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Bone Marrow Transplantation, (1998) 22, 801–808 1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Oral health of children undergoing allogeneic bone marrow transplantation VS Lucas1, GJ Roberts2 and D Beighton3 Departments of 1Microbiology and 2Paediatric Dentistry, Eastman Dental Institute, University of London, and Maxillofacial and Dental Department, The Great Ormond Street Hospital For Children; and 3Joint Dental Research Unit, King’s College School of Medicine and Dentistry, London, UK Summary: The objective of this study was to investigate changes in the oral health of children undergoing allogeneic bone marrow transplantation. The study group comprised 23 children undergoing allogeneic bone marrow transplantation and their matched controls. The study group comprised 23 children undergoing allogeneic bone marrow transplantation and their matched controls. Measurements were taken of the mean decayed, missing and filled surfaces and the mean decayed, missing and filled teeth in both deciduous and permanent dentition at baseline, the mean bacterial plaque and gingival inflammation indices and mucositis at specific eventrelated times during the transplantation period, were measured. The number of decayed, missing and filled surfaces in deciduous teeth was significantly greater in the transplant children than the matched controls (P ⬍ 0.05) at baseline. There was a significant increase in both the mean bacterial plaque score for the deciduous teeth (P ⬍ 0.003) and the permanent teeth (P ⬍ 0.001) and the mean gingival inflammation score for the deciduous (P ⬍ 0.001) and the permanent teeth (P ⬍ 0.001), at 7 days post-transplantation. At 4 months post-transplantation the plaque and gingival inflammation score had returned to baseline levels. There were significantly increased mean bacterial plaque and gingival inflammation scores during the period of intense immunosuppression following allogeneic bone marrow transplantation. Keywords: dental caries; plaque; gingivitis; transplantation In children undergoing bone marrow transplantation chronically infected teeth, untreated or inadequately restored teeth can lead to serious systemic sequelae during the period of profound immunosuppression following the conditioning regimen.1,2 It is, therefore essential to remove all possible foci of infection in the mouth before the conditioning regimen and to start preventive dental care. This Correspondence: Dr VS Lucas, Department of Microbiology, Eastman Dental Institute, University of London, 256 Grays Inn Road, London WC1X 8LD, UK Received 9 April 1998; accepted 30 May 1998 includes effective tooth brushing to reduce the oral bacterial loading and fluoride supplements to reduce the incidence of dental caries. There are few data for dental disease in children undergoing bone marrow transplantation, but there have been a number of reports for children in remission from acute lymphoblastic leukemia (ALL) and long-term survivors of malignant disease. A high prevalence of untreated dental caries has been reported in children both before bone marrow transplantation3 and before starting chemotherapy.4 Other investigators found no difference in dental caries in children with ALL who were treated with three different modalities compared with the normal population.5 Conversely, the caries experience of a Finnish group of ALL children was significantly greater than that of the controls.6 The DMFT (decayed, missing and filled permanent teeth) was also increased in a group of 14–17-year-old adolescents who had been treated with chemotherapy for cancer and survived for a median period of 9 years.7 A different group of children in remission from ALL was found to have a significantly lower number of decayed deciduous teeth and extracted permanent teeth than the controls.8 Thirty children with ALL were followed-up between 6 months and 1 year during chemotherapy for ALL during which time no carious lesions developed.9 Seven children, from a group of 22, developed new carious lesions 1 year after bone marrow transplantation but there was no significant difference between those who underwent pre-transplant conditioning with TBI and chemotherapy and chemotherapy only.10 Nineteen children who were conditioned with TBI and chemotherapy for bone marrow transplantation and a further 57 children treated with chemotherapy were followed-up 3 years post-transplantation and posttreatment. There were no significant differences in the caries experience for both deciduous and permanent teeth.11 Results from a more recent study demonstrated a higher prevalence of untreated disease and developmental defects in long-term survivors.12 No differences were found in the plaque and gingival index of ALL children and those suffering from other malignancies in remission.7,8 Other workers found no difference in the gingival health but an increased plaque score in children in remission.13 Children below the age of 5 years receiving 2400 cGy of cranial irradiation for treatment of ALL had higher plaque and periodontal index scores than those treated with chemotherapy alone or with Dental caries, gingival health and transplantation VS Lucas et al 802 chemotherapy and 1800 cGy of cranial irradiation.5 During a 2-year prospective follow-up of 214 children suffering from cancer14 the children with leukaemia were found to have a significantly greater gingival inflammation score than those with sarcomas or other solid tumours. The effects of chemotherapy, particularly methotrexate or chemotherapy and irradiation together are well documented.4,15–18 These cytotoxic effects lead to changes in local immunity and increased accumulation of micro-organisms on the mucosal surface.19 The integrity of the surface layer of the mucosa may be impaired and this together with increased levels of bacterial plaque and gingival inflammation facilitates entry of commensal bacteria into the systemic circulation. The purpose of this study was to assess changes in the oral health at specific event-related times during the transplantation period. Patients and methods Patients Twenty-three children undergoing allogeneic bone marrow transplantation from the Great Ormond Street Hospital for Children and the Royal Marsden Hospital took part in the study. They were matched for age, gender, ethnicity and social class with healthy children from schools in the Merton and Sutton Area Health Authority. There were 16 boys and seven girls in each group. The mean age of the bone marrow transplant group was 8.3 years (s.d. 1.9) and of the matched control group was 8.4 years (s.d. 1.8). Medication The conditioning regimen for the bone marrow transplant (BMT) recipients comprised 12–14.4 Gy of fractionated total body irradiation over 3 to 5 days, followed by cyclophosphamide 60 mg/kg with mesna. Graft-versus-host disease prophylaxis was with methotrexate 10 mg/m2 on designated days and cyclosporin, starting dose 1.5 mg/kg. Five children receiving matched but unrelated allografts were T-cell depleted with monoclonal antibody, in vivo and the donor bone marrow in vitro. Oral examination Oral examinations were carried out on three separate occasions during the transplantation period. These were: (1) baseline, that is, before the conditioning regimen; (2) 7 days post-transplantation, neutrophil count ⬍108/l; (3) 119 days post-transplantation. The matched control children were examined on two occasions 118 days apart. All oral examinations were carried out in the same manner using a disposable mirror and a Duracell junior torch as light source. Indices were recorded for dental caries, bacterial dental plaque and gingival inflammation using a modification of the method of O’Leary20 at the specified times for the transplant and control children. The presence of mucositis and any other lesions was also recorded. Dental caries All the teeth were examined for caries at baseline only, using the World Health Organisation criteria.21 Indices were recorded as the dmfs/dmft (decayed, missing and filled surfaces of the deciduous teeth/decayed missing and filled deciduous teeth) and the DMFS/DMFT (decayed, missing and filled surfaces of the permanent teeth/decayed missing and filled permanent teeth). The amount of untreated disease was calculated as a percentage of the total dental caries score for each group of children. The percentage of untreated disease includes caries and recurrent caries affecting existing restorations. Bacterial dental plaque Four gingivally related quadrisections of each tooth (mesiobuccal, distobuccal, distolingual and mesiolingual) were visually examined for bacterial dental plaque deposits to give the plaque score. The proportion of tooth quadrisections which had discernible deposits of bacterial dental plaque was calculated as a percentage of the total number of deciduous and permanent tooth quadrisections present.22 Gingival inflammation The gingivae were visually examined for gingival inflammation, determined by the presence or absence of reddened gingival tissue, using a simplified gingival index based on the number of tooth quadrisections with associated gingival inflammation. The proportion of tooth quadrisections with associated gingival inflammation was calculated as a percentage of the total number of deciduous and permanent tooth quadrisections present. It was not possible to use more detailed plaque and gingival indices. Very young children, particularly when unwell, are unable to co-operate for the period of time necessary for more detailed examinations. In addition, examination of the gingival margin and crevice with a probe, albeit a blunt probe, was not permitted in immunocompromised and thrombocytopenic patients because of the risk of bleeding and associated bacteraemia. Mucositis This was recorded using the method of Seto et al:16 grade 1: localized erythema only, with no pain; grade 2: generalized erythema without pain or localized erythema or ulcers with mild pain; grade 3: multiple ulcers or generalized erythema with moderate pain; grade 4: generalized erythema or ulcers with moderate to severe pain. Statistical analysis The data were tested for normality using the Shapiro–Wilks test.23 The data were not normally distributed and non-parametric tests were used to make comparisons both within each group of children (Wilcoxon matched pairs analysis) and between the study and control group (Mann–Whitney test). Dental caries, gingival health and transplantation VS Lucas et al Results the DMFS or DMFT between the BMT and control children (Table 1). Reproducibility of dental indices Studies were completed to assess the reproducibility of recording indices for caries, bacterial dental plaque and gingival inflammation and the Kappa value calculated.24 Dental caries Ten full arch toothblocks were examined by the main examiner (VSL) and a paediatric dentist (GJR) using the World Health Organisation criteria to assess inter-examiner agreement.21 Both examiners had been calibrated for previous dental health surveys. The same toothblocks were examined again after a 2 week period by the main examiner to assess intra-examiner agreement. The results are as follows:Inter-examiner agreement = 96.43% Inter-examiner agreement = 97.47% Kappa = 0.9448 Kappa = 0.9609 Bacterial dental plaque A visual plaque score was carried out on 10 children by both examiners. Inter-examiner agreement = 90.81% Kappa = 0.8322 Untreated caries: There was a greater percentage of untreated caries in the matched control children although this was not significantly different from the BMT children (Table 2). There was no difference in the number of restored deciduous tooth surfaces between the BMT and control children. However, the number of tooth surfaces missing because of extraction of teeth for caries, was significantly greater in the BMT children (P ⬍ 0.04). Bacterial dental plaque: There was no significant difference in the mean plaque score or proportion of tooth quadrisections covered by plaque as a percentage of the total number of deciduous and permanent tooth quadrisections between the BMT and matched control group at baseline (Tables 3 and 4). Gingival inflammation: There was no significant difference in the mean gingival inflammation score or the proportion of quadrisections with associated gingival inflammation as a percentage of the total number of quadrisections in the deciduous and permanent teeth between the BMT and control groups at baseline (Tables 3 and 4). Mucositis: Neither mucositis nor any other mucosal lesions were recorded in either group of children. Gingival inflammation Gingival inflammation was recorded for 10 children by the two examiners. Inter-examiner agreement = 90.12% Kappa = 0.8114 All these values for kappa indicate very high agreement. Dental indices at baseline Dental caries: The proportion of BMT children who were caries free was 47.8%, which was not significantly different from the 65.2% of the matched controls. The dmfs score at baseline was greater than the matched control group (P ⬍ 0.05) and the dmft was also increased but not significantly (Figure 1). There were no significant differences in Dental indices 7 days post-transplantation Three children refused examination. Plaque: There was a significant increase in the mean plaque score from baseline for the deciduous teeth (P ⬍ 0.003) and the permanent teeth (P ⬍ 0.001) (Figure 2). The proportion of tooth quadrisections covered by plaque as a percentage of the total number of tooth quadrisections increased significantly for both the deciduous (P ⬍ 0.003) and permanent dentitions (P ⬍ 0.001) (Tables 5 and 6). Figure 1 Dental caries in the occlusal surfaces of the upper right premolar and molar teeth. 803 Dental caries, gingival health and transplantation VS Lucas et al 804 Table 1 Decayed missing filled surfaces and teeth: bone marrow transplant and matched control groups BMT group (n = 23) dmfs dmft DMFS DMFT Matched control group (n = 23) Mean s.d. Median Min Max Mean s.d. Median Min Max Sig 7.4 2.5 0 0 10.4 2.8 0 0 4 2 0 0 0 0 0 0 40 8 0 0 2.0 1.1 0.1 0.1 3.6 1.8 0.3 0.3 0 0 0 0 0 0 0 0 12 5 1 1 ⬍0.05 NS NS NS Sig = statistical significance; NS = no significant difference. Table 2 Percentage of untreated dental caries: bone marrow transplant and matched control groups BMT group (n = 23) Matched control group (n = 23) Mean s.d. Median Min Max Mean s.d. Median Min Max Sig 9.5 0 30.1 0 0 0 0 0 100 0 20.6 0 39.8 0 0 0 0 0 100 0 NS NS Deciduous dentition Permanent dentition Sig = statistical significance; NS = no significant difference. Table 3 Plaque and gingival inflammation scores at baseline: bone marrow transplant and matched control groups BMT group (n = 23) Matched control group (n = 23) Mean s.d. Median Min Max Mean s.d. Median Min Max Sig Deciduous dentition Plaque Gingival inflammation 6.8 4.1 8.8 5.7 2 0 0 0 28 15 4.4 1.7 5.7 3.1 0 0 0 0 18 6 NS NS Permanent dentition Plaque Gingival inflammation 15.4 17.9 20.7 26.4 9 7 0 0 88 100 8.5 8.3 9.6 9.7 4 4 0 0 36 36 NS NS Sig = statistical significance; NS = no significant difference. Table 4 Percentage of surfaces covered by plaque and quadrisections associated with gingival inflammation at baseline: bone marrow transplant and matched control groups BMT group (n = 23) Matched control group (n = 23) Mean s.d. Median Min Max Mean s.d. Median Min Max Sig Deciduous dentition Plaque Gingival inflammation 12.6 8.6 16.1 12.6 5.6 0 0 0 56.8 38.9 9.4 4.1 12.7 8.4 0 0 0 0 37.5 33 NS NS Permanent dentition Plaque Gingival inflammation 29.2 28.3 28.8 29.6 18.8 17.4 0 0 88.9 100 14.3 14.4 13.56 13.7 10 10 0 0 40 40 NS NS Sig = statistical significance; NS = no significant difference. Dental caries, gingival health and transplantation VS Lucas et al 805 Figure 2 Extensive deposits of bacterial plaque and gingival inflammation with new blood vessel formation in the marginal gingivae. Table 5 Plaque and gingival inflammation scores at baseline and 7 days post-transplantation (neutrophils ⬍108/l): bone marrow transplant group Baseline (n = 20) Mean s.d. Deciduous dentition Plaque Gingival inflammation 5.8 4.4 7.5 5.8 Permanent dentition Plaque Gingival inflammation 14.7 11.5 20.5 13.5 Median 7 Days Post-transplant (n = 20)a Min Max Mean s.d. 1 0 0 0 25 15 18.6 21.2 16.0 18.5 8 5.5 0 0 88 46 33.3 31.6 25.6 18.6 Median Min Max Sig 20 18 0 0 48 60 ⬍0.003 ⬍0.001 29.5 33.5 0 0 112 70 ⬍0.001 ⬍0.001 Sig = statistical significance; NS = no significant difference. a Three children refused. Table 6 Percentage of surfaces covered by plaque and quadrisections associated with gingival inflammation at baseline and 7 days post-transplantation (neutrophils ⬍108/l): bone marrow transplant group Baseline (n = 20) 7 Days Post-transplant (n = 20)a Mean s.d. Median Min Max Mean s.d. Median Min Max Sig Deciduous dentition Plaque Gingival inflammation 11.4 9.0 15.6 12.8 2.8 0 0 0 56.8 38.9 37.3 41.1 32.5 34.3 43.8 50 0 0 100 100 ⬍0.003 ⬍0.001 Permanent dentition Plaque Gingival inflammation 27.70 21.88 28.74 24.53 18.75 15.63 0 0 88.9 88.3 71.9 70.8 36.9 35.2 87.9 81.7 0 0 100 100 ⬍0.001 ⬍0.001 Sig = statistical significance; NS = no significant difference. a Three children refused. Gingival inflammation: There was a significant increase from baseline in the mean gingival inflammation score for both the deciduous (P ⬍ 0.001) and the permanent teeth (P ⬍ 0.001) (Figure 2). The proportion of quadrisections associated with gingival inflammation as a percentage of the total number of quadrisections increased significantly for both the deciduous (P ⬍ 0.001) and the permanent dentitions (P ⬍ 0.001). Spontaneous gingival bleeding was observed in three children (Tables 5 and 6). Mucositis: All the children except for three who had no sign of mucosal inflammation, complained of a sore throat and dysphagia. A further seven children had thick ropy saliva and three refused examination. Five children had noticeable parotid swelling and a further 10 complained of parotid discomfort. Seven children had swollen or sore and cracked lips. Three children had ulcers mainly on the ventral surface and lateral borders of the tongue (grade 3) and two others on Dental caries, gingival health and transplantation VS Lucas et al 806 Table 7 Plaque and gingival inflammation scores at end of study: bone marrow transplant and matched control groups BMT group (n = 16) Mean s.d. Deciduous dentition Plaque Gingival inflammation 4.3 1.8 6.4 2.8 Permanent dentition Plaque Gingival inflammation 10.6 5 21.5 6.9 Median Matched control group (n = 16) Min Max Mean s.d. 2 0 0 0 24 8 3.3 2.1 4.5 3.4 4 1.50 0 0 77 20 8.6 8.6 9.5 9.5 Median Min Max Sig 0 0 0 0 12 12 NS NS 5.5 5.5 0 0 28 28 NS NS Sig = statistical significance; NS = no significant difference. the hard palate, floor of the mouth and the sublingual papillae (grade 4). In two children, the ulcers on the tongue were bleeding. Ten children had generalised mucosal inflammation (grade 3) and two others localised erythema on the buccal mucosa (grade 2). All children required oral or parenteral pain relief. Dental indices 119 days post-transplantation Plaque and gingival inflammation: There were no differences in the plaque and gingival inflammation scores or the proportion of tooth quadrisections covered by plaque or associated with gingival inflammation as a percentage of the deciduous and permanent dentitions between baseline and the end of the study, in the matched control group. There were no significant differences in the mean plaque and gingival inflammation scores or proportion of tooth quadrisections covered by plaque or associated with gingival inflammation as a percentage of the total number of deciduous and permanent teeth between baseline and 119 days post-transplantation in the BMT group. There were no significant differences in the mean plaque score or the proportion of tooth quadrisections covered by plaque as a percentage of the total number of tooth quadrisections, or the mean gingival inflammation scores and proportion of quadrisections associated with gingival inflammation in the deciduous and permanent dentitions, between the BMT group and controls at the end of the study (Tables 7 and 8). Mucositis: There was no evidence of mucositis in the BMT group or any other mucosal lesions in either group of children. Discussion A significantly greater dmfs in the BMT children was an important finding. There were a number of reasons for this. Many of the children had received regular dental care until the intensive treatment necessary for their medical condition became the priority. This treatment may extend over several months and becomes long and protracted particularly if there is a poor response. Side-effects of the chemotherapeutic regimens cause gastro-intestinal disturbances and loss of appetite. This, combined with ingestion of refined carbohydrates to increase the calorie intake and little or no preventive dental care, may be contributory factors in the development of dental caries. There was no significant difference in the mean percentage of untreated disease between the BMT (9.5, s.d. 30.1) and matched control groups (20.6, s.d. 39.8) although the figure was greater in the controls. A possible explanation for this is that unless the child complains of discomfort, caries in the deciduous teeth is not perceived as a serious problem in healthy children. The number of deciduous tooth surfaces missing because of extraction for caries was significantly greater in the BMT children. The reason for this is the importance of removing all foci of infection in the mouth which could Table 8 Percentage of surfaces covered by plaque and quadrisections associated with gingival inflammation at end of study: bone marrow transplant and matched control groups BMT group (n = 16) Matched control group (n = 16) Mean s.d. Median Min Max Mean s.d. Median Min Deciduous dentition Plaque Gingival inflammation 6.4 3.3 8.7 5.6 2.5 0 0 0 30 18.2 6.8 4.9 9.5 8.6 0 0 Permanent dentition Plaque Gingival inflammation 14.1 8.1 19.1 10.0 9.4 3.1 0 0 68.8 28.1 15.8 14.5 12.9 13.2 16.1 15.3 Sig = statistical significance; NS = no significant difference. Max Sig 0 0 25 25 NS NS 0 0 39.3 39.3 NS NS Dental caries, gingival health and transplantation VS Lucas et al give rise to bacteraemia during the period of intense immunosuppression. The dmft for the BMT children in the present study was just within the range reported in the UK dental health surveys co-ordinated by the British Association of Community Dentistry.24 The range of dmft in the UK survey, for 5 to 8 year olds, was 1.2 to 2.8 and the mean value for the BMT children in the present study was 2.5. The dmft is greater than those from two local dental surveys. The dmft for 5 year olds in an affluent area of Surrey was 1.225 and for Greenwich, an inner city area of London, 2.4.26 An important part of the mouthcare regimen for immunosuppressed patients is rinsing with 0.2% chlorhexidine, which if used effectively, reduces plaque accumulation (and bacterial loading).27,28 This has been reported by several groups of investigators,29–31 as has a reduction in the frequency of isolation of the viridans streptococci.30,32 Most of the children in the present study were unable to use the chlorhexidine effectively for two main reasons. Chlorhexidine has an unpleasant taste and the 7% alcohol base causes a burning sensation of the already inflamed mucosa. A significant deterioration in gingival health occurred during the period of intense immunosuppression, associated with a large increase in plaque accumulation and inflammation, around the gingival margin. This was probably due to the concurrent problems of oral pain which occurred as a result and it was understandable that compliance with oral hygiene procedures was often poor. These findings are similar in part to those from an earlier study in which the gingival condition, but not the plaque score deteriorated in children suffering from ALL during treatment.9 It is during this period of immunosuppression and profound neutropenia that infections are most likely to originate from the oral cavity. The significant deterioration in gingival health associated with such a dramatic increase in oral bacterial loading is cause for serious concern because of the risk of septicaemia. Approximately 4 months after transplantation, the oral health indices had returned to baseline levels. Mucositis occurred from approximately day 5 post-transplantation and persisted for several days. It is reported to be strongly associated with oral bacteraemia.32 The sites affected may be discrete, but often most if not all of the oral mucosa is involved. Widespread erythema with ulceration and bleeding of the mucosal surfaces and the areas around the salivary gland ducts provide a large area for systemic ingress of bacteria. It is highly likely that an important site of systemic entry is through the inflamed gingival tissues. In the study reported here, three children had positive blood and/or Hickman line cultures for oral streptococci on day 7 post-transplantation. All three children were suffering from mucositis although there were no ulcers visible to the naked eye. In addition, the plaque and gingivitis scores were also significantly increased. The gingival inflammation is a result of the plaque accumulation which causes ulceration of the gingival crevicular epithelium. Any slight movement of the teeth, for example chewing or parafunctinal movements of the lips and tongue against loose deciduous teeth,22 dislodges bacteria in the plaque around the gingival margin into the blood stream. There is, therefore support for the inflamed gingival epithelium as in important site of entry for bacteria into the bloodstream in addition to the ulcers of mucositis. In conclusion, the dmfs was found to be significantly greater in the bone marrow transplant children than in the matched controls. This was due to a number of factors related to the seriousness of the medical condition and intensity of the treatment. The bacterial plaque and gingival indices were significantly greater 7 days post-transplantation but had returned to the baseline levels 4 months posttransplantation. Gingival and mucosal health are poorest during the period of intense immunosuppression when the children are most at risk of odontogenic bacteraemia. Acknowledgements We would like to thank Dr Paul Veys, Bone Marrow Transplant Consultant, The Great Ormond Street Hospital for Children and Professor Ross Pinkerton, Paediatric Oncology Consultant, The Royal Marsden Hospital, for their help with the project. We are also very grateful to the schoolchildren in the Merton and Sutton Area Health Authority for taking part as matched controls. This work was supported by the Sir Jules Thorne Charitable Trust. References 1 Karr RA, Kramer DC. You can treat the chemotherapy patient. Texas Dent J 1992; 109: 15–20. 2 Cheatham BD, Henry RJ. 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