978, revealed continued severe hemorrhagic esophagitis with plaque-like ulceration throughout the distal two thirds of her esophagus. A biopsy specimen from the esophagus was cultured as in case 1. The culture was positive for herpes simplex virus, type 1. Barium swallow revealed nodular lesions in the distal half of the esophagus with multiple ulcerations. Esophageal manometry revealed a normal LES pressure but disordered peristalsis in the lower third of the esophagus. DISCUSSION Although herpetic esophagitis has been well d o c u m e n t e d in autopsy series to be a c o m m o n cause o f esophageal ulceration (7, 13, 14), diagno-
542
Fig 2. Photomicrograph of cytologic smear from esophageal brushing in patient 1. Multinucleated epithelial cells with groundglass change to nuclei characteristic of herpes are present (x 1280).
sis is rarely made a n t e m o r t u m . Our cases represent a report o f hemorrhagic esophagitis due to herpes simplex proven by culture. E s o p h a g e a l lesions due to herpes virus were first described by Pearce and Dagradi (15). More recently, various autopsy series and c a s e reports have shown herpes virus to be a relatively c o m m o n cause of esophageal ulceration, especially in immunosuppressed hosts and patients with hematologic malignancies (8-10, 13, 16, 17). Herpetic esophagitis has also been associated with renal transplantation (7, 17), cutaneous burns (7), ulcerative colitis (15), corticosteroid t h e r a p y (13, 14), and other forms of c h e m o t h e r a p y and radiotherapy (7). Herpes simplex may invade the esophageal s q u a m o u s Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
HERPES SIMPLEX ESOPHAGITIS
Fig 3. Photomicrograph of esophageal mucosal biopsy from patient 2. Typical eosinophilic intranuclear inclusions within esophageal epithelial cells are present (x 1280).
mucosa that has been initially disrupted by a nasogastric tube. However, herpes esophagitis has been documented in otherwise normal adults (19, 20). Herpes esophagitis cannot be differentiated endoscopically from other causes of erosive esophagitis unless the characteristic vesicular lesions are present (23). The esophagus, in our cases, was extensively involved with an almost confluent whitishyellow exudate, friability, and large ulcerations. Others have reported, as in our second case, finding small discrete vesicular or bullous lesions with an erythematous base (9, 17, 19). It is possible that vesicles may be discerned during an earlier phase of infection, which subsequently becomes exudative and ulcerated. In autopsy series, the typical gross appearance is one of multiple punched-out ulcers in the distal third of the esophagus (7). Therefore, the diagnosis of herpes esophagitis cannot usually be made endoscopicaUy and other diagnostic techniques are necessary. Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
The diagnosis of herpes simplex infection can be validated by viral culture of biopsy material, cytology, or biopsy which reveals the pathognomonic discrete eosinophilic intranuclear inclusions (Cowdry type A)(18). These inclusions are often surrounded by a clear halo, intranuclear vacuoles, and a "ground-glass" appearance of the nucleus with deposition of chromatin beneath the nuclear membrane (18). One of our patients had an incompetent lower esophageal sphincter. The reflux of gastric acid may have disrupted her esophageal mucosa and allowed invasion with the herpes simplex virus. However, it is also possible that the esophagitis produced by the herpes infection led to a reduced lower esophageal sphincter pressure (21). The combination of reflux esophagitis and herpes simplex virus infection may have led to the severe erosive and hemorrhagic esophagitis observed in case 1. The diagnosis of herpes esophagitis may not be
543
FISHBEIN ET AL
obvious since the esophagus may be the only organ affected in 72% of patients (13). However, there can be concurrent herpetic infection of the mouth, respiratory tract, or the central nervous system. Herpes esophagitis generally is not hemorrhagic (20). ~Fhe patients generally present with dysphagia or odynophagia which are occasionally severe enough to prevent the swallowing of saliva. However, except for hematemesis, case 1 was asymptomatic. Cytologic brushings and subsequent viral cultures were obtained only because the esophagitis had not healed. Possibly a great number of patients have asymptomatic herpes esophagitis that is not discovered until autopsy (7). Many patients with hematologic malignancies, odynophagia, multiple ulcerations, and irregular mucosal folds on barium swallow may be misdiagnosed as candidiasis (6, 22). There are no reported sequelae following herpetic esophagitis. The odynophagia is usually.self-limited and can be treated symptomatically with topical anesthetics, analgesics, and sedation. Diagnosis of herpetic esophagitis may be important in patients with esophagitis refractory to the usual medical management. These patients may continue to have episodes of either acute or chronic blood loss. Adenine arabinoside may be effective antiviral therapy for herpetic esophagitis' (24). This drug has shown efficacy in herpetic encephalitis, and it produces minimal side effects. These two patients demonstrate that herpetic esophagitis may result in upper-gastrointestinal bleeding. Possibly a viral etiology should be excluded by biopsy, cytology, or viral cultures of esophageal tissue in patients with refractory erosive esophagitis. ACKNOWLEDGMENTS The authors wish to thank Ms Carmella Crescenzo for secretarial assistance. REFERENCES 1. Castell DO: The lower esophageal sphincter: Physiologic and clinical aspects. Ann Intern Med 83:390-401, 1975 2. Pope CE, II: Pathophysiology and diagnosis of reflux esophagitis. Gastroenterology 70:445-454, 1976
544
3. Snape WJ, Jr, Cohen S: Gastroesophageal reflux: Advances in medical and surgical treatment. Progress in Gastroenterology, Vol III GB Jersy Glass (ed). New York, Grune and Stratton, 1977, pp 695-716 4. Givler RL: Esophageal lesions in leukemia and lymphoma. Am J Dig Dis 15:31-36, 1970 5. Holt J: Candida infection of the esophagus. Gut 9:227-231, 1968 6. Meyers C, Durkin MG, Love L: Radiologic findings in herpes esophagitis. Radiology 119:21-22, 1976 7. Nash G, Ross JS: Herpetic esophagitis; a common cause of esophageal ulceration. Hum Pathol 5:339-345, 1974 8. Weiden PL, Schuffler MD: Herpes esophagitis complicating Hodgkin's disease. Cancer 33:1100-1102, 1974 9. Howiler W, Goldberg HI: Gastroesophageal involvement in herpes simplex. Gastroenterology 70:775-778, 1976 10. Lightdale CJ, Wolf DJ, Marcucci RA, Salyer WR: Herpetic esophagitis in patients with cancer: Antemortem diagnosis by brush cytology. Cancer 39:233-226, 1977 11. Pazin GJ: Herpes simplex esophagitis after trigeminal nerve surgery. Gastroenterology 74:741-743, 1978 12. Yang JPS, Chiang W, Gale JL, Chen NSR: A chick-embryo cell microtest for typing of Herpes virus Hominis. Proc Soc Exp Biol Med 148:324-328, 1975 13. Rosen P, Hajdu SI: Visceral Herpes virus infections in patients with cancer. Am J Clin Pathol 56:459-465, 1971 14. Moses HL, Cheatham WJ: The frequency and significance of human herpetic esophagitis. Lab Invest 12:663-669, 1963 15. Pearce J, Dagradi A: Acute ulceration of the esophagus with associated intranuclear inclusion bodies. Arch Pathol 35:899-897, 1943 16. Muller SA, Herrmann EC, Jr, WinkelmannRK: Herpes simplex infections in hematologic malignancies. Am J Med 52:102-114, 1972 17. Berg JW: Esophageal herpes: A complication of cancer therapy. Cancer 8:731-740, 1955 18. Lasser A: Herpes simplex virus esophagitis. Acta Cytol 21:301-302, 1977 19. Deprew WT, Prentice RSA, Beck IT, et al: Herpes simplex ulcerative esophagitis in a healthy subject. Am J Gastroenterol 68:381-385, 1977 20. Owensby LC, Stammer JL: Esophagitis associated with herpes simplex infection in an immuno-competent host. Gastroenterology 74:1305-1306, 1978 21. Eastwood GL, Castell DO, Higgs RH: Experimental esophagitis in cats impairs lower esophageal sphincter pressure. Gastroenterology 69:146-153, 1975 22. Skucas J, Schrank WW, Meyers PC, et al: Herpes esophagitis: A case studied by air-contrast esophography. Am J Roentgenol 128:497-499, 1977 23. Klotz DA, Silverman L: Herpes virus esophagitis consistent with herpes simplex, visualized endoseopically. Gastrointest Endosc 21:71-73, 1974 24. Whitley RJ, Soong SJ, Dolin R, et al: Adenine abrabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 297:289-294, 1977
Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
Two patients with hemorrhagic esophagitis secondary to esophageal invasion with herpes simplex virus, type 1, are reported. Microscopic examination of the esophageal mucosa revealed multinucleated cells and intranuclear inclusions which are typical of herpes simplex infection. Herpes virus was cultured from each patient. Thus, hemorrhagic esophagitis due to esophageal invasion by herpes simplex virus may be a more frequent cause of upper-gastrointestinal bleeding than previously recognized.
Reflux of gastric acid past an incompetent lower esophageal sphincter into the esophageal squamous epithelium is the most c o m m o n cause for hemorrhagic esophagitis (1-3). Local trauma from caustic ingestion, radiotherapy, or nasogastric tubes may be less c o m m o n c a u s e s o f e r o s i v e e s o p h a g i tis (4, 5). E s o p h a g i t i s due to i n v a s i v e m i c r o organisms, such as Candida, tuberculosis, or herpes simplex virus, generally do not bleed but cause severe odynophagia and dysphagia (6, 7). An occasional case of Monilia may result in hemorrhagic esophagitis (5). At autopsy, herpetic esophagitis is a c o m m o n cause o f esophagitis and esophageal ulceration (7). However, esophagitis due to the herpes simplex virus is u n c o m m o n l y reported in living patients (811).
We report two cases of herpetic esophagitis who presented with the unusual complication of acute upper-gastrointestinal hemorrhage. CASE REPORTS Case 1 H.N. is a 68-year-old white woman who presented to the Emergency Room of the Hospital of the University of From the Gastrointestinal Section, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Address for reprint requests: Dr. William J. Snape, Jr., Gastrointestinal Section, Hospital of the University of Pennsylvania, 36th and Spruce Streets, Philadelphia, Pennsylvania 19104.
540
Pennsylvania on February 13, 1978, with a history of hematemesis and melena the day of admission. The vomiting was associated with chest pain, radiating to her thoracic spine. She had a history of several years of mild intermittent burning substernal chest discomfort that was typical of heartburn. The heartburn was not affected by eating, but the symptoms were exacerbated if she lay down after eating. She intermittently took antacids which relieved the heartburn. She did not complain of nausea, dysphagia, or odynophagia. There had been no weight loss. Her past medical history included chronic psychoneurosis treated with meprobamate, doxepin, and thioridazine. In the Emergency Room, she was pale, tachypneic, and in moderate distress. While lying down her blood pressure was 120/70, but it fell to 90/40 on sitting up. She had concomitant orthostatic changes in her pulse. No skin rashes, cold sores, or pharyngeal lesions were noted. Her conjuctivae were pale. She was without lymphadenopathy. She had bibasilar pulmonic tales and a grade II/VI systolic murmur at the left sternal border. Her abdomen was soft, and hyperactive bowel sounds were present. A large left lower quadrant mass, 4 x 4-cm, movable, and slightly tender, was palpated. There was no hepatosplenomegaly. Pelvic exam was negative, no mass was palpated on rectal examination, but her stool was grossly melenotic and hemoccult positive. Laboratory data on admission included: hemoglobin 5.3 g/100 cc, hematocrit 19%, WBC 18,300/mm3 with 75% neutrophils, 14% lymphocytes, 10% monocytes, 1% basophils. The platelet count was 215,000/mm a. The peripheral smear showed hypochromic and microcytic red blood cells. Her urinalysis and chest x-.rays were normal. Emergency panendoscopy was performed. The esophageal mucosa was erythematous, friable, and covered by Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
0163-2116/79/0700-0540503.00/1 ~3 1979 Digestive Disease Systems, Inc.
HERPES SIMPLEX ESOPHAGITIS
Fig 1. Air contrast barium esophogram from case 1. Multiple mucosal ulcers and nodules are present the entire length of the esophagus.
a white exudate. There was active bleeding in the distal two thirds of the esophagus. Examination of the stomach and duodenum revealed no mucosal erythema, ulceration, or other site of acute bleeding. A diagnosis of hemorrhagic, erosive esophagitis was made. Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
She was transfused 3 units of whole blood, given hourly antacids, and cimetidine 300 mg every 6 hr. On this therapy the hematemesis ceased, and her stools gradually became hemoccult negative over the next two days. Figure 1 shows her double-contrast barium esophagram. Multiple mucosal ulcers and nodules are present. The esophagus has a normal diameter. No peristalsis was present. After a week of vigorous medical therapy for reflux esophagitis, she was reendoscoped. Severe erosive esophagitis persisted throughout the distal two thirds of her esophagus. The mucosa was still friable with a whitish-yellow exudate, and diffuse ulcerations. KOH wetmount examination of the brushings and the biopsy specimens failed to demonstrate Candida. Figure 2 shows a photomicrograph of the cells obtained on cytological brushing. Multinucleated epithelial cells with groundglass change in the nuclei characteristic of herpes simplex infection were present. Viral cultures of an esophageal biopsy specimen were performed. The specimen was inoculated onto human embryonic lung fibroblast cells MRC-5 and onto primary rhesus monkey kidney cells. Viral identification was performed by immunofluorescence using a direct conjugate prepared against herpes hominis (Flow Laboratories). Herpes typing was performed by plaque morphology in chick embryo fibroblasts (12). On the second day after inoculation, typical cytopathological changes were noted. The MRC-5 isolate was identified as herpes simplex hominis virus by fluorescent antibody testing, and as type 1 virus by chick embryo plaque morphology (12). On the fourth hospital day she had a barium enema to evaluate the abdominal mass. An apple core lesion was observed in the proximal sigmoid. Ten days later, an anterior sigmoid resection was performed, and an adenocarcinoma of the colon was removed. Three out of four nodes were involved with tumor, but there was no evidence for distant metastases. She had a positive skin reaction to mumps antigen and streptokinase-streptodornase. She was discharged three weeks later, after an uneventful postoperative course. Following her surgery repeat upper-gastrointestinal exam revealed marked healing of the esophageal ulcerations. Two weeks after surgery, esophageal manometry was performed using perfused catheters. Manometry showed a lower esophageal sphincter pressure of 7 mm Hg (normal 15-30 mm Hg) with absent peristalsis in the distal 7 cm of the esophagus. Thus, she had an incompetent lower esophageal sphincter with a significant motility disorder of the lower end of the esophagus. Case 2 L.M. is a 61-year-old white woman who was transferred to the Hospital of the University of Pennsylvania on May 20, 1978, with acute renal failure. She had moderate hypertension which was treated with a-methyldopa and hydrochlorothiazide. One month prior to hospitalization a maculopapular erruption was noted. The antihypertensives were omitted and the rash resolved temporarily. Ten days prior to admission, she noted purpuric
541
FISHBEIN ET AL lesions on her legs. She was admitted to another hospital. Her BUN was 74 mg/dl, creatinine 4.0 mg/dl, LDH 2000 (IU)/titer, SGOT 600 (IU)/liter, SGPT 139 (IU)/liter, sodium was 109 rag/liter, and calcium 5.6 mg/dl. She was transferred to the Hospital of the University of Pennsylvania for dialysis. On examination, her blood pressure was 130/70 mm Hg. Her skin revealed palpable purpuric lesions on both legs to the knees, with tense hemorrhagic bullae. Her mucus membranes were not involved. Her stool was hemoccult negative. Laboratory data revealed a urinalysis with pigmented granular casts and 4-10 RBC/HPF. Her hemoglobin was 13.8 g/dl and hematocrit was 40%. The WBC was 6500/ram 3 with 66% neutrophils, 28% bands, 1% lymphocytes, and 5% monocytes. Platelets were 107,000/ram a. Her serum albumin was 2.6 g/dl and gamma globulin was 0.87 g/dl. The following laboratory tests were abnormal: BUN 99 mg/dl, bilirubin 1.02 g/dl direct and 1.73 mg/dl total, AST 328 (IU)/liter, ALT 93 (IU)/ liter, CPK 14,280 (IU)/liter. A diagnosis of allergic vasculitis with rhabdomyolysis and acute renal failure was made. Skin biopsy confirmed the presence of vasculitis with neutrophilic infiltration. She was treated with methylprednisolone 60 mg/day with clinical and biochemical improvement. However, she required hemodialysis. Odynophagia appeared on the ninth hospital day while signs of her vasculitis were resolving. Vesicular ulcerations were noted on her upper lip, tongue, and palate. KOH preparation of scrapings from the palate were negative for Monilia. The next day, an episode of hematemesis occurred. Her blood pressure was 110/75 lying and fell slightly to 100/65 standing and her pulse increased to 120/rain from 90/rain. Her hematocrit decreased to 30%. Endoscopy revealed plaque-like lesions throughout the distal two thirds of her esophagus, and one vesicle was seen. Her gastric mucosa was normal. Smears for Candida were negative, but cytologic brushings were interpreted as compatible with herpes simplex infection. The biopsy (Figure 3) revealed eosinophilic intranuclear inclusions within the epithelial cells typical of herpes simplex infection. A few budding yeast were also noted. She was treated with Diclone mouthwash, but she continued to have mild odynophagia. The vomiting ceased, but over the next 10 days her stools remained positive for occult blood. The lip and tongue lesions remained. Reendoscopy on June 9, 1978, revealed continued severe hemorrhagic esophagitis with plaque-like ulceration throughout the distal two thirds of her esophagus. A biopsy specimen from the esophagus was cultured as in case 1. The culture was positive for herpes simplex virus, type 1. Barium swallow revealed nodular lesions in the distal half of the esophagus with multiple ulcerations. Esophageal manometry revealed a normal LES pressure but disordered peristalsis in the lower third of the esophagus. DISCUSSION Although herpetic esophagitis has been well d o c u m e n t e d in autopsy series to be a c o m m o n cause o f esophageal ulceration (7, 13, 14), diagno-
542
Fig 2. Photomicrograph of cytologic smear from esophageal brushing in patient 1. Multinucleated epithelial cells with groundglass change to nuclei characteristic of herpes are present (x 1280).
sis is rarely made a n t e m o r t u m . Our cases represent a report o f hemorrhagic esophagitis due to herpes simplex proven by culture. E s o p h a g e a l lesions due to herpes virus were first described by Pearce and Dagradi (15). More recently, various autopsy series and c a s e reports have shown herpes virus to be a relatively c o m m o n cause of esophageal ulceration, especially in immunosuppressed hosts and patients with hematologic malignancies (8-10, 13, 16, 17). Herpetic esophagitis has also been associated with renal transplantation (7, 17), cutaneous burns (7), ulcerative colitis (15), corticosteroid t h e r a p y (13, 14), and other forms of c h e m o t h e r a p y and radiotherapy (7). Herpes simplex may invade the esophageal s q u a m o u s Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
HERPES SIMPLEX ESOPHAGITIS
Fig 3. Photomicrograph of esophageal mucosal biopsy from patient 2. Typical eosinophilic intranuclear inclusions within esophageal epithelial cells are present (x 1280).
mucosa that has been initially disrupted by a nasogastric tube. However, herpes esophagitis has been documented in otherwise normal adults (19, 20). Herpes esophagitis cannot be differentiated endoscopically from other causes of erosive esophagitis unless the characteristic vesicular lesions are present (23). The esophagus, in our cases, was extensively involved with an almost confluent whitishyellow exudate, friability, and large ulcerations. Others have reported, as in our second case, finding small discrete vesicular or bullous lesions with an erythematous base (9, 17, 19). It is possible that vesicles may be discerned during an earlier phase of infection, which subsequently becomes exudative and ulcerated. In autopsy series, the typical gross appearance is one of multiple punched-out ulcers in the distal third of the esophagus (7). Therefore, the diagnosis of herpes esophagitis cannot usually be made endoscopicaUy and other diagnostic techniques are necessary. Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
The diagnosis of herpes simplex infection can be validated by viral culture of biopsy material, cytology, or biopsy which reveals the pathognomonic discrete eosinophilic intranuclear inclusions (Cowdry type A)(18). These inclusions are often surrounded by a clear halo, intranuclear vacuoles, and a "ground-glass" appearance of the nucleus with deposition of chromatin beneath the nuclear membrane (18). One of our patients had an incompetent lower esophageal sphincter. The reflux of gastric acid may have disrupted her esophageal mucosa and allowed invasion with the herpes simplex virus. However, it is also possible that the esophagitis produced by the herpes infection led to a reduced lower esophageal sphincter pressure (21). The combination of reflux esophagitis and herpes simplex virus infection may have led to the severe erosive and hemorrhagic esophagitis observed in case 1. The diagnosis of herpes esophagitis may not be
543
FISHBEIN ET AL
obvious since the esophagus may be the only organ affected in 72% of patients (13). However, there can be concurrent herpetic infection of the mouth, respiratory tract, or the central nervous system. Herpes esophagitis generally is not hemorrhagic (20). ~Fhe patients generally present with dysphagia or odynophagia which are occasionally severe enough to prevent the swallowing of saliva. However, except for hematemesis, case 1 was asymptomatic. Cytologic brushings and subsequent viral cultures were obtained only because the esophagitis had not healed. Possibly a great number of patients have asymptomatic herpes esophagitis that is not discovered until autopsy (7). Many patients with hematologic malignancies, odynophagia, multiple ulcerations, and irregular mucosal folds on barium swallow may be misdiagnosed as candidiasis (6, 22). There are no reported sequelae following herpetic esophagitis. The odynophagia is usually.self-limited and can be treated symptomatically with topical anesthetics, analgesics, and sedation. Diagnosis of herpetic esophagitis may be important in patients with esophagitis refractory to the usual medical management. These patients may continue to have episodes of either acute or chronic blood loss. Adenine arabinoside may be effective antiviral therapy for herpetic esophagitis' (24). This drug has shown efficacy in herpetic encephalitis, and it produces minimal side effects. These two patients demonstrate that herpetic esophagitis may result in upper-gastrointestinal bleeding. Possibly a viral etiology should be excluded by biopsy, cytology, or viral cultures of esophageal tissue in patients with refractory erosive esophagitis. ACKNOWLEDGMENTS The authors wish to thank Ms Carmella Crescenzo for secretarial assistance. REFERENCES 1. Castell DO: The lower esophageal sphincter: Physiologic and clinical aspects. Ann Intern Med 83:390-401, 1975 2. Pope CE, II: Pathophysiology and diagnosis of reflux esophagitis. Gastroenterology 70:445-454, 1976
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3. Snape WJ, Jr, Cohen S: Gastroesophageal reflux: Advances in medical and surgical treatment. Progress in Gastroenterology, Vol III GB Jersy Glass (ed). New York, Grune and Stratton, 1977, pp 695-716 4. Givler RL: Esophageal lesions in leukemia and lymphoma. Am J Dig Dis 15:31-36, 1970 5. Holt J: Candida infection of the esophagus. Gut 9:227-231, 1968 6. Meyers C, Durkin MG, Love L: Radiologic findings in herpes esophagitis. Radiology 119:21-22, 1976 7. Nash G, Ross JS: Herpetic esophagitis; a common cause of esophageal ulceration. Hum Pathol 5:339-345, 1974 8. Weiden PL, Schuffler MD: Herpes esophagitis complicating Hodgkin's disease. Cancer 33:1100-1102, 1974 9. Howiler W, Goldberg HI: Gastroesophageal involvement in herpes simplex. Gastroenterology 70:775-778, 1976 10. Lightdale CJ, Wolf DJ, Marcucci RA, Salyer WR: Herpetic esophagitis in patients with cancer: Antemortem diagnosis by brush cytology. Cancer 39:233-226, 1977 11. Pazin GJ: Herpes simplex esophagitis after trigeminal nerve surgery. Gastroenterology 74:741-743, 1978 12. Yang JPS, Chiang W, Gale JL, Chen NSR: A chick-embryo cell microtest for typing of Herpes virus Hominis. Proc Soc Exp Biol Med 148:324-328, 1975 13. Rosen P, Hajdu SI: Visceral Herpes virus infections in patients with cancer. Am J Clin Pathol 56:459-465, 1971 14. Moses HL, Cheatham WJ: The frequency and significance of human herpetic esophagitis. Lab Invest 12:663-669, 1963 15. Pearce J, Dagradi A: Acute ulceration of the esophagus with associated intranuclear inclusion bodies. Arch Pathol 35:899-897, 1943 16. Muller SA, Herrmann EC, Jr, WinkelmannRK: Herpes simplex infections in hematologic malignancies. Am J Med 52:102-114, 1972 17. Berg JW: Esophageal herpes: A complication of cancer therapy. Cancer 8:731-740, 1955 18. Lasser A: Herpes simplex virus esophagitis. Acta Cytol 21:301-302, 1977 19. Deprew WT, Prentice RSA, Beck IT, et al: Herpes simplex ulcerative esophagitis in a healthy subject. Am J Gastroenterol 68:381-385, 1977 20. Owensby LC, Stammer JL: Esophagitis associated with herpes simplex infection in an immuno-competent host. Gastroenterology 74:1305-1306, 1978 21. Eastwood GL, Castell DO, Higgs RH: Experimental esophagitis in cats impairs lower esophageal sphincter pressure. Gastroenterology 69:146-153, 1975 22. Skucas J, Schrank WW, Meyers PC, et al: Herpes esophagitis: A case studied by air-contrast esophography. Am J Roentgenol 128:497-499, 1977 23. Klotz DA, Silverman L: Herpes virus esophagitis consistent with herpes simplex, visualized endoseopically. Gastrointest Endosc 21:71-73, 1974 24. Whitley RJ, Soong SJ, Dolin R, et al: Adenine abrabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 297:289-294, 1977
Digestive Diseases and Sciences, Vol. 24, No. 7 (July 1979)
