- Email: [email protected]
Chronic herpetic infection in an immunocompromised patient: Report of a case
VINCKIER
723
ET AL.
8. Cohen J: Etiology of simple bone cysts. J Bone Joint Surg
52A: 1493, 1970 9. Ogden JA, Griswold DM: Solitary cyst of the lams. J Bone Joint Surg 54A: 1309, 1972 10. Pommer G (cited by Olech E, Sicher H, Weinmann JP): Traumatic mandibular bone cyst. Oral Surg 4:1160, 1951 11. Bemier JL, Johnson LC, Whinery JG: Progressive bone cavities of the mandible. Oral Surg 8:970, 1955 12. Starma JN: Hemorrhagic cyst of the mandible in relation to horizontally impacted third molar. Oral Surg 38: 17, 1983 13. Waldron CL: Solitary (hemorrhagic) cyst of the mandible. Oral Surg 7:88, 1954
J Oral Maxillofac
14. Szerlip L: Traumatic bone cysts: resolution without surgery. Oral Surg 21, 201, I%6 15. Olech E, Sicher H, Weinmann JP: Traumatic mandibular bone cysts. Oral Surg 4:1160, 1951 16. Biewald HF: A variation in management of haemorrhagic, traumatic or simple bone cyst. J Oral Surg 25:427, 1%7 17. Thoma KH: The treatment of extravasation cysts with the use of gelfoam. Oral Surg 8:950, 1955 18. Lindsay JS, Martin WR, Green HG: Traumatic bone cyst, treated with homogenous bone graft. Oral Surg 21:536, 1966 19. Hughes CL: Hemorrhagic bone cyst and pathologic fracture of the mandible. J Oral Surg 27:345, 1969
Surg
45~723-728.1987
Chronic Herpetic Infection in an Immunocompromised Patient: Report of a Case F. VINCKIER,
DDS,* M. BOOGAERTS, MD,t D. DE CLERCK,$ E. DE CLERCQ, MD§
Chronic herpes simplex virus infections are often encountered in patients with an underlying immune disorder such as congenital immunodeficiency or acquired immunodeticiency [leukemia, lymphoma, acquired immune deficiency syndrome (AIDS)], or induced immunosuppression (chemotherapy, high doses of corticosteroids). An unusual severe or chronic herpetic infection may also be the first symptom of an underlying malignant condition. l Concomitantly with the increasing use of chemotherapeutic agents and immunosuppressive drugs in the treatment of cancer and the prevention of allograft (i.e., kidney or bone marrow) transplant rejection, severe herpetic infections have been noted
Received from the Departments of *$Stomatology and Dentistry, thledicine (Division of Hematology), and BDepartment of Human Biology (Division of Microbiology), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. * Docent. 0 Docent. $ Research Assistant of the Belgian National Fund for Scientific Research, Department of Dentistry. 5 Professor. Address correspondence and reprint requests to Dr. Vinckier: Department of Stomatology and Dentistry, Capucijnenvoer 7, B 3000 Leuven, Belgium. 0278-2391187 $0.00 + .25
and
with increasing frequency; such infections are frequently atypical and chronic in character. In this report, we describe a case of chronic oral herpes simplex type 1 (HSV-1) infection in a patient with chronic lymphocytic leukemia (CLL). The infection persisted despite successive attempts of treatment with acyclovir (ACV), bromovinyldeoxyuridine (BVDU), dihydroxypropoxymethylguanine (DHPG), and vidarabine (araA). The lesions finally resolved following systemic treatment with phosphonoformate (foscarnet, PFA). Report of a Case A 55-year-old male patient was examined in July 1981 because of persistent ischiatiform pains in the back. A white cell count of 35 x log/L consisting of 78% mature B-lymphocytes was found and the diagnosis of B-CLL (chronic lymphocytic leukemia, rai-stage 0) was made. Because of low grade malignancy no chemotherapeutic treatment was instituted at that time. In April 1985 (Fig. lA), the patient was referred to the Dentistry Department. He complained of a persistent inflammation of the mandibular gingiva and mucosa at the left side of the floor of the mouth. On clinical examination, large necrotic ulcers covered with a grey-white membrane, associated with enlarged submandibular and pre-auricular lymph node was seen. Streptococcus pyogenes was isolated from the lesions and the patient was treated with antibiotics (erythromycin, 500 mg, four
CHRONIC HERPETIC INFECTION
724
FIGURE 1. Clinical course of the different recurrent episodes of oral HSV-1 infection. The severity of the lesions, the antiviral agents that were used and the results of the virus isolations are depicted. ACV, acyclovir: BVDU, bromovinyldeoxyuridine: DHPG, dihydroxypropoxymethylguanine: AraA, adenine arabinoside (vidarabine): PFA. phosphonoformate: +, HSV-1 isolated: and -, HSV-1 not isolated.
times daily). After initial regression, the lesions recurred, with new lesions developing on the labial mucosa of the maxillary left central and lateral incisors and canine (Fig. 2). The lesions were accompanied by pain, severe fetor oris, general malaise, fever (385”C), lymph node enlargement, and swallowing problems. The patient was hospitalized and intravenous antibiotics (chloromycetin, erythromycetin) were administered. An intensive local treatment was instituted, consisting of careful interdental cleaning and daily application of 3% H,O*. The patient also rinsed his mouth four times daily with Kamillosan@ (Degussa Pharma) to alleviate the pain. Mouth rinsing
with a nystatin solution was instituted to prevent fungus overgrowth during the intensive treatment with antibiotics. The lesions continued to enlarge. Streptococcus pyogenes could not be isolated from the lesions. The aspirate of an enlarged, mobile, painful retromandibular lymph node (diameter 3 cm) was sterile and blood cultures were negative. Blood cell count showed 75.2 x log/L white blood cells, 3.86 x 10r2/L red blood cells and 279 x 109/L platelets. On 8 May, 1985, virus isolations were taken. HSV type 1 was isolated and treatment was started with intravenous acyclovir (ACV) at 10 mg/kg, thrice-daily for
FIGURE 2 (left). Lesions on gingiva and mucosa labial to the maxillary left central and lateral incisors and canine. Note the spontaneous bleeding tendency. FIGURE 3 (right).
Lesions on labial mucosa of maxillary left central and lateral incisors and canine nearly completely healed.
VINCKIER
725
ET AL.
FIGURE 4 (lefr). FIGURE 5 (right).
Recurrent lesions on mandibular gingiva. Lesions show no healing despite of acyclovir treatment.
five days. In addition, the patient rinsed his mouth with a 1% aqueous solution of tranexamic acid to limit the spontaneous bleeding tendency of the lesions. Two weeks later the lesions had completely regressed and the lymph node enlargement had disappeared (Fig. 3). At that time the right upper second premolar was removed because of advanced periodontal destruction. No further complications occurred and wound healing was satisfactory. At the end of June 1985 (Fig. lB), the white cell count had reached 172 x 109/L (96% lymphocytes) and on 28 June, 1985, a single dose of 50 mg chlorambucil (Leukeran,@ Wellcome) was administered. In the meantime, a gingival lesion had developed at the lingual side of the right lower second molar. Use of a Povidone-iodine mouthwash (Isobetadine,@ Belgana) was initiated. Despite this treatment, lesions also developed on the left mandibular gingiva (Fig. 4) and soft palate. Marked bilateral submandibular lymph node enlargement occurred. Limited mouth opening and extreme pain made the patient unable to eat. HSV-1 was isolated from the lesions and oral acyclovir (5 x 200 mg/day) was started on 8 July, 1985; however, the lesions continued to enlarge (Fig. 5). On 16 July, 1985, virus isolations were still positive for HSV type 1. On 17 July, 1985, a 20-day-course of oral BVDU (125 mg/day, four times daily) was initiated. Despite this treatment, the lymph node enlargement and trismus increased and the patient became febrile. He lost weight and his
FIGURE 6. Herpetic lesions nearly completely healed after phosphonoformate administration.
general condition deteriorated. HSV type 1 was repeatedly isolated from the lesions. On 29 July, 1985, a second dose of chlorambucil (50 mg) was administered. Because of the severity of the gingivostomatitis, the persistent fever despite the administration of antibiotics, and the cachexia, the patient was hospitalized at the beginning of August 1985. On 16 August, 1985, a two-week course with DHPG (350 mg/day, twice-daily) was started. A slight improvement of the stomatitis lesions was noted during the first week, although HSV-1 could still be isolated. Thereafter, the stomatitis worsened again despite continued DHPG treatment; the general condition of the patient deteriorated further and parenteral feeding became necessary. He developed a bilateral bronchopneumonia from which Pseudomonas aeruginosa and adenovirus could be isolated. From 15 September to 5 October, 1985, vidarabine (araA) was administered IV (900 mg/day or 15 mg/kg/ day). After initial improvement, the stomatitis lesions enlarged and the general condition again deteriorated. Virus isolations remained positive for HSV-1. From 7 October to 21 October, 1985, phosphonoformate (foscamet) was administered as a continuous intravenous infusion at 0.15 mg/kg/minute. From the fifth day after the initiation of the phosphonoformate, virus isolations became negative. The stomatitis lesions regressed (Fig. 6), fever disappeared, and the patient’s general condition improved. Antibiotics wene discontinued, and on the 28th October, the patient was discharged from the hospital. By that time the oral lesions had completely healed. On 11 March, 1986, the patient developed painful lesions from which HSV type 1 was isolated (Fig. 1C). On 14 March, 1986, treatment with oral acyclovir was started (10 x 200 mg/day). Progression of the virus lesions was retarded, but they showed no healing tendency. On 12 June, 1986, the patient was hospitalized with very severe gingivostomatitis, accompanied by lymph node enlargement, fever (38.2”C) and difficulties in swallowing and eating. He was still under intravenous acyclovir treatment. On 26 June, 1986, the acyclovir treatment was discontinued and until 13 July, 1986, phosphonoformate was administered as a continuous intravenous infusion at 0.15 mg/kg/minute. Virus isolations became negative on 30 June, 1986, and the stomatitis lesions regressed. On 9 July, 1986, several tooth extractions were carried
726 Table 1.
CHRONIC HERPETIC
INFECTION
Most Widely Used Antiviral Agents for HSV Infections in Humans Comment
Formulation
Compound
IV: 15 mgikglday
ACV Acyclovir
PO: 200 mg every four hours (Zovirax@) Topical: 5- 10% in PEG 5% in propylene glycol (Zoviraxs)
Clearly efficacious in immunocompromised patients Also efficacious, although lower serum levels are achieved than after IV administration Not effective Seems to be effective
IV: 10 mg/kg/day (vira-A@)
Of some benefit in immunocompromised patients over 40 years of age
PO: 7.5 mg/kg/day
Appears to be effective, as shown by studies in immunocompromised patients
DHPG Dihydroxypropoxymethylguanine
IV: 7.5 or 15 mg/kg/day
Clinical studies have recently begun in immunocompromised patients
IDU Iododeoxyuridine
topical: 5, 10, or 40% in DMSO (Virexen,’ Virpex,@ Herpide)
Assumed to be effective in humans
IV: 0.15 mg/kg/minute (Foscavire)
Apparently effective against TK- HSV infections, as shown by the present study
AraA Adenine arabinoside Vidarabine BVDU Bromovinyldeoxyuridine
PEA Phosphonoformate
Moderately effective in animal studies
Foscamet DMSO, dimethylsulfoxide; PEG, polyethylene glycol.
out because of advanced periodontal destruction and the feeling that the presence of chronic inflamed tissue may have facilitated the recurrent virus infections. Wound healing was uneventful. On 11 August, 1986, the patient was hospitalized again because of bilateral pneumonia with high fever. He developed blisters on the lower lip and labial mucosa of the mandibular left first and second premolars. HSV-1 was isolated from the lesions and treatment with acyclovir was initiated (Fig. 1D). While still on acyclovir treatment, the patient developed new lesions on the left palatal arch; HSV-I was isolated from these lesions. On 5 September, 1986, mouth rinses with phosphonoformate were begun (5 x 20 ml/day, 24 mg/ml solution). On 10 September, 1986, the lesions showed clear signs of healing and virus isolations became negative. By 19 September, 1986, the lesions had completely healed. On 17 October, 1986, new lesions appeared from which HSV-1 was isolated. The patient failed to respond to acyclovir treatment. From 30 October until 12 November, 1986, phosphonoformate was administered (0.15 mg/kg/ minute, continuous IV infusion). Virus isolations became negative on 5 November, 1986, and the lesions healed completely.
Discussion Very few cases of chronic HSV lesions confined to the oral mucosa have been described.2 In most cases there is concomitant involvement of lips,
eyes, or skin. In non-immunocompromised patients, recurrent infection confined to the oral mucosa is even more rare. In these patients such lesions present as a cluster of small lesions with a maximal diameter of l-2 mm.3-5 Consistent with previous findings, the lesions in this patient showed a clear predilection for the heavily keratinized oral mucosa.5y6 An in vitro study by Rones et al.’ demonstrated the sensitivity of fibroblasts and epithelial cells from the gingival sulcus area to HSV infection, and the authors pointed to the possible role of these tissues as a primary site of infection and as a possible reservoir for the latent virus. Based on these findings, we irrigated the pockets daily with a povidone-iodine solution. The usefulness of systemic antiviral agents in the treatment of mucocutaneous HSV infections in immunocompromised patients is well documented.1,2,6s-*2 Table 1 shows a survey of the most widely used antiviral agents. Acyclovir resistant HSV-1 variants have occasionally been isolated from immunosuppressed patients treated with acyclovir.13-18 It is a matter of debate whether the emergence of such drug-resistant HSV-I variants may present clinical diffi-
VINCKIER
ET AL.
Table 2. Fig. 1B
Sensitivity of HSV-1 Isolates to Antiviral Drugs, During the Periods shown in Fig. 1A and Minimal Inhibitory Concentration*
(l&ml)
HSV-I (KOS
Compound ACV BVDU DHPG AraA PEA
StFiiIlt) 0.07 0.01 0.07 7 20
PmACV
(151) 0.07 0.02 0.07 7 20
* Required to inhibit virus-induced cytopathogenicity t Used as the reference HSV-1 strain.
PmACV
(2nd) 70 100 7 7 20
Pre-BVDU
70 100 7 3 20
he-DHPG
70 >lOO 7 7 20
Pre-aI&4
Pre-PFA
70 >lOO 7 10 20
70 >lOO 4 7 20
in human diploid embryonic skin-muscle (E,SM) fibroblasts by 50%.
culties; that is, impede the recovery process. Our results clearly indicate that these resistant HSV-1 strains do have clinical importance and may lead to persistent and even life-threatening infections. HSV-1 was isolated from the lesions on several occasions-each time before a new antiviral drug treatment was initiated (Table 2). The original HSV-1 strain, isolated before the first course of acyclovir treatment, showed the same pattern of sensitivity as the well-established laboratory strain of HSV-1, strain KOS.r9 However, all subsequent isolates of HSV-1 (Fig. 1B) were resistant to acyclovir (lOOO-fold decrease in sensitivity), totally resistant to BVDU (more than 5000-fold decrease in sensitivity), and partially resistant to DHPG (loofold decrease in sensitivity). The sensitivity of the HSV-1 isolates towards araA and PFA, however, did not change during the whole observation period (Table 2). The absence of any clinical response to the second course of acyclovir and to BVDU treatment can be accounted for by resistance of the virus to these drugs. The poor clinical response to DHPG also seems related to the partial resistance the virus had acquired to this drug. On the other hand, the poor clinical response to araA can be attributed to the intrinsic low sensitivity of HSV-1 to araA;r9 apparently, not sufficiently high blood drug levels can be achieved with araA because it is rapidly deaminated to hypoxanthine arabinoside and thereby greatly inactivated.*O The drug resistant HSV-1 strain isolated from our patient appeared to be thymidine kinase deficient (TK-). Consequently, it proved resistant to all antiviral drugs requiring phosphorylation by the HSV-1 encoded thymidine kinase. With the intensive dosage regimen used for PFA (0.15 mg/kg/minute), blood drug levels approximating 100 (50-200) p,g/ml may be expected.*’ This is well above the minimum inhibitory concentration (20 p,g/ml) required for phosphonoformate
to inhibit HSV-1 in vitro (Table 2) and, hence, may explain the healing of the lesions while under PFA therapy. At present, the antiviral agent of choice for treatment of HSV- infections in immunocompromised patients is acyclovir (ACV). Occasionally, acyclovir-resistant HSV-1 variants have been isolated from immunosuppressed patients treated with acyclovir. The clinical importance of these strains has been estimated to be low because of the reduced pathogenicity of the isolates. The case presented here shows the severe morbidity that can be associated with ACV-resistant, HSV-strains. This emphasizes the necessity of determining the in vitro drug sensitivity of the isolated HSV-1 strains so as to select the appropriate antiviral drug for in vivo treatment. This procedure guided us in using phosphonoformate as the ultimate, and apparently successful, therapeutic modality. References 1. Muller SA, Herrmann EC, Winkelmann RK: Herpes simplex infections in hematologic malignancies. Am J Med 52:102, 1972 2. Cohen SG, Greenberg MS: Chronic oral herpes simplex virus infection in immunocompromised patients. Oral Surg 59:465, 1985 3. Griffin JW: Recurrent intra-oral herpes simplex virus infection. Oral Surg 19:209, 1965 4. Muller SA: Recurrent herpes simplex of the hard palate. Arch Dermatol98:273, 1968 5. Greenberg MS, Brightman VJ, Ship II: Clinical and laboratory differentiation of recurrent intra-oral herpes simplex virus infections following fever. J Dent Res 48:385, 1969 6. Skinhoj P: Herpesvirus infections in the immunocompromised patient. Stand J Infect Dis 47(Suppl): 121, 1985 7. Rones Y, Hochman N, Ehrlich J, et al: Sensitivity of oral tissues to herpes simplex virus in vitro. J Periodontol 54:91, 1983 8. Galasso GJ, Merigan TC, Buchanan RA: Antiviral Agents and Viral Diseases of Man, 2nd ed. New York, Raven Press, 1984, pp 36-49, 251-271, 502-512 9. Klein RJ: Pathogenic mechanisms of recurrent herpes simplex virus infections. Arch Virol 51:1, 1976
728
USE OF DEAMINO-8-D ARGENINE
10. De Clercq E: Antiherpesvirus agents and the immune system. Zbl Bakt 13(Suppl):39, 1985 11. De Clercq E: Problems and new aspects of antiviral treatment: herpesvirus infections in immunosuppressed patients, in Jehn U (ed): Infektionen bei Tbmorpatienten. Mtinchen, W. Zuckschwerdt Verlag. 1985, pp 91- 114 12. Meyers JD: Treatment of herpesvirus infections in the immunocompromised host. Stand J Infect Dis 47(Suppl): 128, 1985 13. Crumpacker CS, Schnipper LE. Marlowe SI, et al: Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. New Engl J Med 306:343, 1982 14. Burns WH, Sara1 R, Santos GW, et al: Isolation and characterisation of resistant herpes simplex virus after acyclovir therapy. Lancet 1:421, 1982 15. Sibrack CD, Gutman LT, Wilfert CM, et al: Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeticient child.. J Infect Dis 146:673, 1982 16. Wade JC, McLaren C, Meyers JD: Frequency and signiflcance of acyclovir resistant herpes simplex virus isolated
J Oral Maxillofac 45:729-730,
17. 18. 19.
20.
21.
VASOPRESSIN
from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis 148:1077, 1983 Svennerholm BO. Vahlne A, Lowhagen GB. et al: Sensitivity of HSV strains isolated before and after treatment with acyclovir. Stand J Infect Dis 47(Suppl): 149. 1985 Barrv DW. Nusinoff-Lehrman S. Nixon Ellis M. et al: Viral resistance, clinical experience. Stand J Infect Dis 47(Suppl): 155, 1985 De Clerca E. Descamns J. Verhelst G. et al: Comoarative efficacy of antiher& drugs against different &rains of herpes simplex virus. J Infect Dis 141:563, 1980 Sacks SL, Scullard GH, Pollard RB, et al: Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination. Antimicrob Agents Chemother 21:93, 1982 Klintmalm G, Lonnqvist B, Oberg B, et al: Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients. Stand J Infect Dis 17:157, 1985
Surg
1987
Use of Deamino-8-D Arginine Vasopressin in a Patient with Moderate von Willebrand’s Disease ABUBAKER
OMAR ABUBAKER, DDS, PHD,* FRANKLIN A. BONTEMPO, THOMAS W. BRAUN, DMD, PHD*
Patients with hemophilia and von Willebrand’s disease (VWD) have a high risk of developing hepatitis and other viral infections after receiving cryoprecipitate or factor VIII concentrate.1-3 Fortunately, a safe and effective alternative to plasma products has become available for those patients * Chief Resident, Oral and Maxillofacial Surgery, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania. t Assistant Professor of Medicine, School of Medicine, University of Pittsburgh; Co-Director, Hemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania; Co-Director, Central Blood Bank, Pittsburgh;Pennsylvania. $ Chairman. Deoartment of Oral and Maxillofacial Surgery, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania_Assistant Professor, Departments of Anatomy and Histology and Oral and Maxillofacial Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Address correspondence and reprint requests to Dr. Braun: Department of Oral and Maxillofacial Surgery, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224. 0278-2391187 $0.00 + .25
MD,t AND
with mild factor VIII deficiency or VWD Type I and IIA. Several recent studies have suggested that for these patients 1-deamino 8-D-arginine vasopressin (DDAVP), or desmopressin (Stimate, Armour Pharmaceutical Co., Tarrytown, NY) can be used for acute bleeding episodes and for prophylaxis during dental extraction and other minor surgical procedures.4-8 The present report describes the results of using DDAVP prior to dental extraction in a patient and discusses the principles of DDAVP use in oral and maxillofacial surgery. Report
of a Case
A 29-year-old black female was referred for extraction of multiple carious teeth. Her past medical history was positive for easy bruising, frequent epistaxis, and occasional gingival bleeding following tooth brushing. She also reported prolonged bleeding after menses requiring dilatation and curettage procedures on three occasions. The last of these was complicated by excessive intraoper-
723
ET AL.
8. Cohen J: Etiology of simple bone cysts. J Bone Joint Surg
52A: 1493, 1970 9. Ogden JA, Griswold DM: Solitary cyst of the lams. J Bone Joint Surg 54A: 1309, 1972 10. Pommer G (cited by Olech E, Sicher H, Weinmann JP): Traumatic mandibular bone cyst. Oral Surg 4:1160, 1951 11. Bemier JL, Johnson LC, Whinery JG: Progressive bone cavities of the mandible. Oral Surg 8:970, 1955 12. Starma JN: Hemorrhagic cyst of the mandible in relation to horizontally impacted third molar. Oral Surg 38: 17, 1983 13. Waldron CL: Solitary (hemorrhagic) cyst of the mandible. Oral Surg 7:88, 1954
J Oral Maxillofac
14. Szerlip L: Traumatic bone cysts: resolution without surgery. Oral Surg 21, 201, I%6 15. Olech E, Sicher H, Weinmann JP: Traumatic mandibular bone cysts. Oral Surg 4:1160, 1951 16. Biewald HF: A variation in management of haemorrhagic, traumatic or simple bone cyst. J Oral Surg 25:427, 1%7 17. Thoma KH: The treatment of extravasation cysts with the use of gelfoam. Oral Surg 8:950, 1955 18. Lindsay JS, Martin WR, Green HG: Traumatic bone cyst, treated with homogenous bone graft. Oral Surg 21:536, 1966 19. Hughes CL: Hemorrhagic bone cyst and pathologic fracture of the mandible. J Oral Surg 27:345, 1969
Surg
45~723-728.1987
Chronic Herpetic Infection in an Immunocompromised Patient: Report of a Case F. VINCKIER,
DDS,* M. BOOGAERTS, MD,t D. DE CLERCK,$ E. DE CLERCQ, MD§
Chronic herpes simplex virus infections are often encountered in patients with an underlying immune disorder such as congenital immunodeficiency or acquired immunodeticiency [leukemia, lymphoma, acquired immune deficiency syndrome (AIDS)], or induced immunosuppression (chemotherapy, high doses of corticosteroids). An unusual severe or chronic herpetic infection may also be the first symptom of an underlying malignant condition. l Concomitantly with the increasing use of chemotherapeutic agents and immunosuppressive drugs in the treatment of cancer and the prevention of allograft (i.e., kidney or bone marrow) transplant rejection, severe herpetic infections have been noted
Received from the Departments of *$Stomatology and Dentistry, thledicine (Division of Hematology), and BDepartment of Human Biology (Division of Microbiology), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. * Docent. 0 Docent. $ Research Assistant of the Belgian National Fund for Scientific Research, Department of Dentistry. 5 Professor. Address correspondence and reprint requests to Dr. Vinckier: Department of Stomatology and Dentistry, Capucijnenvoer 7, B 3000 Leuven, Belgium. 0278-2391187 $0.00 + .25
and
with increasing frequency; such infections are frequently atypical and chronic in character. In this report, we describe a case of chronic oral herpes simplex type 1 (HSV-1) infection in a patient with chronic lymphocytic leukemia (CLL). The infection persisted despite successive attempts of treatment with acyclovir (ACV), bromovinyldeoxyuridine (BVDU), dihydroxypropoxymethylguanine (DHPG), and vidarabine (araA). The lesions finally resolved following systemic treatment with phosphonoformate (foscarnet, PFA). Report of a Case A 55-year-old male patient was examined in July 1981 because of persistent ischiatiform pains in the back. A white cell count of 35 x log/L consisting of 78% mature B-lymphocytes was found and the diagnosis of B-CLL (chronic lymphocytic leukemia, rai-stage 0) was made. Because of low grade malignancy no chemotherapeutic treatment was instituted at that time. In April 1985 (Fig. lA), the patient was referred to the Dentistry Department. He complained of a persistent inflammation of the mandibular gingiva and mucosa at the left side of the floor of the mouth. On clinical examination, large necrotic ulcers covered with a grey-white membrane, associated with enlarged submandibular and pre-auricular lymph node was seen. Streptococcus pyogenes was isolated from the lesions and the patient was treated with antibiotics (erythromycin, 500 mg, four
CHRONIC HERPETIC INFECTION
724
FIGURE 1. Clinical course of the different recurrent episodes of oral HSV-1 infection. The severity of the lesions, the antiviral agents that were used and the results of the virus isolations are depicted. ACV, acyclovir: BVDU, bromovinyldeoxyuridine: DHPG, dihydroxypropoxymethylguanine: AraA, adenine arabinoside (vidarabine): PFA. phosphonoformate: +, HSV-1 isolated: and -, HSV-1 not isolated.
times daily). After initial regression, the lesions recurred, with new lesions developing on the labial mucosa of the maxillary left central and lateral incisors and canine (Fig. 2). The lesions were accompanied by pain, severe fetor oris, general malaise, fever (385”C), lymph node enlargement, and swallowing problems. The patient was hospitalized and intravenous antibiotics (chloromycetin, erythromycetin) were administered. An intensive local treatment was instituted, consisting of careful interdental cleaning and daily application of 3% H,O*. The patient also rinsed his mouth four times daily with Kamillosan@ (Degussa Pharma) to alleviate the pain. Mouth rinsing
with a nystatin solution was instituted to prevent fungus overgrowth during the intensive treatment with antibiotics. The lesions continued to enlarge. Streptococcus pyogenes could not be isolated from the lesions. The aspirate of an enlarged, mobile, painful retromandibular lymph node (diameter 3 cm) was sterile and blood cultures were negative. Blood cell count showed 75.2 x log/L white blood cells, 3.86 x 10r2/L red blood cells and 279 x 109/L platelets. On 8 May, 1985, virus isolations were taken. HSV type 1 was isolated and treatment was started with intravenous acyclovir (ACV) at 10 mg/kg, thrice-daily for
FIGURE 2 (left). Lesions on gingiva and mucosa labial to the maxillary left central and lateral incisors and canine. Note the spontaneous bleeding tendency. FIGURE 3 (right).
Lesions on labial mucosa of maxillary left central and lateral incisors and canine nearly completely healed.
VINCKIER
725
ET AL.
FIGURE 4 (lefr). FIGURE 5 (right).
Recurrent lesions on mandibular gingiva. Lesions show no healing despite of acyclovir treatment.
five days. In addition, the patient rinsed his mouth with a 1% aqueous solution of tranexamic acid to limit the spontaneous bleeding tendency of the lesions. Two weeks later the lesions had completely regressed and the lymph node enlargement had disappeared (Fig. 3). At that time the right upper second premolar was removed because of advanced periodontal destruction. No further complications occurred and wound healing was satisfactory. At the end of June 1985 (Fig. lB), the white cell count had reached 172 x 109/L (96% lymphocytes) and on 28 June, 1985, a single dose of 50 mg chlorambucil (Leukeran,@ Wellcome) was administered. In the meantime, a gingival lesion had developed at the lingual side of the right lower second molar. Use of a Povidone-iodine mouthwash (Isobetadine,@ Belgana) was initiated. Despite this treatment, lesions also developed on the left mandibular gingiva (Fig. 4) and soft palate. Marked bilateral submandibular lymph node enlargement occurred. Limited mouth opening and extreme pain made the patient unable to eat. HSV-1 was isolated from the lesions and oral acyclovir (5 x 200 mg/day) was started on 8 July, 1985; however, the lesions continued to enlarge (Fig. 5). On 16 July, 1985, virus isolations were still positive for HSV type 1. On 17 July, 1985, a 20-day-course of oral BVDU (125 mg/day, four times daily) was initiated. Despite this treatment, the lymph node enlargement and trismus increased and the patient became febrile. He lost weight and his
FIGURE 6. Herpetic lesions nearly completely healed after phosphonoformate administration.
general condition deteriorated. HSV type 1 was repeatedly isolated from the lesions. On 29 July, 1985, a second dose of chlorambucil (50 mg) was administered. Because of the severity of the gingivostomatitis, the persistent fever despite the administration of antibiotics, and the cachexia, the patient was hospitalized at the beginning of August 1985. On 16 August, 1985, a two-week course with DHPG (350 mg/day, twice-daily) was started. A slight improvement of the stomatitis lesions was noted during the first week, although HSV-1 could still be isolated. Thereafter, the stomatitis worsened again despite continued DHPG treatment; the general condition of the patient deteriorated further and parenteral feeding became necessary. He developed a bilateral bronchopneumonia from which Pseudomonas aeruginosa and adenovirus could be isolated. From 15 September to 5 October, 1985, vidarabine (araA) was administered IV (900 mg/day or 15 mg/kg/ day). After initial improvement, the stomatitis lesions enlarged and the general condition again deteriorated. Virus isolations remained positive for HSV-1. From 7 October to 21 October, 1985, phosphonoformate (foscamet) was administered as a continuous intravenous infusion at 0.15 mg/kg/minute. From the fifth day after the initiation of the phosphonoformate, virus isolations became negative. The stomatitis lesions regressed (Fig. 6), fever disappeared, and the patient’s general condition improved. Antibiotics wene discontinued, and on the 28th October, the patient was discharged from the hospital. By that time the oral lesions had completely healed. On 11 March, 1986, the patient developed painful lesions from which HSV type 1 was isolated (Fig. 1C). On 14 March, 1986, treatment with oral acyclovir was started (10 x 200 mg/day). Progression of the virus lesions was retarded, but they showed no healing tendency. On 12 June, 1986, the patient was hospitalized with very severe gingivostomatitis, accompanied by lymph node enlargement, fever (38.2”C) and difficulties in swallowing and eating. He was still under intravenous acyclovir treatment. On 26 June, 1986, the acyclovir treatment was discontinued and until 13 July, 1986, phosphonoformate was administered as a continuous intravenous infusion at 0.15 mg/kg/minute. Virus isolations became negative on 30 June, 1986, and the stomatitis lesions regressed. On 9 July, 1986, several tooth extractions were carried
726 Table 1.
CHRONIC HERPETIC
INFECTION
Most Widely Used Antiviral Agents for HSV Infections in Humans Comment
Formulation
Compound
IV: 15 mgikglday
ACV Acyclovir
PO: 200 mg every four hours (Zovirax@) Topical: 5- 10% in PEG 5% in propylene glycol (Zoviraxs)
Clearly efficacious in immunocompromised patients Also efficacious, although lower serum levels are achieved than after IV administration Not effective Seems to be effective
IV: 10 mg/kg/day (vira-A@)
Of some benefit in immunocompromised patients over 40 years of age
PO: 7.5 mg/kg/day
Appears to be effective, as shown by studies in immunocompromised patients
DHPG Dihydroxypropoxymethylguanine
IV: 7.5 or 15 mg/kg/day
Clinical studies have recently begun in immunocompromised patients
IDU Iododeoxyuridine
topical: 5, 10, or 40% in DMSO (Virexen,’ Virpex,@ Herpide)
Assumed to be effective in humans
IV: 0.15 mg/kg/minute (Foscavire)
Apparently effective against TK- HSV infections, as shown by the present study
AraA Adenine arabinoside Vidarabine BVDU Bromovinyldeoxyuridine
PEA Phosphonoformate
Moderately effective in animal studies
Foscamet DMSO, dimethylsulfoxide; PEG, polyethylene glycol.
out because of advanced periodontal destruction and the feeling that the presence of chronic inflamed tissue may have facilitated the recurrent virus infections. Wound healing was uneventful. On 11 August, 1986, the patient was hospitalized again because of bilateral pneumonia with high fever. He developed blisters on the lower lip and labial mucosa of the mandibular left first and second premolars. HSV-1 was isolated from the lesions and treatment with acyclovir was initiated (Fig. 1D). While still on acyclovir treatment, the patient developed new lesions on the left palatal arch; HSV-I was isolated from these lesions. On 5 September, 1986, mouth rinses with phosphonoformate were begun (5 x 20 ml/day, 24 mg/ml solution). On 10 September, 1986, the lesions showed clear signs of healing and virus isolations became negative. By 19 September, 1986, the lesions had completely healed. On 17 October, 1986, new lesions appeared from which HSV-1 was isolated. The patient failed to respond to acyclovir treatment. From 30 October until 12 November, 1986, phosphonoformate was administered (0.15 mg/kg/ minute, continuous IV infusion). Virus isolations became negative on 5 November, 1986, and the lesions healed completely.
Discussion Very few cases of chronic HSV lesions confined to the oral mucosa have been described.2 In most cases there is concomitant involvement of lips,
eyes, or skin. In non-immunocompromised patients, recurrent infection confined to the oral mucosa is even more rare. In these patients such lesions present as a cluster of small lesions with a maximal diameter of l-2 mm.3-5 Consistent with previous findings, the lesions in this patient showed a clear predilection for the heavily keratinized oral mucosa.5y6 An in vitro study by Rones et al.’ demonstrated the sensitivity of fibroblasts and epithelial cells from the gingival sulcus area to HSV infection, and the authors pointed to the possible role of these tissues as a primary site of infection and as a possible reservoir for the latent virus. Based on these findings, we irrigated the pockets daily with a povidone-iodine solution. The usefulness of systemic antiviral agents in the treatment of mucocutaneous HSV infections in immunocompromised patients is well documented.1,2,6s-*2 Table 1 shows a survey of the most widely used antiviral agents. Acyclovir resistant HSV-1 variants have occasionally been isolated from immunosuppressed patients treated with acyclovir.13-18 It is a matter of debate whether the emergence of such drug-resistant HSV-I variants may present clinical diffi-
VINCKIER
ET AL.
Table 2. Fig. 1B
Sensitivity of HSV-1 Isolates to Antiviral Drugs, During the Periods shown in Fig. 1A and Minimal Inhibitory Concentration*
(l&ml)
HSV-I (KOS
Compound ACV BVDU DHPG AraA PEA
StFiiIlt) 0.07 0.01 0.07 7 20
PmACV
(151) 0.07 0.02 0.07 7 20
* Required to inhibit virus-induced cytopathogenicity t Used as the reference HSV-1 strain.
PmACV
(2nd) 70 100 7 7 20
Pre-BVDU
70 100 7 3 20
he-DHPG
70 >lOO 7 7 20
Pre-aI&4
Pre-PFA
70 >lOO 7 10 20
70 >lOO 4 7 20
in human diploid embryonic skin-muscle (E,SM) fibroblasts by 50%.
culties; that is, impede the recovery process. Our results clearly indicate that these resistant HSV-1 strains do have clinical importance and may lead to persistent and even life-threatening infections. HSV-1 was isolated from the lesions on several occasions-each time before a new antiviral drug treatment was initiated (Table 2). The original HSV-1 strain, isolated before the first course of acyclovir treatment, showed the same pattern of sensitivity as the well-established laboratory strain of HSV-1, strain KOS.r9 However, all subsequent isolates of HSV-1 (Fig. 1B) were resistant to acyclovir (lOOO-fold decrease in sensitivity), totally resistant to BVDU (more than 5000-fold decrease in sensitivity), and partially resistant to DHPG (loofold decrease in sensitivity). The sensitivity of the HSV-1 isolates towards araA and PFA, however, did not change during the whole observation period (Table 2). The absence of any clinical response to the second course of acyclovir and to BVDU treatment can be accounted for by resistance of the virus to these drugs. The poor clinical response to DHPG also seems related to the partial resistance the virus had acquired to this drug. On the other hand, the poor clinical response to araA can be attributed to the intrinsic low sensitivity of HSV-1 to araA;r9 apparently, not sufficiently high blood drug levels can be achieved with araA because it is rapidly deaminated to hypoxanthine arabinoside and thereby greatly inactivated.*O The drug resistant HSV-1 strain isolated from our patient appeared to be thymidine kinase deficient (TK-). Consequently, it proved resistant to all antiviral drugs requiring phosphorylation by the HSV-1 encoded thymidine kinase. With the intensive dosage regimen used for PFA (0.15 mg/kg/minute), blood drug levels approximating 100 (50-200) p,g/ml may be expected.*’ This is well above the minimum inhibitory concentration (20 p,g/ml) required for phosphonoformate
to inhibit HSV-1 in vitro (Table 2) and, hence, may explain the healing of the lesions while under PFA therapy. At present, the antiviral agent of choice for treatment of HSV- infections in immunocompromised patients is acyclovir (ACV). Occasionally, acyclovir-resistant HSV-1 variants have been isolated from immunosuppressed patients treated with acyclovir. The clinical importance of these strains has been estimated to be low because of the reduced pathogenicity of the isolates. The case presented here shows the severe morbidity that can be associated with ACV-resistant, HSV-strains. This emphasizes the necessity of determining the in vitro drug sensitivity of the isolated HSV-1 strains so as to select the appropriate antiviral drug for in vivo treatment. This procedure guided us in using phosphonoformate as the ultimate, and apparently successful, therapeutic modality. References 1. Muller SA, Herrmann EC, Winkelmann RK: Herpes simplex infections in hematologic malignancies. Am J Med 52:102, 1972 2. Cohen SG, Greenberg MS: Chronic oral herpes simplex virus infection in immunocompromised patients. Oral Surg 59:465, 1985 3. Griffin JW: Recurrent intra-oral herpes simplex virus infection. Oral Surg 19:209, 1965 4. Muller SA: Recurrent herpes simplex of the hard palate. Arch Dermatol98:273, 1968 5. Greenberg MS, Brightman VJ, Ship II: Clinical and laboratory differentiation of recurrent intra-oral herpes simplex virus infections following fever. J Dent Res 48:385, 1969 6. Skinhoj P: Herpesvirus infections in the immunocompromised patient. Stand J Infect Dis 47(Suppl): 121, 1985 7. Rones Y, Hochman N, Ehrlich J, et al: Sensitivity of oral tissues to herpes simplex virus in vitro. J Periodontol 54:91, 1983 8. Galasso GJ, Merigan TC, Buchanan RA: Antiviral Agents and Viral Diseases of Man, 2nd ed. New York, Raven Press, 1984, pp 36-49, 251-271, 502-512 9. Klein RJ: Pathogenic mechanisms of recurrent herpes simplex virus infections. Arch Virol 51:1, 1976
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USE OF DEAMINO-8-D ARGENINE
10. De Clercq E: Antiherpesvirus agents and the immune system. Zbl Bakt 13(Suppl):39, 1985 11. De Clercq E: Problems and new aspects of antiviral treatment: herpesvirus infections in immunosuppressed patients, in Jehn U (ed): Infektionen bei Tbmorpatienten. Mtinchen, W. Zuckschwerdt Verlag. 1985, pp 91- 114 12. Meyers JD: Treatment of herpesvirus infections in the immunocompromised host. Stand J Infect Dis 47(Suppl): 128, 1985 13. Crumpacker CS, Schnipper LE. Marlowe SI, et al: Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. New Engl J Med 306:343, 1982 14. Burns WH, Sara1 R, Santos GW, et al: Isolation and characterisation of resistant herpes simplex virus after acyclovir therapy. Lancet 1:421, 1982 15. Sibrack CD, Gutman LT, Wilfert CM, et al: Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeticient child.. J Infect Dis 146:673, 1982 16. Wade JC, McLaren C, Meyers JD: Frequency and signiflcance of acyclovir resistant herpes simplex virus isolated
J Oral Maxillofac 45:729-730,
17. 18. 19.
20.
21.
VASOPRESSIN
from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis 148:1077, 1983 Svennerholm BO. Vahlne A, Lowhagen GB. et al: Sensitivity of HSV strains isolated before and after treatment with acyclovir. Stand J Infect Dis 47(Suppl): 149. 1985 Barrv DW. Nusinoff-Lehrman S. Nixon Ellis M. et al: Viral resistance, clinical experience. Stand J Infect Dis 47(Suppl): 155, 1985 De Clerca E. Descamns J. Verhelst G. et al: Comoarative efficacy of antiher& drugs against different &rains of herpes simplex virus. J Infect Dis 141:563, 1980 Sacks SL, Scullard GH, Pollard RB, et al: Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination. Antimicrob Agents Chemother 21:93, 1982 Klintmalm G, Lonnqvist B, Oberg B, et al: Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients. Stand J Infect Dis 17:157, 1985
Surg
1987
Use of Deamino-8-D Arginine Vasopressin in a Patient with Moderate von Willebrand’s Disease ABUBAKER
OMAR ABUBAKER, DDS, PHD,* FRANKLIN A. BONTEMPO, THOMAS W. BRAUN, DMD, PHD*
Patients with hemophilia and von Willebrand’s disease (VWD) have a high risk of developing hepatitis and other viral infections after receiving cryoprecipitate or factor VIII concentrate.1-3 Fortunately, a safe and effective alternative to plasma products has become available for those patients * Chief Resident, Oral and Maxillofacial Surgery, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania. t Assistant Professor of Medicine, School of Medicine, University of Pittsburgh; Co-Director, Hemophilia Center of Western Pennsylvania, Pittsburgh, Pennsylvania; Co-Director, Central Blood Bank, Pittsburgh;Pennsylvania. $ Chairman. Deoartment of Oral and Maxillofacial Surgery, Western Pennsylvania Hospital, Pittsburgh, Pennsylvania_Assistant Professor, Departments of Anatomy and Histology and Oral and Maxillofacial Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Address correspondence and reprint requests to Dr. Braun: Department of Oral and Maxillofacial Surgery, Western Pennsylvania Hospital, 4800 Friendship Avenue, Pittsburgh, PA 15224. 0278-2391187 $0.00 + .25
MD,t AND
with mild factor VIII deficiency or VWD Type I and IIA. Several recent studies have suggested that for these patients 1-deamino 8-D-arginine vasopressin (DDAVP), or desmopressin (Stimate, Armour Pharmaceutical Co., Tarrytown, NY) can be used for acute bleeding episodes and for prophylaxis during dental extraction and other minor surgical procedures.4-8 The present report describes the results of using DDAVP prior to dental extraction in a patient and discusses the principles of DDAVP use in oral and maxillofacial surgery. Report
of a Case
A 29-year-old black female was referred for extraction of multiple carious teeth. Her past medical history was positive for easy bruising, frequent epistaxis, and occasional gingival bleeding following tooth brushing. She also reported prolonged bleeding after menses requiring dilatation and curettage procedures on three occasions. The last of these was complicated by excessive intraoper-