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Oral mucositis in patients undergoing bone marrow transplantation
Oral mucositis in patients undergoing bone marrow transplantation Bradley G. Seto, D.D.S., Matthew Kim, B.S., Lawrence Wolinsky, Ph.D., D.D.S., Ronald S. Mite, D.D.S., and Richard Champlin, M.D., Los Angeles, Calif. DEPARTMENTS OF DENTISTRY AND MEDICINE, CENTER FOR THE HEALTH SCIENCES
THE TRANSPLANTATION
BIOLOGY
PROGRAM.
lJCL.4
Thirty patients who received bone marrow transplantation treatment from HLA identical sibling donors for immunologic and malignant diseases were studied. In essentially all of the patients oral changes developed during the first 30 days following transplant. Oral symptoms frequently constituted the major complaints of the patients during the follow-up period. The oral changes included mucositis, xerostomia. pain, and bleeding. Mucositis was more severe and of longer duration when associated with herpes simplex infections and when optimal oral hygiene was not maintained. Xerostomia which accompanies engraftment was an early sign of acute graft-versus-host disease. A nonbrushing method of oral hygiene was effective in reducing the severity and duration of mucositis. This technique offers a short-term alternative to brushing in pancytopenic patients who are susceptible to bleeding or trauma. (ORAL SURG. ORAL MED. ORAL PATHOL. 60~493-497, 1985)
B one marrow transplantation is an effective treat-
ment for immunologic and malignant diseases.’This procedure is frequently associated with a number of complications in the oral cavity, including mucositis, xerostomia, parotitis, pain, and bleeding.* Oral complications can be the major symptoms for patients receiving combined chemotherapy and irradiation.3 These effects are induced by the chemotherapy and irradiation conditioning treatment given prior to transplantation or by infection, graft-versus-host disease, or immunosuppressive treatment (methotrexate) following transplant.*v4 The purpose of this article is to analyze the oral changes that are seen during the first 30 days following treatment with bone marrow transplantation. PATIENTS AND METHODS
Patients receiving bone marrow transplantation from HLA-A,B,C, and D identical sibling donors at the UCLA Transplantation Biology Unit from March, 1981, to March, 1983, were included for study.
This study was supported in part by Grants CA 23175 from the National Cancer Institute and RR 865 from the United States Public Health Service.
Pretronsplant treatment
chemotherapy
and radletien
Patients received cyclophosphamide (60 mg/kg) intravenously on days -3 and -4 followed by totalbody irradiation, 10 Gy as a single fraction or 11.25 to 13.2 Gy in five to eight fractions from a %obalt source at a dose rate of 5 to 7 cGy/minute. Bone marrow cells (1 to 4 X lO*/kg) were infused intravenously on day 0. Methotrexate was administered following transplant to modify or prevent graftversus-host diseasein a dose of 15 mg/m* on day +l and 10 mg/mm* on days +3, +6, and +I1 and weekly thereafter to day +102. Supportive
care
Patients received oral nonabsorbable antibiotics from the start of the conditioning treatment to the recovery of the granulocytes (>O.S X log/liter). The antibiotics included vancomycin, 500 mg, and polymyxin B, 100 mg orally, three times per day and nystatin suspension, 10 X lo6 units to gargle and swallow every 4 hours, and nystatin oral troches, 100,000 units orally every 4 hours. Granulocytopenic patients with fever or documented bacterial infection received a combination of broad-spectrum antibiotics (moxalactam with either pipericillin or amikacin).5 Patients with suspectedor 493
494
Set0 et al.
WE/Platelet
Oral Surg. November, 1985
vs Mucositis
-
WBC
Fig. 1. Inverse relationship of mucositis incidence to white blood cell and platelet counts.
documented fungal infections were treated with amphotericin B. Patients with localized herpes simplex oral infections did not receive antiviral treatment; those with severe, progressive herpes simplex infections received acyclovir. Patients who had acute graft-versus-host disease (GVHD) received high-dose methylprednisolone (1 gram/day) for 3 days followed by prednisone (100 mg/day), which was tapered with reduction of clinical manifestations of GVHD. Oral/dental
evaluation
ized cleaning of oral hard and soft tissues. A saline rinse completed the oral care. The patient was allowed to use small amounts of mouthwash in the final rinse for flavoring. The quantity of oral debris was determined by visual examination and categorized by the following criteria: Excellent. Observable plaque/debris covering 0% to 10% of hard and soft tissues. Good. Observable plaque/debris covering 10% to 25% of hard and soft tissues. Fair. Observable plaque/debris covering 25% to 75% of hard and soft tissues. Poor. Observable plaque/debris covering on >75% of hard and soft tissues. Mucositis was defined as any change in the mucosa of the oral cavity, including erythema, ulceration, erosion, and sloughing. All patients in whom ulcerations developed underwent swab cultures for bacterial, fungal, and viral organisms. The grading of the mucositis was as follows: Grade I. Localized erythema only, with no pain. Grade ZZ. Generalized erythema without pain or localized erythema or ulcers with mild pain. Grade ZZZ.Multiple ulcers or generalized erythema with moderate pain. Grade IV. Generalized erythema or ulcers with moderate to severe pain. Pain was assessedby the subjective comments of the patient. Mild pain did not require analgesics. Moderate pain was relieved by nonnarcotic oral analgesics. Severe pain may or may not have been relieved by parenteral narcotic analgesics, including Dilaudid and methadone. Patients with moderate to severe pain also received topical anesthetics such as viscous 2% lidocaine or Hurricane* gel. The oral assessmentinformation was collected and recorded by a single investigator to minimize variance in data collection. The data were analyzed by the chi-square test. Significance was accepted if p < 0.05.
Patients were analyzed twice weekly from day -7 to day +30 following transplant. Initial visual examinations and panoramic radiographs evaluated the oral health of each patient, special care being taken to identify acute odontogenic infections. If pain, swelling, and purulence associated with infections were present, the offending teeth were removed; otherwise, teeth were maintained. Subsequent oral changes, such as pain, xerostomia, mucositis, and bleeding, were related to the patient’s peripheral blood counts, maximum daily temperature, the presence of documented infections, and graft-versus-host disease. Brushing and flossing were discontinued when the granulocyte and/or platelet counts were below 0.5 X 109/1 and 20 X 109/1, respectively. An alternative oral hygiene method was recommended for use four times daily. Cotton swabs saturated with a dilute hydrogen peroxide solution (one part 3% peroxide: one part saline) were used for debridement of the teeth, and Toothettes* were used for general-
Thirty patients were included for study. There were thirteen female patients (43%) and 17 male patients (57%). The median age was 27.4 years (females 30.4, range 15 to 48 years; males 23.4, range 12 to 44 years). The diagnoses for treatment are listed in Table I. Twenty-nine of thirty patients (97%) developed mucositis. Erythema, superficial mueosal whitening,
*Toothette-soft, sponge, disposable tooth-cleaning brand, Inc., Willoughby, Ohio.
*Hurricane gel-ethyl aminobenzoate in a water-soluble ene glycol base, Beutlich, Inc., Chicago, Ill.
device, Hal-
RESULTS
polyethyl-
Oral mucositis in bone marrow transplantation
Volume 60 Number 5 fable
I. Diagnosis for bone marrow transplantation Acute lymphocytic leukemia Chronic myelogenous leukemia Acute myelogenous leukemia Aplastic anemia Acute myelomonocytic leukemia Metastatic testicular carcinoma
11 8 6 3 1 -i 30
bilateral parotitis, and mild to moderate xerostomia developed initially. In the more severe cases, there was denudation, ulcerations, or mucosal sloughing. Mucositis that began or worsened after day +7 was characterized by erythematous eroded, ulcerated, and/or pseudomembranous lesions. The number of patients experiencing mucositis on each day after transplant rose from day +3, reached a maximum at days + 12 to + 14, and steadily declined thereafter. The median day of resolution was day +19.4 (range, +8 to +30). The rise in the incidence of mucositis followed the initial drop in the circulating granulocyte count by approximately 4 to 5 days and coincided with the initial day when the circulating granulocyte count was below 0.5 X 109/1 (Fig. 1). The duration of mucositis was longer in the poor and fair oral hygiene groups (average duration, 11.O and 10.7 days, respectively) than in the good and excellent oral hygiene groups (average duration, 6.3 and 5.7 days, respectively) (p < 0.05). The severity of mucositis also decreasedwith improvement in oral hygiene from the poor to the excellent groups but were not statistically significant (Table II). Streptococcus viridans and coagulase-negative Staphylococcus were identified by culture in all patients and were considered the normal flora for this group. In the patients in whom mucositis developed, 97% (28 of 29) had other organisms w&e also isolated (Table III). No correlations seen between mucositis and the bacterial pathogens isolated. Candida albicans was the most common pathogen isolated and generally appeared as a superficial plaque of the oral soft tissue. The normal white color was often stained by the yellowish nystatin suspension. The underlying mucosa would be erythematous, painful, and eroded. However, bleeding was not a problem in the oral Candida infections. No relationship to the duration of mucositis could be documented, since many patients without mucositis also harbored the fungus. The herpes simplex virus was the second most common pathogen isolated and was associatedwith a longer duration of mucositis than the other microor-
Table
495
II. Oral hygiene versus mucositis
POW Fair Ciood Excellent
8 12 7 3
3.13 2.02
2.43 I .67
I I.0 10.7 6.3 s.7
Table III. Microbial isolates identified in patients receiving bone marrow transplantation Streptococcus viridans Staphylococcus (coagulase-negative) Candida species
Herpes simplex Other streptococcus species Neisseria species Corynebacterium species Staphylococcus Morexella Eikonella Acinetobacter Enterobacfer
aureus
100% (30/30) 100% (30/30) 47% (14/30) 37% (11/30) 30% (9/30) 23% (7/30) 23% (7/30) 10% (3/30) 3% (l/30) 3% (l/30) 3% (l/30) 3% (l/30)
ganisms listed on Table III (median, 18 days compared to the median for other organisms, ranging from 10.4 to 14.8 days). The herpes simplex infections began as superficial vesicles or pseudomembranous ulcers of any oral soft tissue, including nonkeratinized mucosa, The lesions ranged in size from punctate vesicles to as large as 1.5 cm with a necrotic membrane or crust. The borders were erythematous but nonindurated. Most herpetic ulcers began as a single lesion or a small locus of lesions. Subsequently, multiple ulcers would frequently follow on other tissues. Bleeding was also seen from herpetic oral ulcers when the platelet count was below 20 X 1Og/1. However, prolonged bleeding generally occurred in patients with platelet counts below 10 X log/l. If superinfection did not occur, healing would coincide with recovery of granulocytes. If engraftment was delayed beyond day +2 1, superinfection was eminent and progressive enlargement would often occur despite systemic antimicrobial therapy, topical or intravenous acyclovir, and local care. In 50% (15/30) of the patients acute graftversus-host disease (GVHD) developed during the follow-up period (median day, +24) after transplant. The dental symptoms included xerostomia, erythema, diffuse denudation of the mucosa, and pain. The progression of the xerostomia after day + 14 was an early symptom of acute GVHD and corresponded to the early signs of engraftment. Denudation was
496
Set0 et al.
generalized, mostly affecting the buccal mucosa and lips; the more severe cases involved the keratinized oral tissues. The oral involvement of GVHD did not correlate well with its severity in other tissues, such as the skin, liver, or gastrointestinal tract. DISCUSSION
Nearly all patients will develop mueosal changes following allogenic bone marrow transplantation ranging from mild, symptomless erythema to painful, generalized ulcerations.*s6Mucositis will develop concomitant with the decline in the peripheral leukocyte and platelet counts following intensive chemoradiotherapy conditioning treatment. Herpes simplex is the causative agent in many instances of oral mucositis, especially when ulcerations are present. Association with herpes will prolong oral healing despite optimal oral hygiene. However, effective removal of oral debris will decreasethe severity and duration of the mueositis. This suggests that colonization by microorganisms exacerbates the oral mucositis produced by chemoradiotherapy or viruses. Oral mucositis during bone marrow transplantation is probably multifactorial in origin, resulting from the toxicity of chemotherapy, radiotherapy, infection, graft-versus-host disease, or trauma.2*3s‘-I* The early effects are related to the chemoradiotherapy on the nonkeratinized mueosal surfaces3 and may progress to include the keratinized mucosa. When trauma or infection contributes to mueositis, keratinized and/or nonkeratinized tissues may be involved. These also tend to occur later in the course of treatment. It is likely that the pathogenesis of mucositis is at least partly related to a microbial interaction with the oral tissues.” This is supported by the relationship of decreasing severity and duration of mucositis to improvement in the quality of oral hygiene.‘3z’4 Our alternative nonbrushing oral hygiene technique was effective in decreasing the duration and severity of mueositis, indicating that this is a reasonable short-term alternative to brushing in pancytopenic patients. However, further study is needed to evaluate the potential risks and benefits of the various nonbrushing oral hygiene methods as compared to toothbrushing for patients receiving bone marrow suppressive therapy. C. albicans is the most commonly seen pathogen associated with bone marrow transplantation.2 Candida is present despite prophylactic use of nystatin and is most commonly seencolonizing the dorsum of the tongue, palate, and bueoal mucosa. However, effective oral care will prevent or decrease mueosal changes resulting from vegetations of C. albicans.
Oral Surg. November. 19XS
Herpes simplex is the major cause of oral ulcerations in patients receiving bone marrow transplants. These Occurrencesprobably represent reactivation of latent infections. The actual incidence of herpes mucositis is probably higheri than documented by culture because many of the ulcerations that appeared consistent with the clinical presentation of the virus were not confirmed by culture. This could be due to the decreasing probability of identifying the virus by culture for each day following initial presentation of the 1esiorP and the fact that few lesions were cultured within 24 hours of initial symptoms. The expected clinical course of recurrent herpes simplex infections for nonimmunocompromised hosts” was not seen in this patient population. First, the herpes infections were self-perpetuating; the initial infection would begin with one or a few lesions in a single region and then progress to involve multiple areas over a period of a few days. Recurrent infections in noneompromised patients are typically limited to a single ulcer or region. Second, the herpetic vesicles were not limited to the keratinized tissues but involved any mucosal surface of the oral cavity. Finally, the lesions did not heal in the normal 7 to 10 days unless engraftment occurred. The relationship of herpes simplex to an increase in the severity and duration of the mucositis is twofold. The discomfort associated with a herpetic mucositis prevented the patient from maintaining adequate oral hygiene, thus increasing the severity and duration of mucositis.13+‘4Herpes simplex vesicles also appear to cause deeper injury to mucosal tissues than the chemoradiotherapy. In approximately one half of the patients receiving allogenic bone marrow transplantation acute graftversus-host disease (GVHD) involving the oral cavity will develop during the first 4 weeks after bone marrow transplantation.’ One of the early signs seen in the oral cavity is the progression of xerostomia with engraftment. The dental professional can provide only palliative support for pain (topical anesthetics) and xerostomia (artificial saliva substitutes) and recommend oral hygiene procedures that are useful when pain and bleeding limit brushing and flossing. Good dental follow-up and oral hygiene, including daily fluoride applications, are important to minimize risk of persistent xerostomia’* leading to rampant decay. REFERENCES 1. Champlin RI?, Gale RP: The role of bone marrow transplantation in the treatment of hematologic malignancies and solid tumors: a critical review of syngeneic, autologous and allogenit transplants. Cancer Treat Rep 68: 145-61, 1984.
Volume 60 Number
Oral mucositis in bone marrow transplantation
497
5
2. Dreizen S, McCredie KB, Dicke KA, Zander AR, Peters LJ: Oral complications of bone marrow transplantation. Postgrad Med 66: 87-193, 196. 1979. 3. Laskiewicz BM: The management of patients undergoing synchronous combined chemotherapy and radiotherapy. J Laryngol Otol 96: 265-275, 1982. 4. Schubert MM. Sullivan KM, Izutsu KT, Truelove EL: Oral complications of bone marrow transplantation. In Peterson DF, Sonis ST (editors): Oral complications of cancer chemotherapy, The Hague. 1983, Martinus Nijhoff Publisher, pp. 93-l 12. 5. Winston DJ, Barnes RC, Ho WG, et al: Moxalactam plus pipercicillin versus moxalactam in febrile granulocytopknic patients. Am J Med 77: 442-450. 1984. 6. Lasser SD, Camitta BM. Needleman HL: Dental management of patients undergoing bone marrow transplantation for aplastic anemia. 0~41. SLRG ORAL MED ORAL PATHOL 43: 181-189, 1977. 7. Dreizen S, Bodey GP, Rodriguez V: Oral complications of cancer chemotherapy. Postgrad Med 58: 78-82, 1975. 8. Guggenheim J, Verbin RS, Appel BN, Schmutz J: Clinicopathologic effects of cancer chemotherapeutic effects on human buccal mucosa. ORAL SURG ORAL MED OR,~L PATH~L 44: 58-63. 1911. 9. Bottomley WK, Perlin E, Ross GR: Antineoplastic agents and their oral manifestations. ORAL SURG ORAL MED ORAL PATtior 44: 527-534, 1977. IO. Dreizen S: Stomatotoxic manifestations of cancer chemotherapy. J Prosthet Dent 40: 650-655, 1978. Il. Shepherd JP: Management of the oral complications of leukemia ORAL SURG ORAI. MED ORAL PATHOL 45: 543-548, 1978.
12. Lockhart PB, Sonis ST: Relationship of or;!/ complications to peripheral blood leukocyte and platelet c’ounts tn patients receiving cancer chemotherapy. ORAI Srle~. OH \I. MFD ORAI PATHOL 48: 2 l-28, 1979. 13. Lindquist SF, Hickey AJ, Drane JP: Etfect of oral hygiene on stomatitis in patients receiving cancer chemotherapy. J Prosthet Dent 40: 312-314, 1978. 14. Beck S: Impact of a systematic oral care protocol on stomatitis after chemotherapy. Cancer Nurs 2: IX+-190, 1979. 15. Meyer JD, Flournoy N, Thomas EO: Infection with herpes simplex virus and cell-mediated immunity after marrow transplant. J Infect Dis 142: 338-346. IOXO 16. Bader C, Crampacker CS, Schnipper l..F, li:~nstl B, Clark JE, Arndt K, Freedberg 1.M: The natural hi,itor\ of recurrent facial oral infection with herpes simplex virs. J Infect Dis 13: 8Y7-905, 197X. 17. Goldman H. Mander M: Physician’s guide IC) dtscases of the oral cavity, Oradell. N.J.. 1982. Medical Economics Company. 18. lrutsu K, Schubert M, Shulman H, Obcrg Y, Sullivan K, Rice J, Morton T, Truelove E: Salivary changes in sraft versus host dlscasc (GVtiD). (/\bstr. 536). .I Dent Kc, 59: 101. 19X0.
Reprint reqursls lo. Dr. Bradley G. Seto Hospital Dental Service Room 13-089 UCLA Center for the Health 10833 Lx Conte Ave. Los Angeles, CA 90024
Sciences
THE TRANSPLANTATION
BIOLOGY
PROGRAM.
lJCL.4
Thirty patients who received bone marrow transplantation treatment from HLA identical sibling donors for immunologic and malignant diseases were studied. In essentially all of the patients oral changes developed during the first 30 days following transplant. Oral symptoms frequently constituted the major complaints of the patients during the follow-up period. The oral changes included mucositis, xerostomia. pain, and bleeding. Mucositis was more severe and of longer duration when associated with herpes simplex infections and when optimal oral hygiene was not maintained. Xerostomia which accompanies engraftment was an early sign of acute graft-versus-host disease. A nonbrushing method of oral hygiene was effective in reducing the severity and duration of mucositis. This technique offers a short-term alternative to brushing in pancytopenic patients who are susceptible to bleeding or trauma. (ORAL SURG. ORAL MED. ORAL PATHOL. 60~493-497, 1985)
B one marrow transplantation is an effective treat-
ment for immunologic and malignant diseases.’This procedure is frequently associated with a number of complications in the oral cavity, including mucositis, xerostomia, parotitis, pain, and bleeding.* Oral complications can be the major symptoms for patients receiving combined chemotherapy and irradiation.3 These effects are induced by the chemotherapy and irradiation conditioning treatment given prior to transplantation or by infection, graft-versus-host disease, or immunosuppressive treatment (methotrexate) following transplant.*v4 The purpose of this article is to analyze the oral changes that are seen during the first 30 days following treatment with bone marrow transplantation. PATIENTS AND METHODS
Patients receiving bone marrow transplantation from HLA-A,B,C, and D identical sibling donors at the UCLA Transplantation Biology Unit from March, 1981, to March, 1983, were included for study.
This study was supported in part by Grants CA 23175 from the National Cancer Institute and RR 865 from the United States Public Health Service.
Pretronsplant treatment
chemotherapy
and radletien
Patients received cyclophosphamide (60 mg/kg) intravenously on days -3 and -4 followed by totalbody irradiation, 10 Gy as a single fraction or 11.25 to 13.2 Gy in five to eight fractions from a %obalt source at a dose rate of 5 to 7 cGy/minute. Bone marrow cells (1 to 4 X lO*/kg) were infused intravenously on day 0. Methotrexate was administered following transplant to modify or prevent graftversus-host diseasein a dose of 15 mg/m* on day +l and 10 mg/mm* on days +3, +6, and +I1 and weekly thereafter to day +102. Supportive
care
Patients received oral nonabsorbable antibiotics from the start of the conditioning treatment to the recovery of the granulocytes (>O.S X log/liter). The antibiotics included vancomycin, 500 mg, and polymyxin B, 100 mg orally, three times per day and nystatin suspension, 10 X lo6 units to gargle and swallow every 4 hours, and nystatin oral troches, 100,000 units orally every 4 hours. Granulocytopenic patients with fever or documented bacterial infection received a combination of broad-spectrum antibiotics (moxalactam with either pipericillin or amikacin).5 Patients with suspectedor 493
494
Set0 et al.
WE/Platelet
Oral Surg. November, 1985
vs Mucositis
-
WBC
Fig. 1. Inverse relationship of mucositis incidence to white blood cell and platelet counts.
documented fungal infections were treated with amphotericin B. Patients with localized herpes simplex oral infections did not receive antiviral treatment; those with severe, progressive herpes simplex infections received acyclovir. Patients who had acute graft-versus-host disease (GVHD) received high-dose methylprednisolone (1 gram/day) for 3 days followed by prednisone (100 mg/day), which was tapered with reduction of clinical manifestations of GVHD. Oral/dental
evaluation
ized cleaning of oral hard and soft tissues. A saline rinse completed the oral care. The patient was allowed to use small amounts of mouthwash in the final rinse for flavoring. The quantity of oral debris was determined by visual examination and categorized by the following criteria: Excellent. Observable plaque/debris covering 0% to 10% of hard and soft tissues. Good. Observable plaque/debris covering 10% to 25% of hard and soft tissues. Fair. Observable plaque/debris covering 25% to 75% of hard and soft tissues. Poor. Observable plaque/debris covering on >75% of hard and soft tissues. Mucositis was defined as any change in the mucosa of the oral cavity, including erythema, ulceration, erosion, and sloughing. All patients in whom ulcerations developed underwent swab cultures for bacterial, fungal, and viral organisms. The grading of the mucositis was as follows: Grade I. Localized erythema only, with no pain. Grade ZZ. Generalized erythema without pain or localized erythema or ulcers with mild pain. Grade ZZZ.Multiple ulcers or generalized erythema with moderate pain. Grade IV. Generalized erythema or ulcers with moderate to severe pain. Pain was assessedby the subjective comments of the patient. Mild pain did not require analgesics. Moderate pain was relieved by nonnarcotic oral analgesics. Severe pain may or may not have been relieved by parenteral narcotic analgesics, including Dilaudid and methadone. Patients with moderate to severe pain also received topical anesthetics such as viscous 2% lidocaine or Hurricane* gel. The oral assessmentinformation was collected and recorded by a single investigator to minimize variance in data collection. The data were analyzed by the chi-square test. Significance was accepted if p < 0.05.
Patients were analyzed twice weekly from day -7 to day +30 following transplant. Initial visual examinations and panoramic radiographs evaluated the oral health of each patient, special care being taken to identify acute odontogenic infections. If pain, swelling, and purulence associated with infections were present, the offending teeth were removed; otherwise, teeth were maintained. Subsequent oral changes, such as pain, xerostomia, mucositis, and bleeding, were related to the patient’s peripheral blood counts, maximum daily temperature, the presence of documented infections, and graft-versus-host disease. Brushing and flossing were discontinued when the granulocyte and/or platelet counts were below 0.5 X 109/1 and 20 X 109/1, respectively. An alternative oral hygiene method was recommended for use four times daily. Cotton swabs saturated with a dilute hydrogen peroxide solution (one part 3% peroxide: one part saline) were used for debridement of the teeth, and Toothettes* were used for general-
Thirty patients were included for study. There were thirteen female patients (43%) and 17 male patients (57%). The median age was 27.4 years (females 30.4, range 15 to 48 years; males 23.4, range 12 to 44 years). The diagnoses for treatment are listed in Table I. Twenty-nine of thirty patients (97%) developed mucositis. Erythema, superficial mueosal whitening,
*Toothette-soft, sponge, disposable tooth-cleaning brand, Inc., Willoughby, Ohio.
*Hurricane gel-ethyl aminobenzoate in a water-soluble ene glycol base, Beutlich, Inc., Chicago, Ill.
device, Hal-
RESULTS
polyethyl-
Oral mucositis in bone marrow transplantation
Volume 60 Number 5 fable
I. Diagnosis for bone marrow transplantation Acute lymphocytic leukemia Chronic myelogenous leukemia Acute myelogenous leukemia Aplastic anemia Acute myelomonocytic leukemia Metastatic testicular carcinoma
11 8 6 3 1 -i 30
bilateral parotitis, and mild to moderate xerostomia developed initially. In the more severe cases, there was denudation, ulcerations, or mucosal sloughing. Mucositis that began or worsened after day +7 was characterized by erythematous eroded, ulcerated, and/or pseudomembranous lesions. The number of patients experiencing mucositis on each day after transplant rose from day +3, reached a maximum at days + 12 to + 14, and steadily declined thereafter. The median day of resolution was day +19.4 (range, +8 to +30). The rise in the incidence of mucositis followed the initial drop in the circulating granulocyte count by approximately 4 to 5 days and coincided with the initial day when the circulating granulocyte count was below 0.5 X 109/1 (Fig. 1). The duration of mucositis was longer in the poor and fair oral hygiene groups (average duration, 11.O and 10.7 days, respectively) than in the good and excellent oral hygiene groups (average duration, 6.3 and 5.7 days, respectively) (p < 0.05). The severity of mucositis also decreasedwith improvement in oral hygiene from the poor to the excellent groups but were not statistically significant (Table II). Streptococcus viridans and coagulase-negative Staphylococcus were identified by culture in all patients and were considered the normal flora for this group. In the patients in whom mucositis developed, 97% (28 of 29) had other organisms w&e also isolated (Table III). No correlations seen between mucositis and the bacterial pathogens isolated. Candida albicans was the most common pathogen isolated and generally appeared as a superficial plaque of the oral soft tissue. The normal white color was often stained by the yellowish nystatin suspension. The underlying mucosa would be erythematous, painful, and eroded. However, bleeding was not a problem in the oral Candida infections. No relationship to the duration of mucositis could be documented, since many patients without mucositis also harbored the fungus. The herpes simplex virus was the second most common pathogen isolated and was associatedwith a longer duration of mucositis than the other microor-
Table
495
II. Oral hygiene versus mucositis
POW Fair Ciood Excellent
8 12 7 3
3.13 2.02
2.43 I .67
I I.0 10.7 6.3 s.7
Table III. Microbial isolates identified in patients receiving bone marrow transplantation Streptococcus viridans Staphylococcus (coagulase-negative) Candida species
Herpes simplex Other streptococcus species Neisseria species Corynebacterium species Staphylococcus Morexella Eikonella Acinetobacter Enterobacfer
aureus
100% (30/30) 100% (30/30) 47% (14/30) 37% (11/30) 30% (9/30) 23% (7/30) 23% (7/30) 10% (3/30) 3% (l/30) 3% (l/30) 3% (l/30) 3% (l/30)
ganisms listed on Table III (median, 18 days compared to the median for other organisms, ranging from 10.4 to 14.8 days). The herpes simplex infections began as superficial vesicles or pseudomembranous ulcers of any oral soft tissue, including nonkeratinized mucosa, The lesions ranged in size from punctate vesicles to as large as 1.5 cm with a necrotic membrane or crust. The borders were erythematous but nonindurated. Most herpetic ulcers began as a single lesion or a small locus of lesions. Subsequently, multiple ulcers would frequently follow on other tissues. Bleeding was also seen from herpetic oral ulcers when the platelet count was below 20 X 1Og/1. However, prolonged bleeding generally occurred in patients with platelet counts below 10 X log/l. If superinfection did not occur, healing would coincide with recovery of granulocytes. If engraftment was delayed beyond day +2 1, superinfection was eminent and progressive enlargement would often occur despite systemic antimicrobial therapy, topical or intravenous acyclovir, and local care. In 50% (15/30) of the patients acute graftversus-host disease (GVHD) developed during the follow-up period (median day, +24) after transplant. The dental symptoms included xerostomia, erythema, diffuse denudation of the mucosa, and pain. The progression of the xerostomia after day + 14 was an early symptom of acute GVHD and corresponded to the early signs of engraftment. Denudation was
496
Set0 et al.
generalized, mostly affecting the buccal mucosa and lips; the more severe cases involved the keratinized oral tissues. The oral involvement of GVHD did not correlate well with its severity in other tissues, such as the skin, liver, or gastrointestinal tract. DISCUSSION
Nearly all patients will develop mueosal changes following allogenic bone marrow transplantation ranging from mild, symptomless erythema to painful, generalized ulcerations.*s6Mucositis will develop concomitant with the decline in the peripheral leukocyte and platelet counts following intensive chemoradiotherapy conditioning treatment. Herpes simplex is the causative agent in many instances of oral mucositis, especially when ulcerations are present. Association with herpes will prolong oral healing despite optimal oral hygiene. However, effective removal of oral debris will decreasethe severity and duration of the mueositis. This suggests that colonization by microorganisms exacerbates the oral mucositis produced by chemoradiotherapy or viruses. Oral mucositis during bone marrow transplantation is probably multifactorial in origin, resulting from the toxicity of chemotherapy, radiotherapy, infection, graft-versus-host disease, or trauma.2*3s‘-I* The early effects are related to the chemoradiotherapy on the nonkeratinized mueosal surfaces3 and may progress to include the keratinized mucosa. When trauma or infection contributes to mueositis, keratinized and/or nonkeratinized tissues may be involved. These also tend to occur later in the course of treatment. It is likely that the pathogenesis of mucositis is at least partly related to a microbial interaction with the oral tissues.” This is supported by the relationship of decreasing severity and duration of mucositis to improvement in the quality of oral hygiene.‘3z’4 Our alternative nonbrushing oral hygiene technique was effective in decreasing the duration and severity of mueositis, indicating that this is a reasonable short-term alternative to brushing in pancytopenic patients. However, further study is needed to evaluate the potential risks and benefits of the various nonbrushing oral hygiene methods as compared to toothbrushing for patients receiving bone marrow suppressive therapy. C. albicans is the most commonly seen pathogen associated with bone marrow transplantation.2 Candida is present despite prophylactic use of nystatin and is most commonly seencolonizing the dorsum of the tongue, palate, and bueoal mucosa. However, effective oral care will prevent or decrease mueosal changes resulting from vegetations of C. albicans.
Oral Surg. November. 19XS
Herpes simplex is the major cause of oral ulcerations in patients receiving bone marrow transplants. These Occurrencesprobably represent reactivation of latent infections. The actual incidence of herpes mucositis is probably higheri than documented by culture because many of the ulcerations that appeared consistent with the clinical presentation of the virus were not confirmed by culture. This could be due to the decreasing probability of identifying the virus by culture for each day following initial presentation of the 1esiorP and the fact that few lesions were cultured within 24 hours of initial symptoms. The expected clinical course of recurrent herpes simplex infections for nonimmunocompromised hosts” was not seen in this patient population. First, the herpes infections were self-perpetuating; the initial infection would begin with one or a few lesions in a single region and then progress to involve multiple areas over a period of a few days. Recurrent infections in noneompromised patients are typically limited to a single ulcer or region. Second, the herpetic vesicles were not limited to the keratinized tissues but involved any mucosal surface of the oral cavity. Finally, the lesions did not heal in the normal 7 to 10 days unless engraftment occurred. The relationship of herpes simplex to an increase in the severity and duration of the mucositis is twofold. The discomfort associated with a herpetic mucositis prevented the patient from maintaining adequate oral hygiene, thus increasing the severity and duration of mucositis.13+‘4Herpes simplex vesicles also appear to cause deeper injury to mucosal tissues than the chemoradiotherapy. In approximately one half of the patients receiving allogenic bone marrow transplantation acute graftversus-host disease (GVHD) involving the oral cavity will develop during the first 4 weeks after bone marrow transplantation.’ One of the early signs seen in the oral cavity is the progression of xerostomia with engraftment. The dental professional can provide only palliative support for pain (topical anesthetics) and xerostomia (artificial saliva substitutes) and recommend oral hygiene procedures that are useful when pain and bleeding limit brushing and flossing. Good dental follow-up and oral hygiene, including daily fluoride applications, are important to minimize risk of persistent xerostomia’* leading to rampant decay. REFERENCES 1. Champlin RI?, Gale RP: The role of bone marrow transplantation in the treatment of hematologic malignancies and solid tumors: a critical review of syngeneic, autologous and allogenit transplants. Cancer Treat Rep 68: 145-61, 1984.
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2. Dreizen S, McCredie KB, Dicke KA, Zander AR, Peters LJ: Oral complications of bone marrow transplantation. Postgrad Med 66: 87-193, 196. 1979. 3. Laskiewicz BM: The management of patients undergoing synchronous combined chemotherapy and radiotherapy. J Laryngol Otol 96: 265-275, 1982. 4. Schubert MM. Sullivan KM, Izutsu KT, Truelove EL: Oral complications of bone marrow transplantation. In Peterson DF, Sonis ST (editors): Oral complications of cancer chemotherapy, The Hague. 1983, Martinus Nijhoff Publisher, pp. 93-l 12. 5. Winston DJ, Barnes RC, Ho WG, et al: Moxalactam plus pipercicillin versus moxalactam in febrile granulocytopknic patients. Am J Med 77: 442-450. 1984. 6. Lasser SD, Camitta BM. Needleman HL: Dental management of patients undergoing bone marrow transplantation for aplastic anemia. 0~41. SLRG ORAL MED ORAL PATHOL 43: 181-189, 1977. 7. Dreizen S, Bodey GP, Rodriguez V: Oral complications of cancer chemotherapy. Postgrad Med 58: 78-82, 1975. 8. Guggenheim J, Verbin RS, Appel BN, Schmutz J: Clinicopathologic effects of cancer chemotherapeutic effects on human buccal mucosa. ORAL SURG ORAL MED OR,~L PATH~L 44: 58-63. 1911. 9. Bottomley WK, Perlin E, Ross GR: Antineoplastic agents and their oral manifestations. ORAL SURG ORAL MED ORAL PATtior 44: 527-534, 1977. IO. Dreizen S: Stomatotoxic manifestations of cancer chemotherapy. J Prosthet Dent 40: 650-655, 1978. Il. Shepherd JP: Management of the oral complications of leukemia ORAL SURG ORAI. MED ORAL PATHOL 45: 543-548, 1978.
12. Lockhart PB, Sonis ST: Relationship of or;!/ complications to peripheral blood leukocyte and platelet c’ounts tn patients receiving cancer chemotherapy. ORAI Srle~. OH \I. MFD ORAI PATHOL 48: 2 l-28, 1979. 13. Lindquist SF, Hickey AJ, Drane JP: Etfect of oral hygiene on stomatitis in patients receiving cancer chemotherapy. J Prosthet Dent 40: 312-314, 1978. 14. Beck S: Impact of a systematic oral care protocol on stomatitis after chemotherapy. Cancer Nurs 2: IX+-190, 1979. 15. Meyer JD, Flournoy N, Thomas EO: Infection with herpes simplex virus and cell-mediated immunity after marrow transplant. J Infect Dis 142: 338-346. IOXO 16. Bader C, Crampacker CS, Schnipper l..F, li:~nstl B, Clark JE, Arndt K, Freedberg 1.M: The natural hi,itor\ of recurrent facial oral infection with herpes simplex virs. J Infect Dis 13: 8Y7-905, 197X. 17. Goldman H. Mander M: Physician’s guide IC) dtscases of the oral cavity, Oradell. N.J.. 1982. Medical Economics Company. 18. lrutsu K, Schubert M, Shulman H, Obcrg Y, Sullivan K, Rice J, Morton T, Truelove E: Salivary changes in sraft versus host dlscasc (GVtiD). (/\bstr. 536). .I Dent Kc, 59: 101. 19X0.
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