The effect of hematopoietic stem cell transplantation on patient-reported subjective oral dryness: a systematic review focusing on prevalence, severity and distress.

OBJECTIVE: The aim of the present systematic review is to assess the prevalence and severity of and distress caused by xerostomia over time in adult hematopoietic stem cell transplantation (HSCT) recipients. METHODS: PubMed, Embase, and the Cochrane Library were searched for papers published between January 2000 and May 2022. Clinical studies were included if patient-reported subjective oral dryness was reported in adult autologous or allogeneic HSCT recipients. Risk of bias was assessed according to a quality grading strategy published by the oral care study group of the MASCC/ISOO, resulting in a score between 0 (highest risk of bias) and 10 (lowest risk of bias). Separate analysis focused on autologous HSCT recipients, allogeneic HSCT recipients receiving a myeloablative conditioning (MAC), and those receiving a reduced intensity conditioning (RIC). RESULTS: Searches yielded 1792 unique records; 22 studies met the inclusion criteria. The quality scores ranged between 1 and 7, with a median score of 4. The prevalence, severity, and distress of xerostomia increased shortly after HSCT. Severity of xerostomia in allogeneic MAC recipients was higher compared to allogeneic RIC recipients 2-5 months post-HSCT (mean difference: 18 points on 0-100 scale, 95% CI: 9-27); after 1-2 years, there was no significant difference anymore. CONCLUSION: The prevalence of xerostomia in HSCT recipients is high in comparison to the general population. The severity of complaints is raised during the first year post-HSCT. The intensity of the conditioning plays a key role in the short-term development of xerostomia, while factors affecting the recovery in the long term remain largely unknown.

Caries, periodontitis and tooth loss after haematopoietic stem cell transplantation: A systematic review.

OBJECTIVE: A systematic review was conducted to assess scientific knowledge concerning the effect of haematopoietic stem cell transplantation (HSCT) on the occurrence of caries, periodontal conditions and tooth loss, and to evaluate the prevalence of these diseases in adult HSCT survivors (PROSPERO 152906). METHODS: PubMed and Embase were searched for papers, published from January 2000 until November 2020 without language restriction, assessing prevalence, incidence or parameters of caries, periodontal conditions and tooth loss in HSCT recipients (≥80% transplanted in adulthood). Bias risk was assessed with checklists from Joanna Briggs Institute, and data synthesis was performed by narrative summary. RESULTS: Eighteen papers were included (1618 subjects). Half were considered at high risk of bias. Longitudinal studies did not show caries progression, decline in periodontal health or tooth loss after HSCT. The prevalence in HSCT survivors ranged from 19% to 43% for caries, 11% to 67% for periodontitis, and 2% to 5% for edentulism. Certainty in the body of evidence was very low. CONCLUSIONS: Haematopoietic stem cell transplantation, on the short term, may have little to no effect on caries, periodontal conditions and tooth loss. Caries and periodontitis may be more common in HSCT survivors compared with the general population, whereas edentulism may be comparable. However, the evidence for all conclusions is very uncertain.

The effect of conditioning regimen and prescribed medications on hyposalivation in haematopoietic cell transplantation (HCT) patients: an 18-month prospective longitudinal study.

OBJECTIVES: Haematopoietic cell transplantation (HCT) preceded by a conditioning regimen is an established treatment option for (non)malignant haematologic disorders. We aim to describe the development of hyposalivation over time in HCT recipients, and determine risk indicators. MATERIALS AND METHODS: A multi-centre prospective longitudinal observational study was conducted. Unstimulated (UWS) and stimulated (SWS) whole saliva was collected before HCT, early post-HCT, and after 3, 6, 12, and 18 months. The effect of type of transplantation (allogeneic vs autologous) and intensity (full vs reduced) of the conditioning regimen on hyposalivation (UWS < 0.2 mL/min; SWS < 0.7 mL/min) was explored. RESULTS: A total of 125 HCT recipients were included. More than half of the patients had hyposalivation early post-HCT; a quarter still had hyposalivation after 12 months. The conditioning intensity was a risk indicator in the development of hyposalivation of both UWS (OR: 3.9, 95% CI: 1.6-10.6) and SWS (OR: 8.2, 95% CI: 2.9-24.6). After 3 and 12 months, this effect was not statistically significant anymore. CONCLUSIONS: Hyposalivation affects the majority of patients early post-HCT. The conditioning intensity and the type of transplantation were significant risk indicators in the development of hyposalivation. The number of prescribed medications, total body irradiation as part of the conditioning regimen and oral mucosal graft-versus-host disease did not influence hyposalivation significantly. CLINICAL RELEVANCE: Because of the high prevalence of hyposalivation, HCT recipients will have an increased risk of oral complications. It might be reasonable to plan additional check-ups in the dental practice and consider additional preventive strategies.

A randomized controlled trial of manual versus powered tooth brushing during haematopoietic stem cell transplantation.

AIM: To compare manual and powered tooth brushing (MT and PT) with respect to patient compliance to brushing frequency advice, plaque removal and severity of oral mucositis (OM) in patients undergoing hematopoietic stem cell transplantation (HSCT) after high-dose chemotherapy. MATERIALS & METHODS: A randomized controlled trial was conducted. Forty-six patients scheduled to receive myeloablative conditioning regimen before autologous HSCT were included and randomly assigned to control (MT, n = 23) or test (PT, n = 23) groups. Starting at day 1 (day of hospital admission for HSCT), brushing frequency (patient recorded diary), plaque scores (Plaque Control Index) and oral mucositis (Oral Mucositis Nursing Index) were recorded daily. Data for days 1 to 17 were analysed using regression analysis and general linear models. RESULTS: Few patients maintained 4 times per day brushing, but most brushed at least 2 times per day throughout the study. In PT, overall plaque scores were lower by 6.98% (p = .006) as compared to MT. No differences were seen in OM scores between the groups (p = .968). A small but significant positive correlation was found between plaque scores and OM severity: R2 =0.15 (p < .01). CONCLUSIONS: Powered tooth brushing resulted in lower plaque scores, but was not associated with reduced OM severity. Individual plaque scores were positively related to OM severity.

Caries Progression after Haematopoietic Stem Cell Transplantation and the Role of Hyposalivation.

Haematopoietic stem cell transplantation (HSCT) preceded by a conditioning regimen is an established treatment option for many haematological diseases. Decreased salivary flow rates after HSCT may increase caries risk. We aim to estimate the extent to which caries lesions develop or progress in adult HSCT recipients and assess its association with salivary flow rates. A multi-centre prospective observational study was conducted in which patients receiving HSCT were followed up for 18 months. We included 116 patients (median age 56 years, 43% female) from two medical centres in the Netherlands. Unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) were collected, and full caries charts were made before HSCT and 3, 6, 12, and 18 months post-HSCT. Caries was scored according to the ICDAS criteria by trained dentist-examiners. New dentine lesions or lesion progression into dentine (ICDAS ≥4 or cavitated root lesions) occurred in 32% of patients over 18 months. The median number of affected surfaces was 2 (range: 1-12) per patient with caries progression. The influence of hyposalivation of unstimulated saliva (<0.2 mL/min) and stimulated saliva (<0.7 mL/min) at baseline and after 3 months on caries progression was determined with a negative binomial regression model. Hyposalivation of SWS 3 months after HSCT was a significant risk indicator for caries progression (incidence rate ratio: 5.30, 95% CI: 2.09-13.4, p < 0.001), while hyposalivation of SWS at baseline and hyposalivation of UWS were not. We conclude that caries progression is a common oral complication in patients after HSCT, and stimulated hyposalivation shortly after treatment is a significant risk indicator for caries progression.

Salivary Changes before and after Hematopoietic Stem Cell Transplantation: A Systematic Review.

Severe oral problems, including oral mucositis (OM) and xerostomia, often occur after conditioning therapy for hematopoietic stem cell transplantation (HSCT). Saliva plays a major role in protecting the oral mucosa and teeth. Alterations in salivary flow rate or salivary components resulting in decreased salivary defence mechanisms may affect oral/mucosal health and may influence the severity of OM. A systematic review was conducted to assess the current scientific knowledge on changes in salivary function and composition before and after HSCT. All English or Dutch articles examining salivary flow rate or salivary components before and after HSCT were included after title/abstract selection by 2 independent reviewers (weighted κ = .91). After quality assessment and exclusion of all research groups with both children age <14 years and adults, 33 articles were included for data analysis. Overall, the salivary flow rate was decreased at several days and months after HSCT. Although several salivary components were studied, most components were examined in only 1 or 2 studies with different patient populations or at different time points after HSCT. At 7 days after HSCT, albumin and proinflammatory cytokines were increased, whereas secretory IgA and components of the salivary antioxidant system were decreased. Secretory IgA levels were still reduced at 1 month after HSCT but returned to pre-HSCT values at 6 months after HSCT. Lactoferrin, secretory leukocyte protease inhibitor, and ß2-microglobulin levels were increased at 6 months after HSCT. Our findings show that changes in saliva reflect an inflammatory response occurring immediately after HSCT, followed by evidence of increased salivary antimicrobial defense mechanisms by 6 months after HSCT.

Subjective Oral Dryness following Hematopoietic Cell Transplantation: A Report from the Orastem Study.

Xerostomia, or subjective oral dryness, is a serious complaint after hematopoietic cell transplantation (HCT). Xerostomia is rated as one of the most bothersome symptoms by HCT recipients, negatively affecting quality of life. This substudy of the Orastem study, a prospective longitudinal, international, observational, multicenter study, aimed to describe the prevalence and severity of xerostomia following HCT. Furthermore, the effect of the conditioning regimen, type of transplantation, and oral mucosal changes related to chronic graft-versus-host disease (cGVHD) in the development of xerostomia were studied. All HCT recipients rated xerostomia on a scale of 0 to 10 before the conditioning regimen, several times early post-HCT, and at 3 months post-HCT, and only allogeneic HCT recipients also rated xerostomia at 6 and 12 months post-HCT. In addition, stimulated whole mouth saliva was collected several times. Linear regression models and longitudinal mixed-effects models were created to investigate the influence of risk indicators on xerostomia. A total of 99 autologous and 163 allogeneic HCT recipients were included from 6 study sites in Sweden, Canada, the Netherlands, and the United States. The prevalence of xerostomia was 40% before the conditioning regimen, 87% early post-HCT, and 64% at 3 months post-HCT. Complaints after autologous HCT were transient in nature, while the severity of xerostomia in allogeneic HCT recipients remained elevated at 12 months post-HCT. Compared to autologous HCT recipients, allogeneic HCT recipients experienced 1.0 point more xerostomia (95% confidence interval [CI], .1 to 2.0) early post-HCT and 1.7 points more (95% CI, .4 to 3.0) at 3 months post-HCT. Allogeneic HCT recipients receiving a high-intensity conditioning regimen experienced more xerostomia compared to those receiving a nonmyeloablative or reduced-intensity conditioning regimen. The difference was 2.0 points (95% CI, 1.1 to 2.9) early post-HCT, 1.8 points (95% CI, .3 to 3.3) after 3 months, and 1.7 points (95% CI, .0 to 3.3) after 12 months. Total body irradiation as part of the conditioning regimen and oral mucosal changes related to cGVHD did not significantly influence the severity of xerostomia. Conditioning regimen intensity was a significant risk indicator in the development of xerostomia, whereas total body irradiation was not. Allogeneic HCT recipients experienced more xerostomia than autologous HCT recipients, a difference that cannot be explained by a reduction in stimulated salivary flow rate or the development of oral mucosal changes related to cGVHD.

Oral health in patients scheduled for hematopoietic stem cell transplantation in the Orastem study.

Despite advances in transplant medicine, prevalence of complications after hematopoietic stem cell transplantation (HSCT) remains high. The impact of pre-HSCT oral health factors on the incidence and severity of complications post-HSCT is poorly understood. The aim of this prospective, observational study was to analyze oral health in patients planned for HSCT. Patients ≥18 years requiring HSCT were included from five sites between 2011-2018. General health, oral findings and patient-reported symptoms were registered in 272 patients. Oral symptoms around disease onset were reported by 43 patients (15.9%) and 153 patients (58.8%) reported oral complications during previous chemotherapy. One third of patients experienced oral symptoms at the oral examination before conditioning regimen and HSCT. In total, 124 (46.1%) patients had dental caries, 63 (29.0%) had ≥one tooth with deep periodontal pockets, 147 (75.0%) had ≥one tooth with bleeding on probing. Apical periodontitis was observed in almost 1/4 and partially impacted teeth in 17 (6.3%) patients. Oral mucosal lesions were observed in 84 patients (30.9%). A total of 45 (17.4%) of 259 patients had at least one acute issue to be managed prior to HSCT. In conclusion, oral symptoms and manifestations of oral disease were prevalent in patients planned for HSCT. The extent of oral and acute dental diseases calls for general oral screening of patients pre-HSCT.

Long-Term Analysis of Resilience of the Oral Microbiome in Allogeneic Stem Cell Transplant Recipients.

Stem cell transplantation (SCT) is associated with oral microbial dysbiosis. However, long-term longitudinal data are lacking. Therefore, this study aimed to longitudinally assess the oral microbiome in SCT patients and to determine if changes are associated with oral mucositis and oral chronic graft-versus-host disease. Fifty allogeneic SCT recipients treated in two Dutch university hospitals were prospectively followed, starting at pre-SCT, weekly during hospitalization, and at 3, 6, 12, and 18 months after SCT. Oral rinsing samples were taken, and oral mucositis (WHO score) and oral chronic graft-versus-host disease (NIH score) were assessed. The oral microbiome diversity (Shannon index) and composition significantly changed after SCT and returned to pre-treatment levels from 3 months after SCT. Oral mucositis was associated with a more pronounced decrease in microbial diversity and with several disease-associated genera, such as Mycobacterium, Staphylococcus, and Enterococcus. On the other hand, microbiome diversity and composition were not associated with oral chronic graft-versus-host disease. To conclude, dysbiosis of the oral microbiome occurred directly after SCT but recovered after 3 months. Diversity and composition were related to oral mucositis but not to oral chronic graft-versus-host disease.

Microbial changes in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients.

The aim of this prospective, two center study was to investigate the dynamics of the microbial changes in relation to the development of ulcerative oral mucositis in autologous SCT (autoSCT) recipients. Fifty-one patients were diagnosed with multiple myeloma and treated with high-dose melphalan followed by autoSCT. They were evaluated before, three times weekly during hospitalization, and three months after autoSCT. At each time point an oral rinse was collected and the presence or absence of ulcerative oral mucositis (UOM) was scored (WHO scale). Oral microbiome was determined by using 16S rRNA amplicon sequencing and fungal load by qPCR. Twenty patients (39%) developed UOM. The oral microbiome changed significantly after autoSCT and returned to pre-autoSCT composition after three months. However, changes in microbial diversity and similarity were more pronounced and rapid in patients who developed UOM compared to patients who did not. Already before autoSCT, different taxa discriminated between the 2 groups, suggesting microbially-driven risk factors. Samples with high fungal load (>0.1%) had a significantly different microbial profile from samples without fungi. In conclusion, autoSCT induced significant and reversible changes in the oral microbiome, while patients who did not develop ulcerative oral mucositis had a more resilient microbial ecosystem.