VARIABLES PREDICTING ORAL MUCOSAL LESIONS IN ALLOGENIC BONE MARROW RECIPIENTS Torsten Mattsson, DDS, Anders Heimdahl, DDS, PhD, Goran Dahllof, DDS, PhD, Bo Nilsson, MD, PhD, Berit Lonnqvist, MD, and Olle Ringden, MD, PhD
One hundred and forty-eight (72%) of 205 allogenic bone marrow transplant recipients developed rnucosal lesions in the oral cavity during the aplastic period after transplantation. Lesions were most frequent 8 to 9 days after transplantation. Factors that correlated with the development of mucosal lesions after univariate and multivariate analysis were a marrow cell dose of 0.5 X lO'/L. No conclusions discerning the difference in the effect of the prophylactic decontamination regimens were made due to lack of placebo controls and randomization. When parenteral antimicrobials had to be used because of systemic infection or fever of unknown origin, an aminoglycoside in combination with co-trimoxazole was generally used. When microbiological identification and susceptibility tests were available, antimicrobial agents directed specifically against the infectious microorganism were instituted. If possible, agents with a minimal effect on the endogenous anaerobic microflora were used to avoid interference with the decontamination regimes." When herpes simplex virus (HSV) infection was diagnosed or suspected, intravenous treatment with acyclovir was instituted. Marrow Aspiration and Infusion. The total number of mononuclear cells per liter in the aspirated blood and marrow were calculated. Aspiration and infusion procedures were performed in accordance with the method described by Thomas et a1 1970.13 The number of bone marrow cells given to the patients ranged from 0.1 x 10' to 8 x 10'kg body weight. The patients could consequently be divided into a low-bone-marrowcell-dose (BMC) group receiving 0.2 x 1 0 9 / ~ ) .
STATISTICAL ANALYSIS
Conceivable potential prognostic factors for the development of mucosal lesions were first analyzed univariantly. Because of the design of the statistical analysis, each patient was recorded as having 1 or more lesions or no lesions. Statistically significant factors in the univariate analyses were then further subjected to a multivariate logistic regression analysis. The analysis permitted the patient to be recorded only once irrespective of the number of lesions found. This multivariate analysis provides a method for studying the simultaneous effects of several factors important for the development of oral lesions.16 RESULTS Univariate Analysis. Ten conceivable potential prognostic variables for the development of oral lesions were analyzed univariatly . Six factors were found to have a statistically significant correlation ( p < 0.01) to the development of oral mucosal lesions. These were recipient age 2 1 3 years, conditioning with TBI, GVHD-prophylaxis including Mtx, BMC 14 days Acute GVHD grade Il-IV Septicemia Recipient HSV-seropositive prior to BMT
No. patients (%) with oral mucosal lesions (n = 148/205)
No. patients (%) without oral mucosal lesions (n = 57/205)
OR
120/148 (81) 107/148 (72) 108/148 (73) 138/148 (93) 112/148 (76) 115/148 (78) 84/148 (57) 107/148 (72) 531148 (36) 127/148 (86)
27/57 (47) 36/57 (63) 46/57 (81) 45/57 (79) 34/57 (60) 31/57 (54) 18/57 (32) 47/57 (82) 12/57 (21) 38/57 (67)
3.72' 1.04 1.18 3.68' 2.1 l t 4.32* 2.92* 1.83 2.09 3.36t
OR, odds ratio, relative rfsk 'p 13 y Conditioning with TBI GVHD prophylaxis including Mtx BMC dose 14 d Recipient HSV-seropositive prior to BMT
Episodes of different mucosal lesions
No. patients with oral mucosal lesionsfn = 148)
No. episodes with oral mucosal lesions fn = 188)
Cytotoxic n=79
Infectious
Traumatic
GVHD
n=69
n=12
n=13
Hernorragic n=15
120 138 108
147 181 135
66 76 63
52 66 45
7 11 6
9 13 8
13 15 13
115
147
63
53
7
9
15
84 127
110 81
53 32
37 45
7 2
7 1
6
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the seropositive patients not receiving acyclovir. The fungal lesions were observed in severely compromised patients who suffered from invasive candida and/or bacterial infections. Traumatic lesions (Table 4) occurred in relation t o accidental mucosal biting or sharp teeth. In one patient an epileptic attack was the reason. Lesions due to acute GVHD (Table 4) were bilateral lesions in the buccal mucosa or the lips with an atrophic surface. Recognition of these lesions was always made in the final part of the aplastic period (>lo days after BMT). Hemorragic lesions (Table 4) due to low numbers of platelets were observed as spontaneous mucosal or gingival bleeding occurring when the number of platelets was below 8 x 109/L. Healing of lesions caused by cytotoxic reactions, infection, trauma, and low platelet levels was coincidental with time for engraftment and disappeared when the WBC increased to more than 0.2 x 109/L and number of platelets increased to >8 x 109/L. Lesions due to GVHD were aggravated when engraftment was observed and healing was associated with successful treatment of the generalized acute GVHD. DISCUSSION
The choice of variables in this study was based on the clinical factors associated with complications during BMT17-19 and analyzed against the etiological classification of oral mucosal lesions described in the present study. The results showed that the bone marrow cell dose (BMC) was one important factor for the development of oral lesions. The marrow cell dose also seems to be important for several other types of complications in the BMT recipient. Thus, we have previously reported that patients with a low BMC had an increased risk of dying from GVHD,20of having infection with cytomegalovirus,21of having disseminated candida infection,22 and of having an overall increased risk of bacterial and fungal infe~ti0ns.l~ We speculate that a high BMC given at the time of transplantation may help the patient to get over the first critical days of leukopenia. In earlier studies, as well as in the present study, multivariate analysis showed that BMC was independent of recipient age, which otherwise may have explained the role of the high marrow cell dose. Younger patients may often get a higher BMC even if this was not significant in our patients. It is also accepted that young patients have a better survival after BMT.23
228
Oral Lesions in Bone Marrow Recipients
The present study confirms earlier observations that a high BMC is related to less-frequent side effects. Thus, the International Bone Marrow Transplant Registry reported that in patients with acute myeloid leukemia a low marrow cell dose was associated with early death after BMT.24 In a study in Seattle, it was observed that patients with severe aplastic anemia given a low BMC had an increased risk of graft rejection.25 In the present study, not only a low BMC but also the length of the aplastic period was observed to be of importance for the development of oral lesions. There was, however, no correlation between BMC and the length of the aplastic period, which might have been expected. Thus, the risk of oral lesions during the aplastic period due to a low BMC increased if the aplastic period was more than 14 days. It is known from studies of patients treated with radiotherapy for head and neck tumors that irradiation is harmful to mucosal tissues. In such radiotherapy the radiation dose is high (>60 Gy) and localized to a restricted area of the oral tissues. In the present study we also observed that TBI in doses of 7.5 or 10 Gy contributed significantly to damage of the oral mucosa. Patients who were HSV-1 seropositive before BMT had a greater risk of developing oral lesions compared with HSV-1 seronegative patients because of reactivation of HSV-1. This was even more obvious if the recipient did not receive antiviral prophylaxis. The importance of the prophylaxis against HSV with acyclovir has been further described in a study in 1985 by Lundgren et a1.26 GVHD-prophylaxis including Mtx has been suggested to contribute to mucosal lesion^.^^.^^ Even though use of Mtx was significantly correlated with oral mucosal lesions in the univariate analysis, this could not be confirmed in the multivariate analysis. If Mtx contributed to the development of cytotoxic lesions in the present study, it was either of minor importance or was not possible to detect because of a multivariable connection with other important factors. In conclusion, this study showed that risk factors for the development of oral lesions during the aplastic period after BMT was if patients received a low marrow cell dose
One hundred and forty-eight (72%) of 205 allogenic bone marrow transplant recipients developed rnucosal lesions in the oral cavity during the aplastic period after transplantation. Lesions were most frequent 8 to 9 days after transplantation. Factors that correlated with the development of mucosal lesions after univariate and multivariate analysis were a marrow cell dose of 0.5 X lO'/L. No conclusions discerning the difference in the effect of the prophylactic decontamination regimens were made due to lack of placebo controls and randomization. When parenteral antimicrobials had to be used because of systemic infection or fever of unknown origin, an aminoglycoside in combination with co-trimoxazole was generally used. When microbiological identification and susceptibility tests were available, antimicrobial agents directed specifically against the infectious microorganism were instituted. If possible, agents with a minimal effect on the endogenous anaerobic microflora were used to avoid interference with the decontamination regimes." When herpes simplex virus (HSV) infection was diagnosed or suspected, intravenous treatment with acyclovir was instituted. Marrow Aspiration and Infusion. The total number of mononuclear cells per liter in the aspirated blood and marrow were calculated. Aspiration and infusion procedures were performed in accordance with the method described by Thomas et a1 1970.13 The number of bone marrow cells given to the patients ranged from 0.1 x 10' to 8 x 10'kg body weight. The patients could consequently be divided into a low-bone-marrowcell-dose (BMC) group receiving 0.2 x 1 0 9 / ~ ) .
STATISTICAL ANALYSIS
Conceivable potential prognostic factors for the development of mucosal lesions were first analyzed univariantly. Because of the design of the statistical analysis, each patient was recorded as having 1 or more lesions or no lesions. Statistically significant factors in the univariate analyses were then further subjected to a multivariate logistic regression analysis. The analysis permitted the patient to be recorded only once irrespective of the number of lesions found. This multivariate analysis provides a method for studying the simultaneous effects of several factors important for the development of oral lesions.16 RESULTS Univariate Analysis. Ten conceivable potential prognostic variables for the development of oral lesions were analyzed univariatly . Six factors were found to have a statistically significant correlation ( p < 0.01) to the development of oral mucosal lesions. These were recipient age 2 1 3 years, conditioning with TBI, GVHD-prophylaxis including Mtx, BMC 14 days Acute GVHD grade Il-IV Septicemia Recipient HSV-seropositive prior to BMT
No. patients (%) with oral mucosal lesions (n = 148/205)
No. patients (%) without oral mucosal lesions (n = 57/205)
OR
120/148 (81) 107/148 (72) 108/148 (73) 138/148 (93) 112/148 (76) 115/148 (78) 84/148 (57) 107/148 (72) 531148 (36) 127/148 (86)
27/57 (47) 36/57 (63) 46/57 (81) 45/57 (79) 34/57 (60) 31/57 (54) 18/57 (32) 47/57 (82) 12/57 (21) 38/57 (67)
3.72' 1.04 1.18 3.68' 2.1 l t 4.32* 2.92* 1.83 2.09 3.36t
OR, odds ratio, relative rfsk 'p 13 y Conditioning with TBI GVHD prophylaxis including Mtx BMC dose 14 d Recipient HSV-seropositive prior to BMT
Episodes of different mucosal lesions
No. patients with oral mucosal lesionsfn = 148)
No. episodes with oral mucosal lesions fn = 188)
Cytotoxic n=79
Infectious
Traumatic
GVHD
n=69
n=12
n=13
Hernorragic n=15
120 138 108
147 181 135
66 76 63
52 66 45
7 11 6
9 13 8
13 15 13
115
147
63
53
7
9
15
84 127
110 81
53 32
37 45
7 2
7 1
6
Oral Lesions in Bone Marrow Recipients
HEAD & NECK
May/June 1991
1
227
the seropositive patients not receiving acyclovir. The fungal lesions were observed in severely compromised patients who suffered from invasive candida and/or bacterial infections. Traumatic lesions (Table 4) occurred in relation t o accidental mucosal biting or sharp teeth. In one patient an epileptic attack was the reason. Lesions due to acute GVHD (Table 4) were bilateral lesions in the buccal mucosa or the lips with an atrophic surface. Recognition of these lesions was always made in the final part of the aplastic period (>lo days after BMT). Hemorragic lesions (Table 4) due to low numbers of platelets were observed as spontaneous mucosal or gingival bleeding occurring when the number of platelets was below 8 x 109/L. Healing of lesions caused by cytotoxic reactions, infection, trauma, and low platelet levels was coincidental with time for engraftment and disappeared when the WBC increased to more than 0.2 x 109/L and number of platelets increased to >8 x 109/L. Lesions due to GVHD were aggravated when engraftment was observed and healing was associated with successful treatment of the generalized acute GVHD. DISCUSSION
The choice of variables in this study was based on the clinical factors associated with complications during BMT17-19 and analyzed against the etiological classification of oral mucosal lesions described in the present study. The results showed that the bone marrow cell dose (BMC) was one important factor for the development of oral lesions. The marrow cell dose also seems to be important for several other types of complications in the BMT recipient. Thus, we have previously reported that patients with a low BMC had an increased risk of dying from GVHD,20of having infection with cytomegalovirus,21of having disseminated candida infection,22 and of having an overall increased risk of bacterial and fungal infe~ti0ns.l~ We speculate that a high BMC given at the time of transplantation may help the patient to get over the first critical days of leukopenia. In earlier studies, as well as in the present study, multivariate analysis showed that BMC was independent of recipient age, which otherwise may have explained the role of the high marrow cell dose. Younger patients may often get a higher BMC even if this was not significant in our patients. It is also accepted that young patients have a better survival after BMT.23
228
Oral Lesions in Bone Marrow Recipients
The present study confirms earlier observations that a high BMC is related to less-frequent side effects. Thus, the International Bone Marrow Transplant Registry reported that in patients with acute myeloid leukemia a low marrow cell dose was associated with early death after BMT.24 In a study in Seattle, it was observed that patients with severe aplastic anemia given a low BMC had an increased risk of graft rejection.25 In the present study, not only a low BMC but also the length of the aplastic period was observed to be of importance for the development of oral lesions. There was, however, no correlation between BMC and the length of the aplastic period, which might have been expected. Thus, the risk of oral lesions during the aplastic period due to a low BMC increased if the aplastic period was more than 14 days. It is known from studies of patients treated with radiotherapy for head and neck tumors that irradiation is harmful to mucosal tissues. In such radiotherapy the radiation dose is high (>60 Gy) and localized to a restricted area of the oral tissues. In the present study we also observed that TBI in doses of 7.5 or 10 Gy contributed significantly to damage of the oral mucosa. Patients who were HSV-1 seropositive before BMT had a greater risk of developing oral lesions compared with HSV-1 seronegative patients because of reactivation of HSV-1. This was even more obvious if the recipient did not receive antiviral prophylaxis. The importance of the prophylaxis against HSV with acyclovir has been further described in a study in 1985 by Lundgren et a1.26 GVHD-prophylaxis including Mtx has been suggested to contribute to mucosal lesion^.^^.^^ Even though use of Mtx was significantly correlated with oral mucosal lesions in the univariate analysis, this could not be confirmed in the multivariate analysis. If Mtx contributed to the development of cytotoxic lesions in the present study, it was either of minor importance or was not possible to detect because of a multivariable connection with other important factors. In conclusion, this study showed that risk factors for the development of oral lesions during the aplastic period after BMT was if patients received a low marrow cell dose
