This study comprehensively compared the effects of chemotherapy on oral health status, caries risk, and oral microbial composition of ALL and healthy counterparts. To assess the oral health of ALL children, the current study evaluated their degree of caries, and the prevalence rate of different oral diseases. And the caries risk was estimated with Cariogram by measuring nine factors of relevance to caries. Moreover, the high-throughput sequencing of 16S rRNA genes was applied to further explore and analyze the oral microbiome of two groups. ALL patients receiving chemotherapy showed high prevalence rate of oral complications and caries risk, compromised oral health and dysbiosis of oral microbiota. While there have been several studies investigating oral health status or microbiota in leukemia patients with chemotherapy, few have conducted a comprehensive analysis of all three [19, 36]. These findings may help to better implement a preventive oral health regimen and minimize the risk of associated oral complications, thereby improving the quality of life of patients with ALL.
Children affected by leukemia receive various forms of treatments including chemotherapeutic agents and stem cell transplants. Methotrexate as a chemotherapeutic drug can produce direct toxicity and affect the oral mucosa through the systemic circulation. Thus, chemotherapy could affect the oral health status of ALL patients, manifested by higher prevalence of five common oral manifestations than healthy counterparts. In our study, the oral disease with the highest prevalence rate from children with ALL was dental caries, accounting for 69.2%. This may be due to the toxic effects of the Methotrexate and its adverse effects on oral hygiene. In the study by Torres et al., gingivitis is a common oral manifestation of chemotherapeutic drugs, affecting 91.84% of the samples [37]. Similar results were obtained in this study, which may be related to poor oral hygiene caused by using chemotherapeutic drugs. Candidiasis, a fungal opportunistic infection, is also common among children with ALL in previous studies [37–39]. The presence of candidiasis could have been caused by the patients’ low immunity, associated with exposure to the virus. The most frequent oral complications were mucositis, candidiasis, periodontitis and gingivitis according to a systematic review and high-dose chemotherapy drugs can also lead to xerostomia [20, 40].
In addition, further research on the caries of ALL patients found that the application of high-dose methotrexate (HDMTX) affected caries related factors, manifested by changes in content and frequency of diets, increased dental plaque, reduced salivary flow rate compared with health counterparts, which also promoted the occurrence of the above-mentioned oral diseases. Chemotherapy will cause a decrease in saliva volume and saliva flow rate in patients with ALL, and manifest as xerostomia in severe cases [41]. Hong et al. considered that leukemia patients tend to consume more high-energy foods and drink sugar-rich beverages to relieve oral dryness [11]. Due to the nausea and vomiting caused by chemotherapy drugs, children with ALL have small food intake, so the number of meals has increased significantly. The high sugar consumption and increased frequency of eating is not conducive to the oral hygiene of patients, promoting the development of caries and increasing the risk of caries in children with ALL. It can be observed that application of chemotherapy seriously damages the oral health status of children with ALL in comparison with counterparts.
As a multi-factorial infectious disease, caries should be evaluated from multiple factors so that the prediction has accuracy and validity. The Cariogram, an interactive computer-based caries risk assessment programme, has developed rapidly in the past years, with many related studies and high evaluations. It has been used to evaluate the caries risk of various populations, including normal populations of different ages [12, 42], patients undergoing oral treatment [43, 44] and patients with systemic diseases [45]. Andreas et al. compared the validity of three caries risk assessment tools and concluded that Cariogram displayed a higher validity in predicting caries increment [46]. In this study, children with ALL revealed lower percent chance of avoiding caries, of which 30.77% children were assessed as extremely high risk of dental caries (0–20% chance of avoiding caries). Therefore, it is necessary to evaluate the caries risk of ALL children during the chemotherapy period and take oral health measures for high-risk children, which can help reduce the incidence of caries in ALL children and improve their quality of life.
In the present study, we sampled supragingival plaque in children with ALL and their healthy counterparts, and analyzed its microbial composition via 16S-based 454 pyrosequencing. ALL children receiving chemotherapy had lower richness and less diversity of oral microbiota compared with healthy counterparts, which pointed to dysbiosis of oral microbiota in ALL patients. Moreover, we reported altered structure and composition of oral microbiota in ALL patients. As we all know, the health of the host is closely related to the microbiome, and the host immune system plays an important role in maintaining the balance of the microbiome. A study on the patients with acute myeloid leukemia (AML) undergoing induction chemotherapy indicated a high degree of intra-patient temporal instability of oral microbial diversity and that increased variability was correlated with adverse clinical outcomes [47]. And a study by Bo-Young Hong et al. demonstrated that chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis [48]. ALL patients may suffer from impaired host immunity due to disorders of lymphoid progenitor cells (the main part of the body's immune system), and the side effects of methotrexate exacerbate this process, leading to disruptions of oral microbiota [34]. Moreover, the application of chemotherapy seriously damaged the oral health status of children with ALL, which also promoted the dysbiosis of oral microbiota.
We studied the differential relative abundance of bacterial taxonomy profiles of children with ALL and healthy counterparts. The results showed notable differences from the phylum down to the genus level in abundance between two groups. The Firmicutes phylum, Bacilli class, Lactobacillales order, Carnobacteriaceae and Aerococcaceae families, Abiotrophia genus are much more abundant in the supragingival plaque of ALL patients than healthy counterparts. At the genus level, the leukemia-depleted genera included Fusobacteria, Comamonas, Actinobacteria, Rothia and so on, while only Abiotrophia were significant leukemia-enriched genera. Bo-Young Hong also studied the association of chemotherapy-induced oral mucositis and oral microbiome, founding the bacteriome depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris [48]. Although the exact mechanism of the interaction between infectious diseases and microbiota has not been clarified, the study of oral microbiota in ALL patients can provide the opportunity for identifying potential infectious diseases. Hence, preventing the dysbiosis of oral microbiota might be a promising measure for decreasing the risk of associated infectious complications in children with ALL. And further precise experimental techniques and cohort studies are needed to elucidate the exact relationship between the two.