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BMC Oral Health
BMC Oral Health
BMC Oral Health
1472-6831
BioMed Central London

39256697
4804
10.1186/s12903-024-04804-7
Research
Salivary flow rate, subjective oral dryness and dental caries 5 years after haematopoietic cell transplantation
Bulthuis Marjolein S. Marjolein.Bulthuis@radboudumc.nl

1
van Gennip Lucky L. A. 1
Thomas Renske Z. 1
van Leeuwen Stephanie J. M. 1
Bronkhorst Ewald M. 1
Laheij Alexa M. G. A. 23
Raber-Durlacher Judith E. 23
Blijlevens Nicole M. A. 4
Huysmans Marie-Charlotte D. N. J. M. 1
1 https://ror.org/05wg1m734 grid.10417.33 0000 0004 0444 9382 Department of Dentistry, Radboud University Medical Center, Nijmegen, The Netherlands
2 grid.424087.d 0000 0001 0295 4797 Department of Oral Medicine, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University, Amsterdam, The Netherlands
3 grid.7177.6 0000000084992262 Department of Oral, Maxillofacial Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
4 https://ror.org/05wg1m734 grid.10417.33 0000 0004 0444 9382 Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands
10 9 2024
10 9 2024
2024
24 105815 3 2024
23 8 2024
© The Author(s) 2024
2024
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Background

The aim of this study was to describe salivary flow rate, subjective oral dryness and dental caries 5 years post haematopoietic cell transplantation (HCT).

Methods

HCT survivors of a previous longitudinal observational cohort study in the Netherlands (the H-OME study) were invited to participate in this additional follow-up after 5 years (the HOME2 study). During the additional follow-up appointment, stimulated (SWS) and unstimulated whole saliva (UWS) was collected, participants rated subjective oral dryness on a 0 – 10 scale, and caries lesions were assessed. Furthermore, dental records, including treatments and radiographs, were requested for the 5 years preceding and the 5 years following transplantation. Paired t-tests were performed to determine changes in UWS and SWS flow rates and subjective oral dryness from pre-HCT, and to compare the number of caries-related dental treatments (restorations, endodontic treatments or extractions) before and after HCT. Hyposalivation of UWS (< 0.2 mL/min) and SWS (< 0.7 mL/min) at 3 and 12 months, was used to explore the predictive potential of hyposalivation on a high dental treatment need (> 3 treatments) over the 5 years post-HCT.

Results

Five years post-HCT, 39 HCT survivors were included. The mean UWS flow rate was 0.36 mL/min (SD 0.26) and the mean SWS flow rate 1.02 (SD 0.57); survivors were diagnosed with a median of 0 dentine lesions (range 0 – 12) and 73% reported a subjective oral dryness score ≥ 1. Survivors underwent a median of 3 (range 0 – 20) dental treatments during the 5 years following transplantation. The mean difference in UWS 5 years post-HCT compared to pre-HCT was 0.03 (95% CI: -0.07 – 10.12), the mean difference for SWS was -0.18 (95% CI: -0.45 – 0.08) and for subjective oral dryness 1.2 (95% CI: 0.2 – 2.1). In the 5 years post-HCT, non-significantly more treatments were performed compared to the 5 years pre-HCT (mean difference: 0.5, 95%CI: -1.2 – 2.2). Seventy eight percent of patients with hyposalivation of SWS at 12 months had a high dental treatment need, compared with 38% with no hyposalivation.

Conclusions

Five years post-HCT, mean UWS and SWS flow rates were not significantly different from pre-HCT levels but subjective oral dryness scores were elevated.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12903-024-04804-7.

Keywords

Haematopoietic stem cell transplantation
Cancer survivors
Xerostomia
Dental caries
Long term adverse effects
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pmcBackground

Haematopoietic cell transplantation (HCT) is an established treatment option for haematologic and lymphoid cancers and many other disorders [1]. Haematopoietic stem cells, that are either harvested from the patient (autologous HCT) or a donor (allogeneic HCT), are infused after a preparative conditioning regimen. This conditioning regimen aims to eradicate the disease and modulate the immune system, consists of chemotherapy with or without total body irradiation (TBI), and can have a high (myeloablative (MAC)), a reduced (RIC), or even a non-myeloablative intensity (NMA). During the past decades, clinical indications for HCT expanded and transplantation procedures improved, leading to an increased number of long-term survivors [2, 3]. Following HCT, development of oral complications and complaints are frequently reported [4, 5].

Cancer treatments are known to induce salivary gland hypofunction [6]. In HCT recipients, stimulated whole saliva (SWS) flow rates were already low before HCT, and decreased further shortly post-HCT [7, 8]. This decline may be related to the high dose conditioning regimen, and the high number of prescribed medications preceding and following the transplantation [8]. SWS flow rates started to increase again 3 or 6 months post-HCT, an increase that lasted until 12 [8] or even 24 months [9]. UWS flow rates seem to follow a comparable but less pronounced pattern over time [8, 10]. It remains unclear whether further recovery of salivary flow rates might be expected more than 24 months post-HCT. Cross-sectional studies reported that long-term HCT survivors had lower UWS [11, 12] and SWS flow rates compared to controls [11]. A reduction in salivary flow rate and impaired recovery in allogeneic HCT recipients might be a result of chronic graft-versus-host disease (cGvHD) [13].

A reduced salivary flow rate might cause the subjective feeling of mouth dryness, or xerostomia [14]. An increase in mouth dryness complaints is reported in HCT recipients, simultaneously with a decrease in salivary flow rate. Subjective oral dryness scores increased shortly after treatment, were still raised 2 – 5 months post-HCT, and values largely comparable to baseline were reached after 12 months [15]. Nevertheless, complaints remained elevated compared to controls, even on the very long term [11].

Since a shortage of saliva influences oral (sugar) clearance and adversely affects salivary buffering of plaque acid [16], a reduced salivary flow rate might contribute to an increased caries risk [17]. In HCT recipients, a reduced SWS flow rate at 3 months post-treatment, resulted in a higher risk of developing dental caries during a period of 18 months [18]. After a median follow-up of 4 years, HCT recipients had a higher number of decayed, missing and filled teeth, and worse dental health compared to healthy matched controls [12]. We hypothesize that even a short period of hyposalivation might result in initial but irreversible damage to the dental enamel, potentially resulting in caries progression leading to the need for restorative treatment.

We previously conducted a prospective, observational, longitudinal study, recording oral side effects in HCT recipients for 12 to 18 months post-treatment: the H-OME study [8, 18–22]. One year post-treatment, 26% of the patients was still diagnosed with hyposalivation of UWS and 25% with hyposalivation of SWS. This raised the questions how dental health would evolve during the following years, and whether further recovery of salivary flow rates could be expected on the longer term. The aim of the present study was to describe UWS and SWS flow rate, subjective oral dryness and dental caries 5 years post-HCT, in the same population. Furthermore, salivary flow rates and subjective oral dryness scores were compared to pre-HCT values. Finally, we explored whether dental treatment need increased as a result of HCT, and whether hyposalivation predicted dental treatment need during a period of 5 years post-HCT, using data from dental records.

Materials and methods

This observational cohort study adds one additional follow-up to the previously closed H-OME study, that focussed on oral side effects pre-HCT, shortly after HCT, and up to 18 months post-HCT. The protocol of the H-OME study is published in the Dutch Trial Register (NL5645) and approval was obtained by the Medical Research Ethical Committee (NL52117.018.15). In short, adult patients (≥ 18 years old) scheduled to receive an autologous or allogeneic HCT at Amsterdam University Medical Centre (UMC), location AMC, or Radboud university medical center (Radboudumc) Nijmegen were included. Surviving participants from this H-OME study were invited to participate in this additional 5-year follow-up study. Participants that received a second HCT since inclusion in the H-OME study, and those without a remaining natural dentition, were excluded. The current study was registered as HOME2 in the Dutch Trial Register (NL9825). The Local Ethical Committee (registration number 2021–12963) stated that this research was not subjected to the law governing research involving human subjects and no approval from the Local Ethical Committee was necessary. The study was conducted according to GCP guidelines and the World Medical Association Declaration of Helsinki. Before participating, all patients signed a renewed informed consent.

General health and use of medication

Participants were interviewed using questions regarding general health, cancer treatments and comorbidities. Furthermore, patients were asked to bring a list of medications they were using at the time of the 5-year follow-up appointment. When patients forgot this list, they were asked to recall the medications that they were using. Medications were divided into the following categories:Antimicrobials: antibiotics, antifungals, antiviral medications

Supportive medication: sleep medication, antidepressants, anxiolytics, antacids, antiemetics, analgesics, antihistamines, laxatives, diuretics

Anticancer and immunosuppressive medication: cytostatics, oncolytics, colony stimulating factors, corticosteroids, other immunosuppressives, protein kinase inhibitors

Other medication

Caries assessment and dental treatments

Dental examinations were carried out by experienced dentists: AL assessed caries lesions from patients treated at the Amsterdam UMC, location AMC, while MB recorded caries lesions from patients treated at the Radboudumc. Caries was assessed clinically according to the ICDAS II [23, 24]. ICDAS scores of 2 and higher were recorded for every crown surface; a distinction was made between cavitated and non-cavitated lesions in the recording of root caries.

If patients consented, dental records were requested from dentists treating the patients. Records, including radiographs, were requested for the 5 years preceding, and 5 years following HCT. The number of dental check-ups, tooth extractions, endodontic treatments and restorations (at tooth and surface level) performed during both time periods were extracted. Furthermore, dental records were searched for indications for treatments, and, if not reported, intra-oral radiographs were assessed by experienced dentists (LvG and MB) to determine whether a cariological diagnosis was plausible.

Saliva collection

The protocols for the collection of whole saliva were based on the guidelines for saliva collection of the University of Southern California School of Dentistry [25]. Patients were asked to refrain from eating, drinking, toothbrushing and use of chewing gum 1 h before the collection. The collection of UWS started immediately after one swallow. Patients were asked to spit all accumulating saliva in a pre-weighed plastic cup for 5 min without making any effort to increase the salivary flow. SWS was also collected for 5 min, and the collection was preceded by swallowing after 1 min of chewing. Directly after collection, samples were weighed and flow rates were estimated by assuming 1 g of saliva equals 1 mL. Hyposalivation of UWS was defined as a flow rate of < 0.2 mL/min, and hyposalivation of SWS as < 0.7 mL/min [26–28].

Current subjective oral dryness

To assess the severity of oral dryness, patients were asked to complete the following question: How would you rate your mouth dryness during the last 24 h? This Likert scale ranged from 0 (no dryness) to 10 (worst possible dryness). The same question was also completed during the previous phases of the H-OME study. Furthermore, patients were asked to complete the EORTC QLQ-OH15 [29]. This oral health module comprises a question on mouth dryness on a 4-point Likert scale.

Statistical analysis

UWS and SWS flow rates are reported as mean and standard deviation (SD); median scores and ranges are shown in boxplots. Paired t-tests were performed comparing the 5-year results from a subgroup (only HCT recipients treated at the Radboudumc) with previously reported pre-HCT values [8]. Furthermore, unpaired t-test were used to compare differences between subgroups.

Subjective oral dryness scores are reported as mean and SD; median scores and ranges are shown in boxplots. Paired t-test were used to compare subjective oral dryness scores 5 years post-HCT with pre-HCT levels, and unpaired t-tests were used to compare differences between subgroups 5 years post-HCT.

Spearman’s correlations, used to determine the correlation between salivary flow rates and subjective oral dryness on the one hand, and the number of used medications and dentine lesions on the other, were reported as Spearman’s rho with p-value.

Number of dental treatments (tooth extractions, endodontic treatments and restorations) performed during the 5 years preceding and the 5 years following HCT are reported as median and range. Paired t-test were used to compare the total number of treatments and dental check-ups post-HCT with those pre-HCT.

Hyposalivation of UWS and SWS, measured after 3 and 12 months, was used to predict dental treatment need over the 5 years post-HCT. The number of treatments performed post-HCT was dichotomised based on the median value, resulting in a group that received 0 – 3 treatments (low dental treatment need), and a group with > 3 treatments (high dental treatment need). Results of the crosstabs are presented in bar charts, and sensitivity, specificity, and positive and negative predictive values were calculated.

Statistical analyses were performed using with R (version 4.1.3; R Foundation for Statistical Computing, Vienna, Austria) and SPSS (version 29) and graphs were made using R and Excel.

Results

Of the 113 dentate HCT recipients that were included in the H-OME study, 74 were still alive 5 years post-treatment. Of these, 9 were excluded because they received a second HCT. Two patients were not invited (due to health and unknown reason) and 24 patients were not able to come or refused to come due to health (n = 4), logistic (n = 8), other (n = 5) or unknown (n = 7) reasons, resulting in the inclusion of 39 (53% of the) survivors. The flow chart, summarizing the number of patients in the H-OME and HOME2 study, is reported in Fig. 1. Baseline characteristics of all 113 dentate HCT recipients and the subgroup of included survivors are listed in Table 1.Fig. 1 Flow chart combining the number of patients (n) in the previous closed H-OME study and the current HOME2 study. *Pre-HCT, UWS and SWS flow rates were only reported from patients treated at the Radboudumc due to higher precision measurements performed in this centre. Five years post-HCT, SWS flow rate was missing in one patient due to unknown reasons and subjective oral dryness scores of 2 patients were excluded, because of conflicting answers to the 11-point and 4-point Likert scale that was part of the QLQ-OH15. Abbreviations: UWS, unstimulated whole saliva; SWS, stimulated whole saliva

Table 1 Pre-HCT characteristics and HCT related information of all included dentate patients and those included in the 5-year follow-up

	All patients (113)	Survivors (39)	
Median age at HCT in years (range)	56 (19 – 74)	55 (19 – 74)	
Gender, n (% female)	51 (45%)	14 (36%)	
Centre, n	
 AMC	42	10	
 Radboudumc	71	29	
Type of HCT; intensity of conditioning, n	
 Autologous	49 (43%)	15 (38%)	
 Allogeneic MAC	14 (12%)	7 (18%)	
 RIC	23 (20%)	9 (23%)	
 NMA	27 (24%)	8 (21%)	
Diagnoses, n	
 Acute Myeloid Leukaemia	27 (24%)	6 (15%)	
 Acute Lymphoblastic Leukaemia	5 (4%)	3 (8%)	
 Lymphoma	7 (6%)	6 (15%)	
 Chronic Lymphocytic Leukaemia	3		
 Myelodysplastic Syndrome	9 (8%)	3 (8%)	
 Chronic Myeloid Leukaemia	2	1	
 Myelofibrosis	4	1	
 Severe Aplastic Anaemia	2	1	
 Multiple myeloma	51 (45%)	16 (41%)	
 Other	3	2	
Total body irradiation, n	43 (38%)	14 (36%)	
No total body irradiation, n	70 (62%)	25 (64%)	
Hyposalivation UWS	31%	27%	
Hyposalivation SWS	27%	32%	
Mean subjective oral dryness score (SD)	1.9 (2.3)	1.5 (1.8)	
Median dentine lesions (range)	1 (0 – 10)	0 (0 – 8)	
Median DMFT (range)	18 (0 – 28)	17 (2 – 25)	
Abbreviations: MAC Myeloablative conditioning, RIC Reduced intensity conditioning, NMA Non-myeloablative conditioning, UWS Unstimulated whole saliva, SWS Stimulated whole saliva, SD Standard deviation, DMFT Decayed missing and filled teeth

Two patients were not registered with a dental healthcare provider; the other 37 patients consented in requesting dental records from their dentist. We received a response from 36 dentists: 26 dental records comprised the complete period of 5 years before and 5 years post-HCT, another 9 records comprised the period partially, and one record did not contain any relevant information.

General health

New medical diagnoses following HCT were reported by 74%. The most frequently self-reported medical conditions were infections (n = 9), orthopaedic conditions (n = 8) and problems of the skin and eyes (n = 5). Furthermore, hypertension, cardiovascular diseases, and neuropathies were each reported by four patients; thyroid abnormalities, another diagnosis of cancer and swallowing problems, by two patients each.

HCT survivors used a median of 3 (range 0 – 15) medications at the time of the 5-year follow-up. The mean number of medications pre-HCT (as reported previously [8]) and 5 years post-HCT, divided into 4 categories, is reported in Fig. 2. Autologous HCT survivors, who were all diagnosed with multiple myeloma (MM), used a median of 6 medications 5 years post-HCT: 6 out of 15 autologous HCT survivors used medications aiming to treat MM. Of the allogeneic HCT survivors, 2 used medications to suppress cGvHD. HCT survivors that were 54 years or younger at HCT used a median of 1 (range 0 – 12) medications, while older patients used a median of 5 (range 0 – 15) medications. The number of used medications was correlated to the severity of subjective oral dryness (Spearman’s rho 0.37, p = 0.022), but not to salivary flow rate (Table S1).Fig. 2 Mean number of medications pre-HCT (during the dental screening) and 5 years post-HCT

Salivary flow rate

Median UWS and SWS flow rates 5 years post-HCT are visualised in Fig. 3a; the mean scores for several subgroups are reported in Table S2. Eleven out of 39 patients (28%) were diagnosed with hyposalivation of UWS and 13/38 patients (34%) were diagnosed with hyposalivation of SWS. Median pre-HCT salivary flow rates from patients treated at the Radboudumc are also shown in Fig. 3a. Change in salivary flow rate was determined in 27 patients for whom the two measurements were available. The mean UWS flow rate increased with 0.03 mL/min (95%CI: – 0.07 – 0.12; p: 0.559) and the mean SWS flow rate decreased (mean difference -0.18; 95%CI: -0.45 – 0.08; p: 0.167). On average, salivary flow rates did not change significantly, but an increase or decrease was seen in the majority of patients (Fig. 4). Mean change scores in several subgroups are reported in Table S3.Fig. 3 a Boxplot of unstimulated (UWS) and stimulated (SWS) whole saliva in mL/min collected pre-HCT and 5 years post-HCT. b boxplot of subjective oral dryness scores (0 – 10) collected pre-HCT and 5 years post-HCT

Fig. 4 Prevalence of either increase or decrease in UWS flow rate, SWS flow rate and subjective oral dryness score from pre-HCT to 5 years post-HCT

Current subjective oral dryness

Subjective oral dryness scores 5 years post-HCT are shown in Fig. 3b; mean mouth dryness scores for several subgroups are reported in Table S2. Five years post-HCT, 27 out of 37 patients (73%) experienced an oral dryness score ≥ 1 recently. If oral dryness scores 5 years post-HCT are compared with pre-HCT scores (also shown in Fig. 3b), a mean increase of 1.2 points was reported (95%CI: 0.2 – 2.1; p: 0.019). Mean change scores from baseline in several subgroups are reported in Table S3. An increase in complaints of ≥ 1 points was seen in the majority of patients (Fig. 4).

Dental caries

When HCT survivors visited our dental clinic 5 years post-HCT, a median of 0 (mean 1.3) dentine lesions (range 0 – 12) was diagnosed. Thirty-eight percent of the 46 detected lesions were non-cavitated coronal lesions (ICDAS 4), 16% were cavitated coronal lesions (ICDAS 5 or 6) and 46% were cavitated root lesions. The number of detected lesions was not correlated to the salivary flow rate 5 years post-HCT (Table S1).

Caries-related dental treatments

During the 5 years before HCT, 123 dental treatments (tooth extractions, endodontic treatments and restorations) were performed in 26 patients. Of these, only 4 treatments (3 extractions and 1 restoration) were performed after the focal infection screening and preceding HCT. Based on data retrieved from dental records and radiographs, it could be established for 11% of the 123 treatments that they were performed due to caries.

During the 5 years following HCT, 170 treatments were performed by the dentist in 35 patients, while an additional 12 treatments were performed in the academical medical centre. Overall, survivors underwent a median of 3 (range 0 – 20) dental treatments. Thirty-three percent of these treatments was performed due to caries, 23% due to other reasons (mostly fracture, trauma and wear) and in 43%, no diagnosis was reported. Based on retrieved radiographs, we established that another 5% of the treatments, in which no diagnosis was reported, was probably performed due to caries. In the 5 years post-HCT, non-significantly more treatments were performed compared to the 5 years pre-HCT (mean difference: 0.5; 95%CI: -1.2 – 2.2). The number of dental check-ups performed in the general dental practices was comparable pre- and post-HCT (mean difference -0.1; 95%CI: -1.2 – 1.0). In addition to these check-ups, HCT survivors also saw a study dentist several times as part of the H-OME study: these visits were not counted as dental check-ups. Median number of dental treatments (including treatments performed in the academical medical centre) pre- and post-HCT are reported in Table 2. Table 2 Median number of caries-related dental treatments and check-ups during 5 years before, and 5 years following HCT

	5 years before
(n = 26)	5 years after
(n = 35)	
dental check-ups (range)	6 (2 – 9)	5 (0 – 10)	
restorations (range)	2 (0 – 19)	3 (0 – 20)	
restored surfaces (range)	10 (0 – 80)	7 (0 – 79)	
extractions (range)	0 (0 – 4)	0 (0 – 2)	
endodontic treatments (range)	0 (0 – 4)	0 (0 – 4)	

The predictive potential of hyposalivation in dental treatment need

The number of patients who underwent 0 – 3 treatments (low dental treatment need) and those who underwent > 3 dental treatments (high dental treatment need) in the 5 years following HCT is shown in Fig. 5, while a distinction is made between patients with and without hyposalivation. Looking at hyposalivation of UWS (Fig. 5, top row), it is shown that the majority of patients with hyposalivation had a low dental treatment need, and half of the patients with a normal UWS flow rate had a low dental treatment need. The same applies to hyposalivation of SWS at 3 months post-treatment (Fig. 5, bottom left side). Looking at hyposalivation of SWS at 12 months post-treatment (Fig. 5, bottom right side), we see a different picture: the majority (78%) of patients with hyposalivation had a high dental treatment need, while the majority (62%) of patients without hyposalivation had a low dental treatment need. Hyposalivation was considered to be a potential predictor for a high dental treatment need in the current population, and the sensitivity, specificity, and positive and negative predictive values were calculated and reported in Table S4.Fig. 5 The relation between hyposalivation of unstimulated (UWS) and stimulated whole saliva (SWS), measured 3 and 12 months post-HCT and dental treatment need during 5 years post-HCT. Bar charts represent the number of patients with hyposalivation (hypo) and a high or low dental treatment need

Discussion

The aim of the present study was to describe UWS and SWS flow rates, subjective oral dryness and dental caries 5 years post-HCT. This study added one additional follow-up to the previous closed H-OME study, in which HCT recipients were followed from a pre-HCT measurement to 18 months post-treatment. Data on salivary flow rate [8] and caries progression [18] during the first 18 months were reported previously. The longitudinal follow-up of the same population, made it possible to compare the recently collected 5-year results with the previously published pre-HCT data. Even though the 5-year response rate was quite high, given the high mortality rate and the increased vulnerability in this population, only 39 HCT recipients could be included. This small number of participants limited the possibility of statistical analyses to a mainly descriptive level.

Five years post-HCT, the mean UWS flow rate in 39 survivors was 0.36 mL/min (SD 0.26), and the mean SWS flow rate was 1.02 mL/min (SD 0.57). These results could not be compared to other populations of HCT survivors, as this is the first study assessing oral side effects longitudinally more than 2 years post-HCT. The mean UWS flow rate 5 years post-HCT could be considered as normal, while the mean SWS flow rates remained lowered compared to normal levels (1.5 – 2 mL/min) as reported in literature [30]. Mean UWS and SWS flow rates 5 years post-HCT were not significantly different from pre-HCT levels. It should be emphasized that differences between survivors were large, and that an unchanged mean score does not mean that individual patients reach their own pre-HCT value 5 years post-HCT.

Five years post-HCT, 73% of the patients experienced recently a subjective oral dryness score of ≥ 1. Oral dryness was measured with a non-validated 0 – 10 Likert scale, asking for mouth dryness during the last 24 h, which can be considered as a limitation of the current publication. The prevalence of subjective oral dryness, or xerostomia, cannot be easily compared with other populations of HCT survivors, as several different questions were used to determine its prevalence in literature [15]. Based on five cross-sectional studies, in which subjective mouth dryness was assessed with a simple question or a score ≥ 1 on a 4- or 5-point Likert scale, the prevalence ranged between 22 and 68% [15]. In our study, survivors reported to experience a subjective oral dryness score that was 1.2 points higher (0 – 10 scale; 95%CI: 0.2 – 2.1) compared to pre-HCT.

We reported previously that the intensity of the conditioning regimen was a significant risk indicator in the development of hyposalivation and subjective oral dryness during the first year post-HCT, but its effect tended to diminish over time [8, 15]. Five years post-HCT, allogeneic HCT recipients who received a MAC conditioning regimen still had lower salivary flow rates and higher subjective oral dryness scores compared to those with an NMA/RIC regimen, but these differences did not reach statistical significance (Table S2). In addition to these previous studied risk indicators, many other variables might contribute to hyposalivation and oral dryness 5 years post-HCT, like the actual health status, comprising potential recurrence of disease and comorbidities and medication use. Due to the small number of patients that could be included in the current investigation, we can only speculate on potential causes for the development of hyposalivation and subjective oral dryness in HCT recipients. The population was divided in several subgroups, based on some potential causal factors (Table S2), but the differences between these subgroups should be interpreted with caution.

Looking at salivary flow rate, a remarkable difference between subgroups was seen for TBI. Allogeneic patients that received TBI as part of the conditioning had lower UWS and SWS flow rates than those without TBI. However, changes in salivary flow rate from baseline did not reach significance in both groups, indicating that the difference between the subgroups did already exist before the transplantation, and that TBI did not cause a reduction in salivary flow rate. It was reported previously that there was no association between salivary hypofunction and TBI between 6 months and 6 years post-HCT [5], and 2 years post-HCT [31].

Looking at subjective oral dryness, another difference is noticeable. Patients who used 4 or more medications at the 5-years follow-up experienced more subjective oral dryness and demonstrated a significant increase in complaints compared to baseline, while patients who used up to 3 medications experienced half as much complaints and returned to pre-HCT levels after 5 years. The relation between medication intake and subjective oral dryness is in agreement with literature [32].

At the 5 year follow-up, HCT survivors were diagnosed with a median of 0 dentine lesions (range 0 – 12). Because the majority of patients visited the dentist regularly, and this likely resulted in the detection and restoration of caries lesions, this number does not tell us much about caries risk. Therefore, it was not surprising that the number of detected caries lesions was not related to the current salivary flow rate. To gain a better understanding of the progression of caries lesions, we chose to report dental treatment need. It should be emphasised that his approach has it shortcomings. The number of dental treatments might have been underestimated: treatments performed by other dental healthcare providers, emergency dentists for example, which were not listed in the dental records might have been missed. Furthermore, the number of performed dental treatments might be a result of caries progression, but also of other causes like trauma, fracture and wear, and will be influenced by operator and patient related factors [33]. Previously, it was reported that caries was the most common reason for initial restorations and restoration replacement [34]. In the current population, the indication for dental treatment remained unclear in 38% post-HCT.

In a previous publication regarding the H-OME population, we concluded that hyposalivation UWS was not related to caries progression, while hyposalivation of SWS 3 months post-HCT was a significant risk indicator [18]. A risk indicator does not have to be a useful predictor, as is confirmed in the current study: hyposalivation of SWS 3 months post-HCT did not predict the number of dental treatments during the first 5 years post-HCT. This finding might be caused by the temporary nature of hyposalivation: SWS flow rates in half of the patients with hyposalivation at 3 months, recovered to normal levels after 12 months. On the other hand, 80% of the HCT survivors that was diagnosed with hyposalivation at 12 months, had also hyposalivation of SWS 5 years post-treatment. Those who were diagnosed with hyposalivation of SWS at the 12 months follow-up, were likely to have an increased dental treatment need. Because, in most cases, several years are needed for caries lesions to develop and make restorative treatment necessary [35], it is not surprising that the duration of hyposalivation is an important factor to predict dental treatment need. In the current study, salivary flow rates were only measured at some predetermined times, as a result of which we do not know how salivary flow rates evolved over time. Nevertheless, it seems to be plausible that subjects who were diagnosed with hyposalivation twice, had a prolonged period of insufficient salivary flow.

If hyposalivation of SWS 12 months post-HCT was considered as a predictor for dental treatment need, this test resulted in a low sensitivity and high specificity in the current population. In accordance with this, it was reported previously that a lowered salivary flow rate has a low sensitivity and a high specificity in the prediction of caries prevalence or incidence [17]. We want to emphasise that a prolonged period of hyposalivation is only one potential predictor for caries progression or dental treatment need, and that multivariable models are likely needed [36].

Conclusions

Mean unstimulated and stimulated salivary flow rates 5 years after haematopoietic cell transplantation were not significantly different from pre-HCT levels while mean subjective oral dryness scores were increased. Dental treatment need did not increase significantly as a result of HCT. A shortage of UWS and a short-term lowered SWS flow rate did not predict dental treatment need, while a sustained reduction in SWS flow rate might play a role in the prediction of dental treatments.

Supplementary Information

Supplementary Material 1.

Abbreviations

DMFT Decayed, missing and filled teeth

HCT Haematopoietic cell transplantation

MAC Myeloablative conditioning

MM Multiple myeloma

NMA Non-myeloablative conditioning

RIC Reduced intensity conditioning

SWS Stimulated whole saliva

TBI Total body irradiation

UWS Unstimulated whole saliva

Acknowledgements

The authors are grateful to E.E.J. Maijer for contributing to the collection and recording of clinical data for patients treated at the AMC.

Authors’ contributions

JRD, NB and MH contributed to the design of the H-OME study, while LvG, MB, RT, SvL, MH and AL designed the current HOME2 study. AL, LvG and MB collected the clinical data and EB and MB performed the statistical analysis. MB drafted the paper and the manuscript was critically reviewed by all authors.

Funding

The study was partially funded by the Dutch Cancer Society (ACTA 2014–7468).

Availability of data and materials

The datasets analysed during the current study are not publicly available because participants did not give permission to share individual data.

Declarations

Ethics approval and consent to participate

The Local Ethical Committee (registration number 2021–12963) stated that this research was not subjected to the law governing research involving human subjects and no approval from the Local Ethical Committee was necessary. The study was conducted according to GCP guidelines and the World Medical Association Declaration of Helsinki and all patients signed informed consent before participating.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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