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Esophagitis associated with herpes simplex infection in an immunocompetent host
0016-5085/78/7406-130~2.00/0 GA~EOSNTEROUXSY74~1305-1306, 1978
Vol. 74, No. 6 Printed in U.S.A.
Copyright0 1978by the AmericanGastroenterological Association
ESOPHAGITIS ASSOCIATED WITH HERPES SIMPLEX AN IMMUNOCOMPETENT HOST LOREN C. OWENSBY, M.D., Gastroenterology
INFECTION IN
AND JAMES L. STAMMER,M.D.
Service, Department
of Medicine, Brooke Army Medical Center, Fort Sam Houston,
Texas
We present a case of acute hemorrhagic esophagitis temporally associated with herpes simplex virus type 1 infection, as confirmed by culture and serology, without any evidence of other typical herpetic lesions in an immunocompetent host. Acute ulcerative esophagitis presumed to be caused by herpes simplex virus was first described in 1943 by Pearce and Dagradi, who used cytologic techniques to make the diagnosis. 1 Heretofore, all cases of herpetic esophagitis have been reported in severely debilitated or immunocompromised hosts and have generally lacked tissue culture support. Most often the diagnosis is made on necropsy. The following case is one of culturally and serologically proved herpes simplex virus infection occurring in an immunocompetent host and temporally associated with development of ulcerative esophagitis. Case Report The patient, a 29-year-old, previously healthy male physician, presented with severe odynophagia. Liquid antacids had given no relief, and the patient had begun to notice severe retrostemal and subxiphoid pain, even on dry swallows. He denied nausea, vomiting, heartburn, or ingestion of very hot or corrosive substances. There was no history to suggest trauma to the esophagus such as that caused by irradiation, chemotherapy, or nasogastric intubation. He had had an upper respiratory tract infection with sore throat, fever, and myalgias of 3-days duration, beginning 10 days before the onset of odynophagia. He specifically denied ever having had “fever blisters;” however, his newlywed wife had had a recrudescence of herpes labialis approximately 3 weeks before his illness. Physical examination revealed a healthy-appearing white male whose vital signs were normal. Examination of the lips, mouth, and pharynx revealed no lesions. The neck was supple and was without adenopathy. Examination of the lungs, heart, abdomen, genitalia, and skin was normal. Stool tested negatively for occult blood. Laboratory data included normal electrolytes, urinalysis, Received September 29,1977. Accepted January 3, 1978. Address requests for reprints to: Loren C. Owensby, M.D., Gastroenterology Service, Department of Medicine, Brooke Array Medical Center, Fort Sam Houston, Texas 78234. The opinions or assertions contained herein are the private views ofthe authors and are not to be construed as reflecting the views of the Department of the Army or of the Department of Defense. The authors wish to thank the following persons for their assistance in preparing this case report: Steven K. Koester and Winnie R. Callahan, Virology Section, United States Army Medical Laboratory; Dan Marmer, Clinical Pathology, Brooke Army Medical Center; LTC Russell W. Steele, MC, Department of Pediatrics, BAMC; LTC Theodore R. McNitt, MC, Department of Medicine, BAMC.
and chemistry profile. White blood count was 7500 with 60% polymorphonuclear leukocytes and 5% band forms. Hematocrit was 48%. Chest X-ray was unremarkable. Roentgenological examination of the upper gastrointestinal tract, including barium esophagogram, was normal. The patient underwent esophagogastroduodenoscopy on the 2nd day of his illness. Extending 20 cm from the incisors to the esophagogastric junction were diffuse, superficial esophageal ulcers, measuring from 2 mm to 1.5 cm in diameter, with coalescence of many of the ulcers distally. The area of the esophagogastric junction was diffusely hemorrhagic before advancement of the endoscope through this region. The stomach, pylorus, and duodenum were normal. Biopsies of the margins and centers of the esophageal ulcers on subsequent histological examination revealed acute inflammatory changes. Tissue sections were negative for intranuclear inclusions and pseudohyphae. Brushings of the esophageal ulcers were submitted in trypticase soy broth for viral culture. Herpes simplex (Herpesvirus hominis), type 1 (HSVl), was isolated on human embryonic kidney, African green monkey kidney, and baboon kidney tissue. Complement fixation titers for HSV-1 rose from 0 on the 2nd day of his illness to 1:128 on the 17th day. The patient’s immune defense status was investigated on the 5th day of his illness. Quantitation of IgG was 1203 mg per 100 ml, IgA was 250 mg per 100 ml, and IgM was 244 mg per 100 ml. T and B cell lymphocyte quantitation revealed 56% E rosettes (T lymphocytes) and 45% erythrocyte antibody-complement rosettes (B lymphocytes). Mitogen stimulation to pokeweed, phytohemagglutinin, concanavalin A, and streptokinase-streptodomase was normal. Symptomatic treatment with antacids, viscous lidocaine, and diazepam resulted in marked resolution of odynophagia over a 3-day period. Hematocrit fell from 48% on the 1st day of illness to 34% on the 10th day without evidence of hypovolemia or hemolysis. Stools tested positively for occult blood from the 3rd to the 12th hospital days. ‘I’he patient was not transfused but was given iron sulfate therapy which resulted in reticulocytosis and rise in hematocrit.
Discussion Herpes simplex virus is a DNA-core virus which has been shown to be a causative agent of encephalitis, hepatitis, esophagitis, gastritis, and pneumonitis. These visceral herpetic infections have been described previously only in immunosuppressed or severely debilitated patients, frequently as a preterminal event.2+ The patient presented here differs from previously re-
1305
1306
CASE REPORTS
ported cases of herpetic esophagitis in that he was neither severely debilitated nor immunosuppressed. There was no evidence for antecedent injury to the esophagus. The severity of this patient’s esophagitis is similar to that reported in primary herpetic infections which tend to be more severe than recrudescences or reinfections. Esophageal hemorrhage has not been described in herpetic esophagitis. In the present case, gross hemorrhage was seen in the distal 3 to 4 cm of the esophagus. Because there was no evidence of excessive diagnostic phlebotomy or of hemolysis and because stools became positive for blood, it was assumed that this hemorrhagic lesion was responsible for a 1Cpoint drop in the patient’s hematocrit, although he remained hemodynamically stable throughout his course. Diagnosis of visceral herpes usually rests on the cytological finding of Cowdry type A intranuclear inclusion bodies in the appropriate clinical setting.6,7 In autopsy series, the incidence of herpes as an etiology of esophageal ulceration varies from 2 to 10% if cytology is the method used for diagnosis8 There are disadvantages to using cytology as the sole means of diagnosing herpetic infections. Cytology does not allow for differentiatiolt between HSV-1 and HSV-2; furthermore, intranuclear inclusion bodies have been demonstrated in nonviral disease.s The endoscopic appearance of herpes esophagitis, as previously described, lo-l2is similar to what was seen in the present case. Herpetic esophagitis begins with vesicle formation, followed by the appearance of small, punched-out, superficial ulcers covered with fibrinous exudate. These ulcers may coalesce, forming a diffuse erosive esophagitis. Biopsy of the margin of one of the ulcers may reveal evidence of herpetic involvement and should reveal pseudohyphae if Candida is the causative agent. It is known that herpetic ulcers may become overgrown with Candida; therefore, evidence of the two agents may coexist in the same tissue specimen. Tissue culture isolation of the specific herpes virus and serological confirmation of acute herpetic infection by observing a 4-fold rise in complement-fixing antibody in the patient’s serum to HSV-1 are extremely helpful from a diagnostic standpoint. The patient presented here had tissue culture proof of herpetic infection with no obvious lesion demonstrable except for esophagitis and had a 7fold rise in complement-fixing antibody to HSV-1. It is known that chronic oropharyngeal shedding of HSV-1 occurs in some asymptomatic persons.13 In the present case, oropharyngeal contamination was not
Vol.74,No. 6
excluded and histological confirmation of viral inclusion bodies was not established. Treatment of herpes esophagitis is largely supportive. Important aspects of this supportive therapy are sedation and adequate analgesia. In the present case, resolution was spontaneous and occurred over a lo-day period. The major intent and potential significance of this report is to call attention to the possibility that herpetic esophagitis may occur in immunocompetent hosts apparently without antecedent esophageal injury. The frequency with which this may occur will depend on subsequent studies done with an awareness that this disease may occur in noncompromised hosts, and utilizing methods to exclude the possibility of contamination, i.e., show the histological response characteristic for viral infection of the esophagus, or demonstrate increased quantity of virus from esophageal brushings, as opposed to throat washings. REFERENCES 1. Pearce J, Dagradi A: Acute ulceration of the esophagus with
associated intranuclear inclusion bodies. Arch Path01 35:889897, 1943 2. Berg JW: Esophageal herpes: a complication of cancer therapy. Cancer 8:731-740, 1955 3.Rosen P, Hajdu SI: Visceral herpesvirus infections in patients with cancer. Am J Clin Path01 56:459-465, 1971 Weiden PL, SchufRer MD: Herpes esophagitis complicating Hodgkin’s disease. Cancer 33:1100-1102, 1974 Nahmias AJ, Roizman B: Infection with herpes simplex viruses 1 and 2. N Engl J Med 289:667-674, 719-724, 781-789, 1973 Nash G, Ross JW: Herpetic esophagitis: a common cause of esophageal ulceration. Hum Path01 5:339-345, 1974 Alan BPN, Reagan JW, Lindner E: The cellular manifestations of primary and recurrent herpes genitalis. Acta Cytol 14:124129, 1970 6. Moses HL, Cheatham WJ: The frequency and significance of human herpetic esophagitis: an autopsy study. Lab Invest 12:663-669, 1963 9. Sobel HJ, Schwarz R, Marguet E: Nonviral nuclear inclusions. I. Cytoplasmic invaginations. Arch Path01 87:179-192, 1969 10. Howiler W, Goldbert HI: Gastroesophageal involvement in herpes simplex. Gastroenterology 70:775-778, 19’76 11. Klotz DA, Silverman L: Herpes virus esophagitis consistent with herpes simplex, visualized endoscopically. Gastrointest Endosc 21:71-73, 1974 12. Kaye MD: Herpetic conjunctivitis as an unusual occupational hazard (endoscopists’eye). Gastrointest Endosc 21:69-70, 1974 13. Douglas RG, Couch RB: A prospective study of chronic herpes simplex virus infection and recurrent herpes labialis in humans. J Immunol 104:289-295, 1970
Vol. 74, No. 6 Printed in U.S.A.
Copyright0 1978by the AmericanGastroenterological Association
ESOPHAGITIS ASSOCIATED WITH HERPES SIMPLEX AN IMMUNOCOMPETENT HOST LOREN C. OWENSBY, M.D., Gastroenterology
INFECTION IN
AND JAMES L. STAMMER,M.D.
Service, Department
of Medicine, Brooke Army Medical Center, Fort Sam Houston,
Texas
We present a case of acute hemorrhagic esophagitis temporally associated with herpes simplex virus type 1 infection, as confirmed by culture and serology, without any evidence of other typical herpetic lesions in an immunocompetent host. Acute ulcerative esophagitis presumed to be caused by herpes simplex virus was first described in 1943 by Pearce and Dagradi, who used cytologic techniques to make the diagnosis. 1 Heretofore, all cases of herpetic esophagitis have been reported in severely debilitated or immunocompromised hosts and have generally lacked tissue culture support. Most often the diagnosis is made on necropsy. The following case is one of culturally and serologically proved herpes simplex virus infection occurring in an immunocompetent host and temporally associated with development of ulcerative esophagitis. Case Report The patient, a 29-year-old, previously healthy male physician, presented with severe odynophagia. Liquid antacids had given no relief, and the patient had begun to notice severe retrostemal and subxiphoid pain, even on dry swallows. He denied nausea, vomiting, heartburn, or ingestion of very hot or corrosive substances. There was no history to suggest trauma to the esophagus such as that caused by irradiation, chemotherapy, or nasogastric intubation. He had had an upper respiratory tract infection with sore throat, fever, and myalgias of 3-days duration, beginning 10 days before the onset of odynophagia. He specifically denied ever having had “fever blisters;” however, his newlywed wife had had a recrudescence of herpes labialis approximately 3 weeks before his illness. Physical examination revealed a healthy-appearing white male whose vital signs were normal. Examination of the lips, mouth, and pharynx revealed no lesions. The neck was supple and was without adenopathy. Examination of the lungs, heart, abdomen, genitalia, and skin was normal. Stool tested negatively for occult blood. Laboratory data included normal electrolytes, urinalysis, Received September 29,1977. Accepted January 3, 1978. Address requests for reprints to: Loren C. Owensby, M.D., Gastroenterology Service, Department of Medicine, Brooke Array Medical Center, Fort Sam Houston, Texas 78234. The opinions or assertions contained herein are the private views ofthe authors and are not to be construed as reflecting the views of the Department of the Army or of the Department of Defense. The authors wish to thank the following persons for their assistance in preparing this case report: Steven K. Koester and Winnie R. Callahan, Virology Section, United States Army Medical Laboratory; Dan Marmer, Clinical Pathology, Brooke Army Medical Center; LTC Russell W. Steele, MC, Department of Pediatrics, BAMC; LTC Theodore R. McNitt, MC, Department of Medicine, BAMC.
and chemistry profile. White blood count was 7500 with 60% polymorphonuclear leukocytes and 5% band forms. Hematocrit was 48%. Chest X-ray was unremarkable. Roentgenological examination of the upper gastrointestinal tract, including barium esophagogram, was normal. The patient underwent esophagogastroduodenoscopy on the 2nd day of his illness. Extending 20 cm from the incisors to the esophagogastric junction were diffuse, superficial esophageal ulcers, measuring from 2 mm to 1.5 cm in diameter, with coalescence of many of the ulcers distally. The area of the esophagogastric junction was diffusely hemorrhagic before advancement of the endoscope through this region. The stomach, pylorus, and duodenum were normal. Biopsies of the margins and centers of the esophageal ulcers on subsequent histological examination revealed acute inflammatory changes. Tissue sections were negative for intranuclear inclusions and pseudohyphae. Brushings of the esophageal ulcers were submitted in trypticase soy broth for viral culture. Herpes simplex (Herpesvirus hominis), type 1 (HSVl), was isolated on human embryonic kidney, African green monkey kidney, and baboon kidney tissue. Complement fixation titers for HSV-1 rose from 0 on the 2nd day of his illness to 1:128 on the 17th day. The patient’s immune defense status was investigated on the 5th day of his illness. Quantitation of IgG was 1203 mg per 100 ml, IgA was 250 mg per 100 ml, and IgM was 244 mg per 100 ml. T and B cell lymphocyte quantitation revealed 56% E rosettes (T lymphocytes) and 45% erythrocyte antibody-complement rosettes (B lymphocytes). Mitogen stimulation to pokeweed, phytohemagglutinin, concanavalin A, and streptokinase-streptodomase was normal. Symptomatic treatment with antacids, viscous lidocaine, and diazepam resulted in marked resolution of odynophagia over a 3-day period. Hematocrit fell from 48% on the 1st day of illness to 34% on the 10th day without evidence of hypovolemia or hemolysis. Stools tested positively for occult blood from the 3rd to the 12th hospital days. ‘I’he patient was not transfused but was given iron sulfate therapy which resulted in reticulocytosis and rise in hematocrit.
Discussion Herpes simplex virus is a DNA-core virus which has been shown to be a causative agent of encephalitis, hepatitis, esophagitis, gastritis, and pneumonitis. These visceral herpetic infections have been described previously only in immunosuppressed or severely debilitated patients, frequently as a preterminal event.2+ The patient presented here differs from previously re-
1305
1306
CASE REPORTS
ported cases of herpetic esophagitis in that he was neither severely debilitated nor immunosuppressed. There was no evidence for antecedent injury to the esophagus. The severity of this patient’s esophagitis is similar to that reported in primary herpetic infections which tend to be more severe than recrudescences or reinfections. Esophageal hemorrhage has not been described in herpetic esophagitis. In the present case, gross hemorrhage was seen in the distal 3 to 4 cm of the esophagus. Because there was no evidence of excessive diagnostic phlebotomy or of hemolysis and because stools became positive for blood, it was assumed that this hemorrhagic lesion was responsible for a 1Cpoint drop in the patient’s hematocrit, although he remained hemodynamically stable throughout his course. Diagnosis of visceral herpes usually rests on the cytological finding of Cowdry type A intranuclear inclusion bodies in the appropriate clinical setting.6,7 In autopsy series, the incidence of herpes as an etiology of esophageal ulceration varies from 2 to 10% if cytology is the method used for diagnosis8 There are disadvantages to using cytology as the sole means of diagnosing herpetic infections. Cytology does not allow for differentiatiolt between HSV-1 and HSV-2; furthermore, intranuclear inclusion bodies have been demonstrated in nonviral disease.s The endoscopic appearance of herpes esophagitis, as previously described, lo-l2is similar to what was seen in the present case. Herpetic esophagitis begins with vesicle formation, followed by the appearance of small, punched-out, superficial ulcers covered with fibrinous exudate. These ulcers may coalesce, forming a diffuse erosive esophagitis. Biopsy of the margin of one of the ulcers may reveal evidence of herpetic involvement and should reveal pseudohyphae if Candida is the causative agent. It is known that herpetic ulcers may become overgrown with Candida; therefore, evidence of the two agents may coexist in the same tissue specimen. Tissue culture isolation of the specific herpes virus and serological confirmation of acute herpetic infection by observing a 4-fold rise in complement-fixing antibody in the patient’s serum to HSV-1 are extremely helpful from a diagnostic standpoint. The patient presented here had tissue culture proof of herpetic infection with no obvious lesion demonstrable except for esophagitis and had a 7fold rise in complement-fixing antibody to HSV-1. It is known that chronic oropharyngeal shedding of HSV-1 occurs in some asymptomatic persons.13 In the present case, oropharyngeal contamination was not
Vol.74,No. 6
excluded and histological confirmation of viral inclusion bodies was not established. Treatment of herpes esophagitis is largely supportive. Important aspects of this supportive therapy are sedation and adequate analgesia. In the present case, resolution was spontaneous and occurred over a lo-day period. The major intent and potential significance of this report is to call attention to the possibility that herpetic esophagitis may occur in immunocompetent hosts apparently without antecedent esophageal injury. The frequency with which this may occur will depend on subsequent studies done with an awareness that this disease may occur in noncompromised hosts, and utilizing methods to exclude the possibility of contamination, i.e., show the histological response characteristic for viral infection of the esophagus, or demonstrate increased quantity of virus from esophageal brushings, as opposed to throat washings. REFERENCES 1. Pearce J, Dagradi A: Acute ulceration of the esophagus with
associated intranuclear inclusion bodies. Arch Path01 35:889897, 1943 2. Berg JW: Esophageal herpes: a complication of cancer therapy. Cancer 8:731-740, 1955 3.Rosen P, Hajdu SI: Visceral herpesvirus infections in patients with cancer. Am J Clin Path01 56:459-465, 1971 Weiden PL, SchufRer MD: Herpes esophagitis complicating Hodgkin’s disease. Cancer 33:1100-1102, 1974 Nahmias AJ, Roizman B: Infection with herpes simplex viruses 1 and 2. N Engl J Med 289:667-674, 719-724, 781-789, 1973 Nash G, Ross JW: Herpetic esophagitis: a common cause of esophageal ulceration. Hum Path01 5:339-345, 1974 Alan BPN, Reagan JW, Lindner E: The cellular manifestations of primary and recurrent herpes genitalis. Acta Cytol 14:124129, 1970 6. Moses HL, Cheatham WJ: The frequency and significance of human herpetic esophagitis: an autopsy study. Lab Invest 12:663-669, 1963 9. Sobel HJ, Schwarz R, Marguet E: Nonviral nuclear inclusions. I. Cytoplasmic invaginations. Arch Path01 87:179-192, 1969 10. Howiler W, Goldbert HI: Gastroesophageal involvement in herpes simplex. Gastroenterology 70:775-778, 19’76 11. Klotz DA, Silverman L: Herpes virus esophagitis consistent with herpes simplex, visualized endoscopically. Gastrointest Endosc 21:71-73, 1974 12. Kaye MD: Herpetic conjunctivitis as an unusual occupational hazard (endoscopists’eye). Gastrointest Endosc 21:69-70, 1974 13. Douglas RG, Couch RB: A prospective study of chronic herpes simplex virus infection and recurrent herpes labialis in humans. J Immunol 104:289-295, 1970