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Chronic oral herpes simplex virus infection in immunocompromised patients
oral medicine Editor: JAME,S W. LITTLE, D.M.D., M.SN.D.
School of Dentistry University of Minrmota 515 SE. Delaware St. Minneapolis, Minn. 55455
Chronic: oral herpes simplex virus infection in immunocom.promised patients S. Gary Cohen, D.M.D.,” and Martin S. Greenberg, D.D.S.,** Philadelphia, Pa. UNIVERSITY
OF PENNSYLVANIA
SCHOOL
OF DENTAL
MEDICINE
Recurrent herpes simplex virus infection is usually benign and self-limiting, but in immunosuppressed patients it can be a chronic destructive process, Eight patients with chronic aggressive herpes simplex virus infection of the oral mucosa are described. All cases occurred in immunocompromised patients. The distinctive clinical presentation of the oral lesions, the diagnosis, and treatment are discussed. (ORAL SURG. ORAL MED. ORAL PATHOL. 59:465-471,
1985)
H
erpes simplex virus (HSV) infections are classically divided into a primary and a recurrent form. The primary episode occurs in patients without prior immunity to the virus and causes both local lesions and systemic manifestations. Recurrent HSV infections result from reactivation of HSV latent in nerve tissue of patients with prior immunity and cause only a cluster of local lesions without systemic manifestations. Since the increased use of immunosuppressive drugs in casesof organ transplantation and in cancer chemotherapy, severechronic HSV lesions have been reported in both the medical and dermatologic literature but not, to our knowledge, in the dental literature. These chronic HSV lesions have a different clinical appearance than either the primary or the recurrent form and may have serious sequelae if left untreated. In 1967 Park and co-workers’ reported the caseof a renal transplant patient who had vesicles of the lip and chin consistent with a recurrent HSV infection. These lesions did not resolve and continued to enlarge over a 6-week period until they covered large *Clinical Associate Professor of Oral Medicine; A.ttending in Dental Medicine, Hospital of the University of Pennsylvania. **Chairman, Department of Dental Medicine, Hospital of the University of Pennsylvania; Professor of Oral Medicine, University of Pennsylvania School of Dental Medicine.
portions of the upper lip and nares. In 1959 Montgomerie and co-workers* reported four cases of progressively enlarging recurrent HSV lesions in renal transplant patients. Three of the for patients had lesions that began as typical recurrent HSV infections and gradually enlarged. One patient eventually died of a disseminated HSV infection; severe herpetic oral lesions were a contributing factor in a second death. In 1979 Schneidman and associates3 described a case of chronic perirectal herpetic ulcers developing in a patient with underlying metastatic carcinoma. Those authors also reviewed 17 other cases of chronic cutaneus HSV infection.3 All 17 patients were immunocompromised; they included 7 renal transplant patients, 5 leukemic patients, 3 patients with lymphoma, 1 patient who was taking high dosesof corticosteroids, and 1 patient with renal failure. Twelve of the patients had labial lesions, four had intraoral lesions, three had perianal lesions, and three patients had genital lesions. None of the patients had HSV lesions confined just to the oral mucosa. In 19’72 Muller and co-workers4 reviewed the problem of HSV infections in 51 patients with malignant hematologic conditions. In six of these patients large necrotic HSV ulcers of the skin developed. Recent reports of chronic HSV infections have 465
466
Cohen and Greenberg
Oral Surg. May, 1985
1. A 0.2 X 0.4 cm and a 0.3 cm (diameter) shallow Fig. ulcer with raised white margins on the mucosal surface of the lower lip.
involved patients with acquired immune deficiency syndrome (AIDS). Dotz and Berman5 described a 22-year-old homosexual man with AIDS who had severeenlarging perianal and nasolabial lesions from which HSV type II was cultured. These lesions responded to intravenous acyclovir. Siegal and coworkers6 reported severe chronic HSV infections developing in four homosexual males with AIDS. In three of the four cases, chronic enlarging perianal herpetic lesions were among the initial signs of AIDS. All lesions were caused by HSV type II. In one of the patients nasolabial lesions as well as perianal lesions developed. This article will describe eight new cases of chronic HSV infections seen in the Department of Dental Medicine of the Hospital of the University of Pennsylvania from 1981 to 1983. In all casesthe oral cavity was the only or major involved site. The clinical characteristics of these oral mucosal infections are described, so that these potentially dangerous lesions will be recognized and distinguished from other oral mucosal diseases seen in immunocomromised patients and treated early. CASE 1
A 75year-old white man with a diagnosis of severe Paget’s disease of the spine and pelvis was treated with 70 mg of prednisone per day 6 weeks prior to admission. On the third day of this hospitalization he was evaluated by the staff of the Department of Dental Medicine concerning his complaint of oral pain of 4 to 6 weeks’ duration. He had a past history of recurrent herpes labialis (RHL) but no history of recurrent intraoral ulcers. Multiple large (1 to 2 cm) lesions with raised white borders were evident bilaterally on the alveolar mucosa, gingiva, lip, and palate (Fig. 1). A biopsy at that time revealed multinucleated giant cells consistent with a diagnosis of HSV infections. The patient
g. 2. A, A 3.0 X 2.0 cm shallow ulcer with irregularly aped raised white margins on the right buccal mucosa. A 0.7 X 0.7 cm crateriform ulcer with raised white margins involving the inner canthus of the right eye.
was treated by gradual reduction of the steroid dosage to 35 mg of prednisone daily and by the application of topical idoxuridine to the lesions. The iesions healed in 2 weeks.
A 23-year-old white man was admitted to the Hospital of the University of Pennsylvania for a second cadaver renal transplant. The patient had a 3-year history of end-stage renal disease. Shortly after the transplantation he developed acute rejection and was treated with SoluMedrol, Imuran, and antilymphocyte globulin (ALG). On the thirty eighth day, recurrent herpes labialis appeared on the upper and lower lips. Within 3 days lesions were evident on the alveolar and buccai mucosa, gingiva, palate, and right eye (Fig. 2, A and B). These lesions were cultured and specimens were sent for cytopathologic evaluation. The cytology specimen contained multinucleated cells consistent with HSV changes, and the cultures were positive for HSV. The patient was treated initially with topical idoxuridine and later with intravenous idoxuridine in doses of later 10 mg per kilogram of body weight daily. The lesions were beginning to heal after 10 days of treatment, when the patient died of complications of pneumonia and congestive heart failure.
Volume 59 Number 5
Fig. 3. A 1.0 X 0.8 cm shallow ulcer with a red, raw central area and raised white margins involving the palate just lingual to the upper right first and second premolam.
Chronic oral herpes simplex infection
467
Fig. 4. A 1.4 cm and a 0.6 cm ulcer with a red, raw central area and a raised white margin along the attached gingiva of the lower right canine to the lower right first molar.
Fig. 5. A, A 1.5 X 0.4 cm and a 0.9 X 0.2 cm crateriform ulceration with irregularly shaped raised white borders on lthe dorsal surface of the tongue. B, A 0.7 X 0.3 cm and a 0.8 X 1.5 cm ovoid ulcer, each with a gray-white pseudomembranous eschar and irregularly shaped raised white margins on the ventral surface of the tongue.
468
Cohen and Greenberg
Table
I
Age
Diagnosis
M.S.
14
2 R.S.
23
Paget’s disease, on 70 mg. prednisone daily Kidney transplant
3 O.K. 4 D.F.
69 28
AML Erythroleukemia
5 B.A.
24
ALL
6 S.B. 7 R.H.
38 41
AMML Kidney transplant
8
39
Kidney transplant
Patient 1
L.W.
Oral Surg, May, 1985
Clinical location Alveolar mucosa, gingiva, palate Eyes, palate, buccal mucosa, lip. tongue, chest, finger, esophagus Soft palate, lip, uvula Lip, buccal mucosa. uvula, tongue Buccal mucosa, gingiva, tongue, palate Lip, gingiva, tongue, palate Tongue, buccal mucosa palate Buccal mucosa tongue, gingiva, finger
CASE 3
Cytology
Virus isolation
ND
/ I
Serology
Biopsy
ND
ND
+
+
+
ND
ND
+ +
+ +
ND NQ
ND ND
+
+
ND
ND
+ +
ii
I:32 ND
ND ND
+
+
ND
+
Topical treatment with 5% acyclovir ointment was initiated. After 2 days no new lesions formed. The lesions slowly healed with topical acyclovir treatment over the next 10 days.
A 69-year-old white man was admitted to the Hospital of the University of Pennsylvania in June, 1982, in relapse of acute myelogenous leukemia for reinduction therapy with daunorubicin, cytosine arabinoside (ARA-C), and 6-thioguanine (DAT). After 4 weeks the patient became febrile. A periodontal abscessinvolving the mandibular left second premolar and a 1.5 X 1.5 cm ulcer to the right of the uvula were noted. The ulcer was crateriform and well demarcated, with a raised, white border. The white blood count at the time was 800 cells per cubic millimeter with no neutrophils. Cultures of the periodontal abscessand blood were positive for Pseudomonas aeruginosa. The fever resolved and blood cultures becamenegative after the infected tooth was extracted. Two days later a second ulcer, approximately 1.Ocm in diameter, was noted on the palate (Fig. 3). The patient had a positive history of RHL but not of intraoral lesions. The initial ulcer continued to increase in size. Viral cultures and cytologic smears were taken from both ulcers. All specimens were positive for HSV. Topical acyclovir ointment (5%) was applied six times a day to the oral ulcers. After 12 days the ulcers were completely healed.
A 29-year-old white man was admitted to the Hospital of the University of Pennsylvania on Oct. 7, 1982, with a fever following reinduction therapy (methotrexate and L-asparaginase) for treatment of acute lymphocytic leukemia. On admission, he was found to be pancytopenic with a white count of 300 cells per cubic millimeter and a platelet count of 20,000 cells per cubic millimeter. A rectal source of infection was presumed to be the cause of his fever, and treatment was initiated with gentamicin, ticarcillin, and clindamycin. He was noted to have ulcers on the right buccal mucosa, labial and palatal gingiva, ventral surface of the tongue, and the hard and soft palate. This patient had a positive history of RHL. The lesions were shallow with red bases,had raised white borders, and ranged from 0.4 cm to 1.5 cm in diameter. Cytopathologic evaluation revealed cellular changes consistent with HSV. Topical acyclovir promoted healing of the ulcers within 8 days.
CASE 4
CASE 6
A 28-year-old black man with a diagnosis of erythroleukemia was admitted to the Hospital of the University of Pennsylvania complaining of dyspnea and weakness.During his stay he became febrile, and areas of erythema and ulceration were observed on the oral mucosa. This patient had a positive history of RHL but not of intraoral lesions. He was in severepain from the oral ulcers and was unable to eat. Oral examination revealed multiple ulcers on the right and left buccal mucosa, uvula, dorsal and ventral surfaces of the tongue, and lower labial mucosa. The lesions ranged from 0.4 to 1.0 cm. in diameter. Several were crateriform, with raised, white borders. A cytologic smear and viral cultures were taken. The smear was consistent with HSV and the culture was positive for HSV.
A 30-year-old white woman with a diagnosis of acute monomyelogenous leukemia was admitted for consolidation chemotherapy. During her stay in the hospital she had an episode of bacteremia from an unknown source and spiked fevers up to 103” F. At that time the white blood count was 200 cells per cubic millimeter with 4% neutrophils. The patient complained of fever blisters and mouth ulcers. She had a positive history for RHL. Vesicles were noted on the mandibular gingiva, and an ulcer approximately 0.6 cm in diameter was noted on the left buccal mucosa. Viral cultures and a cytology specimen were taken from each lesion; serum was taken for antibody titers. The next day the gingival lesions had enlarged dramatically and had coalesced to form one large, flat ulcer, which
CASE 5
Chronic oral herpes simplex infection
Volume 59 Number 5
Steroids, topical idoxuridine Topicall idoxuridine, IV ARA-A
Healing at discharge
Yes, lip Yes, lip
5% topical acyclovir 5% topical acyclovir
Yes, lip
5% topical acyclovir
Healed within 1 week Healed slowly over 10 days Healed at discharge
Yes, lip Yes, lip
5% topical acyclovir 5% topical acyclovir
Yes, lip
Topical and IV acyclovir
Yes, lip Yes, lip
469
Lesions healing at time of death
Healing after 5 days Healing at discharge (12 days) Healed within 2 weeks
extended from the mandibular right canine to the right first molar (Fig. 4). The borders of all lesions were raised and white. The cytology specimen and cultures were all consistent with or positive for HSV. Initial neutralizing antibody titers were positive at 1:32. Topical acyclovir ointment (5%) was applied to the lesions six times a day. No new lesions had formed after 3 days. All lesions were healing after 5 days. CASE 7 A 47-year-old male post-renal-transplant patient was admitted with an elevated serum creatinine level. Treatment with antilymphocyte globulin and Solu-Medrol resulted in a decreasein the creatinine level. On the ninth day after admission the patient complained of mouth sores. He had a positive history of RHL. Examination revealed multiple ulcers on the hard and soft palate, tongue, floor of the mouth, and m.andibular ridge (Fig. 5, A and B). Lesions ranged.from 0.3 to 1.3 cm in diameter, with raised, sharply demarcated, vesicular white borders. These lesions were: tender and painful. Viral cultures and cytologic smears taken from them were positive for HSV and multinucleated giant cells. Topical treatment with 5% acyclovir ointment six times daily resulted in resolution after 12 days. CASE 8 A 39-year-old white woman admitted for a cadaver renal transplant had an episode of transplant rejection which was treated with Solu-Medrol and ALG. On the twenty-third day (of hospitalization she complained of mouth ulcers. She had a history of RHL lesions. Shallow lesions with raised, white borders were noted on the palate, left and right. buccal mucosa, gingiva, tongue, and lip (Fig. 6, A and 8). These lesions ranged from 0.3 to 1.0 cm in diameter. Cultures were positive for HSV. Cytologic and biopsy specimens exhibited classic HSV changes. Topical and intravenous administration of acyclovir was initiated. No new oral lesions were observed
Fig. 6. A, A 0.3 to 1.0 cm wide shallow ulcer with serpentine raised white borders extending along the lingual attached gingiva from the lower left central incisor to the lower right first premolar. B, A 0.8 cm (diameter) shallow ulcer with a 0.2 cm raised white circular border affecting the: left buccal mucosa.
after 3 days. However, there were new lesions on the left hand, thumb, and fifth finger. These lesions were cultured and were positive for HSV. The patient was advised to use topical acyclovir ointment (5%) on her fingers as well as on the oral lesions. The lesions had healed significantly after 12 days. DISCUSSION
This article has presented eight cases of chronic oral HSV infection (Table I). All casesoccurred in immunosuppressed patients: four patients with leukemia, three kidney-transplant recipients, and one patient who was taking high dosesof corticosteroids. In the dermatologic and medical literature these lesions have been referred to as chronic HSV infections to distinguish them from routine primary or recurrent infection.7 Since these lesions can now be successfully treated early with acyclovir, the term chronic is often not accurate and a term such as aggressive recurrent HSV infection may be more appropriate. The lesions occurred on all oral mucous mem-
470 Cohen and Greenberg branes, but the most common site was the mucosa of the palate and alveolar ridges. Sevenof the 8 patients had palatal lesions, and 4 had lesions of the edentulous alveolar ridge. Lesions of the tongue (3 patients), lip (3 patients), buccal mucosa (2 patients), gingiva (2 patients), labial mucosa (2 patients), and floor of the mouth (I patient) were also observed. This predilection for the heavily keratinized mt.tCosais consistent with a previous finding that recurrent intraoral HSV infections in otherwise normal patients occur most frequently on the palate, gingiva, and alveolar ridges.g Lesions of the finger (2), eye (1), and chest (1) were also observedin these patients. The intraoral HSV lesions appeared as crateriform ulcers with well-defined, raised, white borders. On close inspection, the borders contained small vesicles. Some of the lesions had a raw, red central area, while others had a gray-white pseudomembrane. On the skin of the face, nose, and lips the lesions usually begin as vesicles which rapidly become necrotic and crusted. Both the mucosal and skin lesions will continue to enlarge until they are treated with antiviral agents. Among the leukemic patients, the lesions occurred during periods of neutropenia and fever, whereas in the transplant patients the lesions followed high-dose corticosteroid and ALG therapy. Patients who are immunosuppressed (IS) may experience oral mucosal ulcers from a variety of sources, including neutropenia, direct cytotoxic effects of chemotherapy, fungal infections, bacterial infections, and viral infections. These patients may also experience the wide variety of oral lesions, such as recurrent aphthous stomatitis and erythema multiforme, seenin otherwise normal patients. Clinicians treating immunocompromised patients have the difficult task of distinguishing among the various causes of oral ulcers, since each is a potential source of pain or fatal generalized infection. Chronic or aggressive HSV may be overlooked by clinicians who are not experienced in detecting HSV lesions in immunocompromised patients, with the danger tha inappropriate or ineffective treatment will be initiated. If left untreated, these lesions will continue to enlarge, leading to severepain and possibly a potentially fatal viremiae4 Since these lesions can now be treated successfully with acyclovir, early diagnosis has important clinical significance. In the first case a biopsy specimen taken from the margin was used in making the diagnosis. In the subsequent casesthe diagnosis was suspectedon the basis of the clinical appearance of the lesions and confirmed by cytologic examination via Tzank prep-
OraI Surg. May, I985
arations from the margins of the ulcers. Preparations taken from the center of the lesion are usually negative, since virally infected cells are no longer present. Viral cultures were obtained in the usual manner. In Case 6 neutralizing antibody titers were obtained at the time the lesions first appeared. These were positive at 1:32, thus confirming that the lesions were not a primary infection but a variant of the recurrent form. In the other cases serum was not obtained, but each of the patients had a past history of recurrent herpes labialis. This is consistent with the findings of Montgomerie and colleagues,2 who detected neutralizing antibody to HSV in the sera of their patients with chronic HSV infection prior to the onset of clinical infection, confirming that chronic HSV infection is a form of recurrent, not primary, infection. In this group of patients topical idoxuridine or intravenous vidarabine was given the first two patients. Topical or intravenous acyclovir, a more effective therapy, was used in the later cases. This new antiviral agent has been shown to decrease the duration and severity of mucocutaneous HSV infections in IS patients. 9*10Our experience shows that topical acyclovir ointment (5%) was effective in alleviating the signs and symptoms of chronic (aggressive) herpes when used on the intraoral lesions six times daily. When this is not effective, intravenous administration of acyclovir should be initiated. An oral form of the medication is now being tested and may soon be marketed. Chronic HSV infections have a distinctive clinical presentation and have been reported only in patients with immunosuppressing diseases. Therefore, if a chronic HSV infection is diagnosed in a patient without a known systemic disorder, the patient should be referred for a complete medical evaluation to rule out an underlying malignant condition or immunosuppressive disease. REFERENCES 1. Park RK, Goltz RW, Carey TB: Unusual cutaneous infections associated with immunosuppressive therapy. Arch Dermatol 95: 345-350, 1967. 2. Montgomerie JA, et al: IIerpes simplex virus infection after renal transplantation. Lancet 2: 867-871, 1969. 3. Schneidman DW, Barr RJ, Graham JH: Chronic cutaneous herpes simplex. JAMA 241: 592-594, 1979. 4. Muller SA, Herrmann EC, Winkelman RK: Herpes simplex infections in hematologic malignancies. Am J Med 52: 102-l 14, 1972. 5. Dotz WI, Berman B: Kaposis sarcoma, chronic ulcerative herpes simplex, and acquired immunodeficiency. Arch Dermat01 119: 93-94, 1983. 6 Siegal FP, et al: Severe acquired immunodeliciency in male homosexuals, manifested by chronic p&anal ulcerative herpes simplex lesions. N Engl J Med 305: 1439-1444, 1981.
Volume 59 Number 5 7. Logan WS, Tindal .JP, Elson ML: Chronic cutaneous herpes simplex. Arch Dermatol 103: 606-614, 1971. 8. Greenberg MS, Brightman V, Ship II: Clinical and laboratory differentiation of recurrent intraoral herpes simplex virus infections following fever. J Dent Res 48: 385-391, 1969. 9. Straus SE, et al: Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Ann Intern Med 96: 270-277, 1982. 10. Straus SE, et al: Oral acyclovir to suppress recurring herpes
Chronic oral herpes simplex infection simplex virus infections in immunodeficient Intern Med 100: 522-524, 1984.
47 I
patients. Ann
Reprint requests to: Dr. S. Gary Cohen Department of Dental Medicine University of Pennsylvania School of Dental Medicine 4001 West Spruce St. Philadelphia, PA 19 104
School of Dentistry University of Minrmota 515 SE. Delaware St. Minneapolis, Minn. 55455
Chronic: oral herpes simplex virus infection in immunocom.promised patients S. Gary Cohen, D.M.D.,” and Martin S. Greenberg, D.D.S.,** Philadelphia, Pa. UNIVERSITY
OF PENNSYLVANIA
SCHOOL
OF DENTAL
MEDICINE
Recurrent herpes simplex virus infection is usually benign and self-limiting, but in immunosuppressed patients it can be a chronic destructive process, Eight patients with chronic aggressive herpes simplex virus infection of the oral mucosa are described. All cases occurred in immunocompromised patients. The distinctive clinical presentation of the oral lesions, the diagnosis, and treatment are discussed. (ORAL SURG. ORAL MED. ORAL PATHOL. 59:465-471,
1985)
H
erpes simplex virus (HSV) infections are classically divided into a primary and a recurrent form. The primary episode occurs in patients without prior immunity to the virus and causes both local lesions and systemic manifestations. Recurrent HSV infections result from reactivation of HSV latent in nerve tissue of patients with prior immunity and cause only a cluster of local lesions without systemic manifestations. Since the increased use of immunosuppressive drugs in casesof organ transplantation and in cancer chemotherapy, severechronic HSV lesions have been reported in both the medical and dermatologic literature but not, to our knowledge, in the dental literature. These chronic HSV lesions have a different clinical appearance than either the primary or the recurrent form and may have serious sequelae if left untreated. In 1967 Park and co-workers’ reported the caseof a renal transplant patient who had vesicles of the lip and chin consistent with a recurrent HSV infection. These lesions did not resolve and continued to enlarge over a 6-week period until they covered large *Clinical Associate Professor of Oral Medicine; A.ttending in Dental Medicine, Hospital of the University of Pennsylvania. **Chairman, Department of Dental Medicine, Hospital of the University of Pennsylvania; Professor of Oral Medicine, University of Pennsylvania School of Dental Medicine.
portions of the upper lip and nares. In 1959 Montgomerie and co-workers* reported four cases of progressively enlarging recurrent HSV lesions in renal transplant patients. Three of the for patients had lesions that began as typical recurrent HSV infections and gradually enlarged. One patient eventually died of a disseminated HSV infection; severe herpetic oral lesions were a contributing factor in a second death. In 1979 Schneidman and associates3 described a case of chronic perirectal herpetic ulcers developing in a patient with underlying metastatic carcinoma. Those authors also reviewed 17 other cases of chronic cutaneus HSV infection.3 All 17 patients were immunocompromised; they included 7 renal transplant patients, 5 leukemic patients, 3 patients with lymphoma, 1 patient who was taking high dosesof corticosteroids, and 1 patient with renal failure. Twelve of the patients had labial lesions, four had intraoral lesions, three had perianal lesions, and three patients had genital lesions. None of the patients had HSV lesions confined just to the oral mucosa. In 19’72 Muller and co-workers4 reviewed the problem of HSV infections in 51 patients with malignant hematologic conditions. In six of these patients large necrotic HSV ulcers of the skin developed. Recent reports of chronic HSV infections have 465
466
Cohen and Greenberg
Oral Surg. May, 1985
1. A 0.2 X 0.4 cm and a 0.3 cm (diameter) shallow Fig. ulcer with raised white margins on the mucosal surface of the lower lip.
involved patients with acquired immune deficiency syndrome (AIDS). Dotz and Berman5 described a 22-year-old homosexual man with AIDS who had severeenlarging perianal and nasolabial lesions from which HSV type II was cultured. These lesions responded to intravenous acyclovir. Siegal and coworkers6 reported severe chronic HSV infections developing in four homosexual males with AIDS. In three of the four cases, chronic enlarging perianal herpetic lesions were among the initial signs of AIDS. All lesions were caused by HSV type II. In one of the patients nasolabial lesions as well as perianal lesions developed. This article will describe eight new cases of chronic HSV infections seen in the Department of Dental Medicine of the Hospital of the University of Pennsylvania from 1981 to 1983. In all casesthe oral cavity was the only or major involved site. The clinical characteristics of these oral mucosal infections are described, so that these potentially dangerous lesions will be recognized and distinguished from other oral mucosal diseases seen in immunocomromised patients and treated early. CASE 1
A 75year-old white man with a diagnosis of severe Paget’s disease of the spine and pelvis was treated with 70 mg of prednisone per day 6 weeks prior to admission. On the third day of this hospitalization he was evaluated by the staff of the Department of Dental Medicine concerning his complaint of oral pain of 4 to 6 weeks’ duration. He had a past history of recurrent herpes labialis (RHL) but no history of recurrent intraoral ulcers. Multiple large (1 to 2 cm) lesions with raised white borders were evident bilaterally on the alveolar mucosa, gingiva, lip, and palate (Fig. 1). A biopsy at that time revealed multinucleated giant cells consistent with a diagnosis of HSV infections. The patient
g. 2. A, A 3.0 X 2.0 cm shallow ulcer with irregularly aped raised white margins on the right buccal mucosa. A 0.7 X 0.7 cm crateriform ulcer with raised white margins involving the inner canthus of the right eye.
was treated by gradual reduction of the steroid dosage to 35 mg of prednisone daily and by the application of topical idoxuridine to the lesions. The iesions healed in 2 weeks.
A 23-year-old white man was admitted to the Hospital of the University of Pennsylvania for a second cadaver renal transplant. The patient had a 3-year history of end-stage renal disease. Shortly after the transplantation he developed acute rejection and was treated with SoluMedrol, Imuran, and antilymphocyte globulin (ALG). On the thirty eighth day, recurrent herpes labialis appeared on the upper and lower lips. Within 3 days lesions were evident on the alveolar and buccai mucosa, gingiva, palate, and right eye (Fig. 2, A and B). These lesions were cultured and specimens were sent for cytopathologic evaluation. The cytology specimen contained multinucleated cells consistent with HSV changes, and the cultures were positive for HSV. The patient was treated initially with topical idoxuridine and later with intravenous idoxuridine in doses of later 10 mg per kilogram of body weight daily. The lesions were beginning to heal after 10 days of treatment, when the patient died of complications of pneumonia and congestive heart failure.
Volume 59 Number 5
Fig. 3. A 1.0 X 0.8 cm shallow ulcer with a red, raw central area and raised white margins involving the palate just lingual to the upper right first and second premolam.
Chronic oral herpes simplex infection
467
Fig. 4. A 1.4 cm and a 0.6 cm ulcer with a red, raw central area and a raised white margin along the attached gingiva of the lower right canine to the lower right first molar.
Fig. 5. A, A 1.5 X 0.4 cm and a 0.9 X 0.2 cm crateriform ulceration with irregularly shaped raised white borders on lthe dorsal surface of the tongue. B, A 0.7 X 0.3 cm and a 0.8 X 1.5 cm ovoid ulcer, each with a gray-white pseudomembranous eschar and irregularly shaped raised white margins on the ventral surface of the tongue.
468
Cohen and Greenberg
Table
I
Age
Diagnosis
M.S.
14
2 R.S.
23
Paget’s disease, on 70 mg. prednisone daily Kidney transplant
3 O.K. 4 D.F.
69 28
AML Erythroleukemia
5 B.A.
24
ALL
6 S.B. 7 R.H.
38 41
AMML Kidney transplant
8
39
Kidney transplant
Patient 1
L.W.
Oral Surg, May, 1985
Clinical location Alveolar mucosa, gingiva, palate Eyes, palate, buccal mucosa, lip. tongue, chest, finger, esophagus Soft palate, lip, uvula Lip, buccal mucosa. uvula, tongue Buccal mucosa, gingiva, tongue, palate Lip, gingiva, tongue, palate Tongue, buccal mucosa palate Buccal mucosa tongue, gingiva, finger
CASE 3
Cytology
Virus isolation
ND
/ I
Serology
Biopsy
ND
ND
+
+
+
ND
ND
+ +
+ +
ND NQ
ND ND
+
+
ND
ND
+ +
ii
I:32 ND
ND ND
+
+
ND
+
Topical treatment with 5% acyclovir ointment was initiated. After 2 days no new lesions formed. The lesions slowly healed with topical acyclovir treatment over the next 10 days.
A 69-year-old white man was admitted to the Hospital of the University of Pennsylvania in June, 1982, in relapse of acute myelogenous leukemia for reinduction therapy with daunorubicin, cytosine arabinoside (ARA-C), and 6-thioguanine (DAT). After 4 weeks the patient became febrile. A periodontal abscessinvolving the mandibular left second premolar and a 1.5 X 1.5 cm ulcer to the right of the uvula were noted. The ulcer was crateriform and well demarcated, with a raised, white border. The white blood count at the time was 800 cells per cubic millimeter with no neutrophils. Cultures of the periodontal abscessand blood were positive for Pseudomonas aeruginosa. The fever resolved and blood cultures becamenegative after the infected tooth was extracted. Two days later a second ulcer, approximately 1.Ocm in diameter, was noted on the palate (Fig. 3). The patient had a positive history of RHL but not of intraoral lesions. The initial ulcer continued to increase in size. Viral cultures and cytologic smears were taken from both ulcers. All specimens were positive for HSV. Topical acyclovir ointment (5%) was applied six times a day to the oral ulcers. After 12 days the ulcers were completely healed.
A 29-year-old white man was admitted to the Hospital of the University of Pennsylvania on Oct. 7, 1982, with a fever following reinduction therapy (methotrexate and L-asparaginase) for treatment of acute lymphocytic leukemia. On admission, he was found to be pancytopenic with a white count of 300 cells per cubic millimeter and a platelet count of 20,000 cells per cubic millimeter. A rectal source of infection was presumed to be the cause of his fever, and treatment was initiated with gentamicin, ticarcillin, and clindamycin. He was noted to have ulcers on the right buccal mucosa, labial and palatal gingiva, ventral surface of the tongue, and the hard and soft palate. This patient had a positive history of RHL. The lesions were shallow with red bases,had raised white borders, and ranged from 0.4 cm to 1.5 cm in diameter. Cytopathologic evaluation revealed cellular changes consistent with HSV. Topical acyclovir promoted healing of the ulcers within 8 days.
CASE 4
CASE 6
A 28-year-old black man with a diagnosis of erythroleukemia was admitted to the Hospital of the University of Pennsylvania complaining of dyspnea and weakness.During his stay he became febrile, and areas of erythema and ulceration were observed on the oral mucosa. This patient had a positive history of RHL but not of intraoral lesions. He was in severepain from the oral ulcers and was unable to eat. Oral examination revealed multiple ulcers on the right and left buccal mucosa, uvula, dorsal and ventral surfaces of the tongue, and lower labial mucosa. The lesions ranged from 0.4 to 1.0 cm. in diameter. Several were crateriform, with raised, white borders. A cytologic smear and viral cultures were taken. The smear was consistent with HSV and the culture was positive for HSV.
A 30-year-old white woman with a diagnosis of acute monomyelogenous leukemia was admitted for consolidation chemotherapy. During her stay in the hospital she had an episode of bacteremia from an unknown source and spiked fevers up to 103” F. At that time the white blood count was 200 cells per cubic millimeter with 4% neutrophils. The patient complained of fever blisters and mouth ulcers. She had a positive history for RHL. Vesicles were noted on the mandibular gingiva, and an ulcer approximately 0.6 cm in diameter was noted on the left buccal mucosa. Viral cultures and a cytology specimen were taken from each lesion; serum was taken for antibody titers. The next day the gingival lesions had enlarged dramatically and had coalesced to form one large, flat ulcer, which
CASE 5
Chronic oral herpes simplex infection
Volume 59 Number 5
Steroids, topical idoxuridine Topicall idoxuridine, IV ARA-A
Healing at discharge
Yes, lip Yes, lip
5% topical acyclovir 5% topical acyclovir
Yes, lip
5% topical acyclovir
Healed within 1 week Healed slowly over 10 days Healed at discharge
Yes, lip Yes, lip
5% topical acyclovir 5% topical acyclovir
Yes, lip
Topical and IV acyclovir
Yes, lip Yes, lip
469
Lesions healing at time of death
Healing after 5 days Healing at discharge (12 days) Healed within 2 weeks
extended from the mandibular right canine to the right first molar (Fig. 4). The borders of all lesions were raised and white. The cytology specimen and cultures were all consistent with or positive for HSV. Initial neutralizing antibody titers were positive at 1:32. Topical acyclovir ointment (5%) was applied to the lesions six times a day. No new lesions had formed after 3 days. All lesions were healing after 5 days. CASE 7 A 47-year-old male post-renal-transplant patient was admitted with an elevated serum creatinine level. Treatment with antilymphocyte globulin and Solu-Medrol resulted in a decreasein the creatinine level. On the ninth day after admission the patient complained of mouth sores. He had a positive history of RHL. Examination revealed multiple ulcers on the hard and soft palate, tongue, floor of the mouth, and m.andibular ridge (Fig. 5, A and B). Lesions ranged.from 0.3 to 1.3 cm in diameter, with raised, sharply demarcated, vesicular white borders. These lesions were: tender and painful. Viral cultures and cytologic smears taken from them were positive for HSV and multinucleated giant cells. Topical treatment with 5% acyclovir ointment six times daily resulted in resolution after 12 days. CASE 8 A 39-year-old white woman admitted for a cadaver renal transplant had an episode of transplant rejection which was treated with Solu-Medrol and ALG. On the twenty-third day (of hospitalization she complained of mouth ulcers. She had a history of RHL lesions. Shallow lesions with raised, white borders were noted on the palate, left and right. buccal mucosa, gingiva, tongue, and lip (Fig. 6, A and 8). These lesions ranged from 0.3 to 1.0 cm in diameter. Cultures were positive for HSV. Cytologic and biopsy specimens exhibited classic HSV changes. Topical and intravenous administration of acyclovir was initiated. No new oral lesions were observed
Fig. 6. A, A 0.3 to 1.0 cm wide shallow ulcer with serpentine raised white borders extending along the lingual attached gingiva from the lower left central incisor to the lower right first premolar. B, A 0.8 cm (diameter) shallow ulcer with a 0.2 cm raised white circular border affecting the: left buccal mucosa.
after 3 days. However, there were new lesions on the left hand, thumb, and fifth finger. These lesions were cultured and were positive for HSV. The patient was advised to use topical acyclovir ointment (5%) on her fingers as well as on the oral lesions. The lesions had healed significantly after 12 days. DISCUSSION
This article has presented eight cases of chronic oral HSV infection (Table I). All casesoccurred in immunosuppressed patients: four patients with leukemia, three kidney-transplant recipients, and one patient who was taking high dosesof corticosteroids. In the dermatologic and medical literature these lesions have been referred to as chronic HSV infections to distinguish them from routine primary or recurrent infection.7 Since these lesions can now be successfully treated early with acyclovir, the term chronic is often not accurate and a term such as aggressive recurrent HSV infection may be more appropriate. The lesions occurred on all oral mucous mem-
470 Cohen and Greenberg branes, but the most common site was the mucosa of the palate and alveolar ridges. Sevenof the 8 patients had palatal lesions, and 4 had lesions of the edentulous alveolar ridge. Lesions of the tongue (3 patients), lip (3 patients), buccal mucosa (2 patients), gingiva (2 patients), labial mucosa (2 patients), and floor of the mouth (I patient) were also observed. This predilection for the heavily keratinized mt.tCosais consistent with a previous finding that recurrent intraoral HSV infections in otherwise normal patients occur most frequently on the palate, gingiva, and alveolar ridges.g Lesions of the finger (2), eye (1), and chest (1) were also observedin these patients. The intraoral HSV lesions appeared as crateriform ulcers with well-defined, raised, white borders. On close inspection, the borders contained small vesicles. Some of the lesions had a raw, red central area, while others had a gray-white pseudomembrane. On the skin of the face, nose, and lips the lesions usually begin as vesicles which rapidly become necrotic and crusted. Both the mucosal and skin lesions will continue to enlarge until they are treated with antiviral agents. Among the leukemic patients, the lesions occurred during periods of neutropenia and fever, whereas in the transplant patients the lesions followed high-dose corticosteroid and ALG therapy. Patients who are immunosuppressed (IS) may experience oral mucosal ulcers from a variety of sources, including neutropenia, direct cytotoxic effects of chemotherapy, fungal infections, bacterial infections, and viral infections. These patients may also experience the wide variety of oral lesions, such as recurrent aphthous stomatitis and erythema multiforme, seenin otherwise normal patients. Clinicians treating immunocompromised patients have the difficult task of distinguishing among the various causes of oral ulcers, since each is a potential source of pain or fatal generalized infection. Chronic or aggressive HSV may be overlooked by clinicians who are not experienced in detecting HSV lesions in immunocompromised patients, with the danger tha inappropriate or ineffective treatment will be initiated. If left untreated, these lesions will continue to enlarge, leading to severepain and possibly a potentially fatal viremiae4 Since these lesions can now be treated successfully with acyclovir, early diagnosis has important clinical significance. In the first case a biopsy specimen taken from the margin was used in making the diagnosis. In the subsequent casesthe diagnosis was suspectedon the basis of the clinical appearance of the lesions and confirmed by cytologic examination via Tzank prep-
OraI Surg. May, I985
arations from the margins of the ulcers. Preparations taken from the center of the lesion are usually negative, since virally infected cells are no longer present. Viral cultures were obtained in the usual manner. In Case 6 neutralizing antibody titers were obtained at the time the lesions first appeared. These were positive at 1:32, thus confirming that the lesions were not a primary infection but a variant of the recurrent form. In the other cases serum was not obtained, but each of the patients had a past history of recurrent herpes labialis. This is consistent with the findings of Montgomerie and colleagues,2 who detected neutralizing antibody to HSV in the sera of their patients with chronic HSV infection prior to the onset of clinical infection, confirming that chronic HSV infection is a form of recurrent, not primary, infection. In this group of patients topical idoxuridine or intravenous vidarabine was given the first two patients. Topical or intravenous acyclovir, a more effective therapy, was used in the later cases. This new antiviral agent has been shown to decrease the duration and severity of mucocutaneous HSV infections in IS patients. 9*10Our experience shows that topical acyclovir ointment (5%) was effective in alleviating the signs and symptoms of chronic (aggressive) herpes when used on the intraoral lesions six times daily. When this is not effective, intravenous administration of acyclovir should be initiated. An oral form of the medication is now being tested and may soon be marketed. Chronic HSV infections have a distinctive clinical presentation and have been reported only in patients with immunosuppressing diseases. Therefore, if a chronic HSV infection is diagnosed in a patient without a known systemic disorder, the patient should be referred for a complete medical evaluation to rule out an underlying malignant condition or immunosuppressive disease. REFERENCES 1. Park RK, Goltz RW, Carey TB: Unusual cutaneous infections associated with immunosuppressive therapy. Arch Dermatol 95: 345-350, 1967. 2. Montgomerie JA, et al: IIerpes simplex virus infection after renal transplantation. Lancet 2: 867-871, 1969. 3. Schneidman DW, Barr RJ, Graham JH: Chronic cutaneous herpes simplex. JAMA 241: 592-594, 1979. 4. Muller SA, Herrmann EC, Winkelman RK: Herpes simplex infections in hematologic malignancies. Am J Med 52: 102-l 14, 1972. 5. Dotz WI, Berman B: Kaposis sarcoma, chronic ulcerative herpes simplex, and acquired immunodeficiency. Arch Dermat01 119: 93-94, 1983. 6 Siegal FP, et al: Severe acquired immunodeliciency in male homosexuals, manifested by chronic p&anal ulcerative herpes simplex lesions. N Engl J Med 305: 1439-1444, 1981.
Volume 59 Number 5 7. Logan WS, Tindal .JP, Elson ML: Chronic cutaneous herpes simplex. Arch Dermatol 103: 606-614, 1971. 8. Greenberg MS, Brightman V, Ship II: Clinical and laboratory differentiation of recurrent intraoral herpes simplex virus infections following fever. J Dent Res 48: 385-391, 1969. 9. Straus SE, et al: Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Ann Intern Med 96: 270-277, 1982. 10. Straus SE, et al: Oral acyclovir to suppress recurring herpes
Chronic oral herpes simplex infection simplex virus infections in immunodeficient Intern Med 100: 522-524, 1984.
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Reprint requests to: Dr. S. Gary Cohen Department of Dental Medicine University of Pennsylvania School of Dental Medicine 4001 West Spruce St. Philadelphia, PA 19 104