Download Oral health of children undergoing allogeneic bone marrow

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.
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