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 Table of Contents  
Year : 2019  |  Volume : 6  |  Issue : 2  |  Page : 47-53

Oral mucositis in children associated with hematopoietic stem cells transplant

Department of Preventive Oral Science, Division of Pediatric Dentistry, Riyadh Elm University, Riyadh, Saudi Arabia

Date of Web Publication19-Aug-2019

Correspondence Address:
Dr. Sarah A Mubaraki
Department of Preventive Oral Science, Division of Pediatric Dentistry, Riyadh Elm University, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjos.SJOralSci_31_19

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Oral mucositis is one of the most common complication of Hematopoietic stem cell transplant. It is extremely painful and affect the quality of life. 67%–99% of the patients develop oral mucositis and they are at a high risk of developing various infections. Several methods was introduced aiming to reduce the incidence and severity of oral mucositis. The objective of this review is to summarize the different modalities to reduces the incidence and severity of oral mucositis. The review includes human clinical trails with or without randomization, meta-analysis and systematic review. The review suggests that proper oral hygiene, mouth lubricant and the epidermal growth factor can help to reduce the severity of oral mucositis.

Keywords: Hematopoietic stem cell transplant, oral complication, oral mucositis

How to cite this article:
Mubaraki SA. Oral mucositis in children associated with hematopoietic stem cells transplant. Saudi J Oral Sci 2019;6:47-53

How to cite this URL:
Mubaraki SA. Oral mucositis in children associated with hematopoietic stem cells transplant. Saudi J Oral Sci [serial online] 2019 [cited 2021 Jan 22];6:47-53. Available from: https://www.saudijos.org/text.asp?2019/6/2/47/264762

  Introduction Top

Hematopoietic stem cell transplant (HSCT) is defined as the infusion of multipotent stem cells, which are derived from the bone marrow, cord blood, or peripheral blood to reconstitute the hematopoietic system.[1],[2] This transplant is used to cure certain diseases and diverse hematopoietic disorders.[3],[4]

Oral mucositis (OM), a common and an important complication of HSCT,[5] is an inflammation of oral mucosa often extending to the oropharynx as a result of cancer therapy, typically manifesting as atrophy, swelling, erythema, and ulceration.[6],[7],[8] It affects 67%–99% of patients receiving high-dose chemotherapy and/or total body irradiation (TBI) for HSCT [9],[10] and usually occurs between 2 and 18 days following the initiation of the chemotherapy.[7]

Moreover, OM may cause severe oral pain and may hamper the oral intake. It also facilitates the entry of pathogenic microorganisms leading to bacteremia and possible septicemia.

  Oral Mucositis Pathophysiology Top

OM-related chemotherapy may result from direct effect on the mucosal tissue or indirectly from the consequences of chemotherapeutic drug-induced bone marrow myelosuppression.[11],[12] The mechanism has been studied extensively by several researchers, and presently, it is accepted that OM occurs in four phases.[2],[13],[14] The first phase, that is, the inflammatory/vascular phase occurs after administering the chemotherapeutic agent, as the oral mucosa immediately releases cytokines, causing local tissue damage. The second phase commences when the mucosal turnover decreases and presents clinically as atrophy and ulceration. The first two phases occur within the first 5 days. The third phase occurs after the epithelial tissue rupture and ulcer development. The fourth and final phase is the healing stage between days 12 and 16 after the chemotherapy.[13]

  Healing and Cellular Turnover in Oral Mucosa Top

The oral mucosa is well adapted to protect the underlying tissues against mechanical damage and inhibits the entry of microorganisms and their toxic materials.[15] Wounds and ulcers in the oral mucosa heal quickly and with improved scar quality than those on the skin due to high blood supply.[16]

Saliva creates a humid environment, which is beneficial for wound healing,[17],[18] by preventing tissue dehydration and cell death and accelerating angiogenesis and increasing the breakdown of dead tissue and fibrin.[18]

Proteins within human saliva comprise classical growth factors, as well as deference, cathelicidin, and trefoil factors, which are known for their positive healing effects.[19],[20]

The cellular turnover rate of the oral mucosa occurs between 7 and 14 days. The rapid basal cell turnover and resultant improvement in healing occur more rapidly in the younger age group.[21]

  Clinical Implications of Oral Mucositis Top

It has been reported that mucositis causes painful inflammation and ulcers that affect the mucosal membrane, from the oral cavity to the rectum.[22] Nevertheless, the literature review states that OM refers to a particular inflammation and ulceration that affects only the oral cavity.[2],[12],[14],[23]

The most common signs and symptoms of OM are erythema, edema, burning sensation, increased sensitivity to hot and spicy foods,[12] and white patches on mucous membranes of the cheeks, lips, tongue, and palate [Figure 1].[24]
Figure 1: Clinical presentation of oral mucositis

Click here to view

OM is extremely painful and can cause a drastically reduced quality of life.[25] Pain due to this ulceration can interfere with the patient's ability to eat and drink,[26] thereby leading to weight loss and may necessitate total parenteral feeding.[27] Documented evidence of OM have been found that suggest an increased need for narcotics to manage the pain.[2],[28]

It has been reported that 75% of patients with OM are at a high risk of developing various infections including septicemia,[28],[29] fungemia,[2] and viral infections, in particular, herpes infections.[12],[28] It has been reported that neutropenia resulting from the chemotherapeutic treatment is the primary cause of these infections.[12]

  Incidence and Severity of Oral Mucositis Top

The occurrence of OM generally depends on several factors patient tolerance to the treatment, type of cytotoxic agent, dose, the application of TBI, disease severity and subtype, as well as the remission status.[1],[30],[31],[32] Nevertheless, younger patients tend to develop OM more often than older patients who are being treated for the same malignancy.[21]

OM occurs in 40% of the patients receiving chemotherapy without HSCT. The incidence is significantly increased to 67%–99% in patients receiving chemotherapy for HSCT.[10]

Several risk factors such as tumor type, patient age,[21] dental health, oral hygiene before and during the chemotherapy, and nutrition status are known to influence and substantially affect the OM severity.[33]

The association between infection and the OM severity has been studied in detail. Carious teeth, periodontal diseases, and periradicular infection are associated with systemic complications.[34] Previous studies reported that treating any odontogenic infection will decrease the risk of local and systemic infections.[35] Before subjecting the patient to HSCT, prompt eradication of acute and chronic infections is necessary within the provided time limit. Hence, teeth with severe caries and dental infections are managed by extractions.[36] The use of immunosuppressive drugs after the HSCT infusion can lead to infection in about 73% of the cases.[37]

The overall impact of OM is enormous for patients, caregivers, and the medical system. Furthermore, it can be directly related to the reduced overall survival in patients, as well as increase in the medical costs [5],[38],[39] and hospitalization time.[40]

  Oral Mucositis Interventions Top

Studies related to OM in pediatric patients receiving HSCT are scarce; however, OM is of considerable clinical significance as it essentially facilitates the entry microorganisms, native to the oropharyngeal region, into the systemic circulation.[12]

The OM incidence and severity for patients undergoing HSCT emphasize the importance of good prevention. Patient and parent's education about good oral hygiene to minimize the oral complication before, during, and after the treatment is crucial and important.

The incidence and severity of OM for patients undergoing HSCT underline the importance of good prevention. Patient and parent's education toward good oral hygiene in order to minimize the oral complication before, during, and after the treatment is very critical and important. Current literature on the different preventive methods agonist OM is reviewed below:

Normal saline

It is a harmless bland isotonic oral rinse, which is beneficial in maintaining appropriate oral hygiene due to its safety, low toxicity, and physiological properties.[41] While it is not recognized as an effective intervention to alleviate the symptoms of OM, several studies have used it as a control for comparison with other regimens [42],[43] or as a vehicle combined with other mouth rinses.[44],[45]


While fluoride mouth rinses are less effective in reducing the OM incidence or severity, few studies have used fluoride mouth rinse in their control groups.[46],[47],[48]

Banava et al. used a fluoridated paste of casein phosphopeptide-amorphous calcium phosphate (CPP-ACPF) on the oral cavity and salivary status of patients undergoing chemotherapy. On assessing the clinical effects, they found that although no change was observed on salivary signs, the resting and stimulated saliva rates and saliva buffering capacity significantly improved in patients using the CPP-ACPF paste.[49]

Chlorhexidine gluconate mouthwash

Chlorhexidine gluconate (CHX) is a broad-spectrum antibacterial mouthwash present in a concentration of 0.12% and 0.2%. It is generally accepted that it prevents the buildup of dental plaque.[50] It mechanically binds to the oral surface by reversible electrostatic bonds with salivary glycoproteins.[51] While no concrete evidence exists regarding its beneficial effects on OM.

Several studies have tested CHX extensively in randomized trials to evaluate its effect in preventing OM in patients undergoing chemotherapy.[43],[46],[52],[53],[54] CHX presented unfavorable characteristics such as a temporary alteration of taste,[55] unpleasant sensation,[54] staining of teeth and tongue, and soreness of the oral mucosa.[52],[56]

Sodium bicarbonate mouthwash

Sodium bicarbonate is a bland mouthrinse that is harmless and beneficial for oral hygiene maintenance.[41] There are a few published articles on the use of sodium bicarbonate mouthwash for preventing OM in patients undergoing chemotherapy.[54],[57] While Kenny (1990) suggested that it might be a valid aid to reduce the severity of OM,[57] Dodd et al. 2000 reported that the evidence in this regard was inconclusive.[54]

Standardized oral hygiene regimen

Since the 1980s, investigators have explored the link between oral hygiene and the OM incidence and severity. Bavier (1989) and Sampiano (2012) concluded that there was a well-known strong correlation between the OM severity and poor oral hygiene.

While there is no controversy in the literature about the need for oral hygiene, there is considerable debate about how best to achieve it. It is a well-documented fact that physical methods such as toothbrushes are far more effective than chemical methods alone. Several guidelines have addressed the use of soft toothbrush and parentally assisted brushing among children.[58] The American Academy of Pediatric Dentistry 2013 recommended in their guidelines that patients should maintain good oral hygiene by brushing their teeth and tongue two to three times daily regardless of their hematological status.[59],[60],[61]

Different Oral Hygiene Protocols developed for patients undergoing chemotherapy with or without HCST instruct the patients to brush their teeth to prevent gingival inflammation and bacterial colonization.[62]

Supersaturated calcium phosphate rinse

The supersaturated calcium phosphate rinse (SCPR) has been introduced in oral health care management for oncology patients with the aim of lubricating the oral cavity, to minimize severe OM. SCPR is a natural electrolyte solution containing calcium and phosphate ions that resemble the ionic and pH balance of saliva.

Theoretically, the highly concentrated ions of Ca2+/PO43− diffuse into the intercellular spaces of the oral epithelium. The Ca2+ ions are crucial in the inflammatory process, the blood clotting cascade, fibrin production, and tissue repair. PO43− ions are important in facilitating intracellular signaling and regulating the voltage potential inside the cell; both mechanisms are important in repairing and protecting the damaged mucosal surfaces.

Although several studies in the literature reporting the positive effect of SCPR in reducing OM, peak, and duration of pain,[48],[63] little is known about the efficacy of SCPR in pediatric patients undergoing HSCT.

In a study of 40 patients undergoing allogeneic transplants, Markiewicz et al(2010). have reported a significant reduction in the OM severity in patients using SPCR when compared to 20 patients of the control group. A pilot study reported that SCPR used for 34 adult patients undergoing HSCT from the initial step of conditioning resulted in a significant reduction in the OM severity.[64]

In contrast, a study of 56 patients undergoing autologous or allogeneic HSCT revealed that OM developed in 19 patients using SCPR compared to 24 patients of the control group. Furthermore, the study found no significant difference in the OM severity between the two groups.[65]

A more recent randomized control study by Markiewicz et al. (2012), testing the effect of SCPR found a reduction in the oral toxicity, mouth pain, and disease course duration compared to the control group.

A study by Lalioui et al. (2012) and Quinn (2013) in the pediatric patients undergoing autologous HSCT reported that half of the participants using SCPR developed OM.


Cryotherapy (CT) acts as vasoconstrictor and results in decreased toxicity of the chemotherapeutic agents associated with mucosal damage.[28],[66] In 1991, the first published report on CT and its effect on OM suggested that when applied during the time of peak serum 5FU levels, CT could cause vasoconstriction to oral mucous membranes and significantly lower intensity of OM.[66]

It has been recommended by the Multinational Association of Supportive Care in the Cancer/International Society of Oral Oncology (MASCC/ISOO) in 2007, to use CT as a preventive measure.[33]

Several studies have examined the effect of CT on OM and suggested the use of CT to prevent OM in patients receiving high-dose melphalan, with or without TBI, as conditioning for HSCT.[8],[67],[68]

Few studies have been conducted on children. In 2006, a study was conducted for children aged between 2 and 16 years undergoing chemotherapy and autologous peripheral blood stem cells transplantation and found that combination of propantheline and oral CT may be feasible and effective for reducing the mucosal toxicity in patients with malignancy who are undergoing high-dose chemotherapy.[69] A prospective randomized study found in that CT during methotrexate administration did not reduce severe OM in patients undergoing myeloablative allogeneic HSCT.[70]

CT significantly affected OM in patients receiving short half-life chemotherapeutic agent.[71],[72] Nevertheless, some patients experienced uncomfortable sensation while holding ice in their mouth for 30 min.[71]

Benzydamine hydrochloride

This is a nonsteroidal anti-inflammatory mouthwash, which also possesses pain relieving, antimicrobial, antifungal, and anesthetic properties.[73],[74] Benzydamine is acceptable and well tolerated.[73] Only few published articles are available on the use of benzydamine, and as a result, no guideline can be published for its use to prevent chemotherapy-induced mucositis. Nevertheless, in two studies, 0.15% benzydamine hydrochloride presented to be less effective than 0.2% CHX in the OM incidence and severity in a pediatric population.[75],[76]


It is a well-known plant used for several medicinal purposes. It has anti-inflammatory, antibacterial, and antifungal properties.[77],[78] Few studies have tested the effect of chamomile drops mixed with water on OM. Fidler et al. (1996) conducted a randomized trial on 164 patients, and they reported that the solution was well tolerated by patients with OM.


Povidone–iodine a widely used antimicrobial solution.[79] There is a significant reduction in the incidence, severity, and duration of OM in a group of patients using regular mouthwashes of povidone– iodine; however, no further studies were conducted on the use of povidone–iodine for treating OM.

Epidermal growth factor

The epidermal growth factor (EGF) regulates epithelial cell proliferation, growth, and migration. In addition, it enhances mucosal wound healing and tissue generation, which indicate that EGF may be effective in the treatment of ulcerative OM.[80]

Since 1997, there is evidence suggesting that decreased salivary EGF is associated with more severe mucositis;[81] however, no clinically applicable preparation of EGF is available for the management of OM.

Human keratinocyte growth factors

Human keratinocyte growth factors belong to the family of fibroblast growth factors. Palifermin is one of the most common human recombinant keratinocyte growth factors. It is mitogenic for epithelial and endothelial cells, fibroblast, and keratinocytes and supports the barrier integrity.[82]

Animal studies suggested that KGF-1 decreased graft versus host disease associated with allogeneic HSCT.[83]

The Mucositis Study Group of the MASCC/ISOO has published clinical practice guidelines for mucositis.[84],[85] These have resulted in a recommendation for the use of palifermin for 3 days before the conditioning treatment and for 3 days posttransplant to prevent OM.

Worthington et al., (2011) found a statistically significant result for palifermin in reducing the incidence of OM.

Morris et al., (2016) published the first clinical trial of palifermin for the treatment of OM in 27 children. The results revealed that there were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population, and no differences were observed between the three different age groups studied.

Granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor

These are specific hematopoietic growth factors needed for bone marrow progenitor cells to form mature blood cells. Granulocyte colony-stimulating factor (G-CSF) stimulates the development of neutrophils, eosinophils, and basophils; whereas, granulocyte–macrophage CSF (GM-CSF) stimulates the generation of cells belonging to the monocyte/macrophage lineage.[85] Nevertheless, no guideline is available for using G-CSF due to insufficient evidence. Several studies concluded that GM-CSF mouthwashes are not effective in preventing OM in the HSCT.[85],[86],[87]

  Conclusion Top

The problem of OM in children who are undergoing HSCT is vital importance because of the morbidity and impact, it has on the quality of life of the patient.

The treatment of OM remains focused on symptomatic topical relief; different methods were introduced to reduce the incidence and severity of OM.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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1 The efficacy of two different oral hygiene regimens on the incidence and severity of oral mucositis in pediatric patients receiving hematopoietic stem cell transplantation: A prospective interventional study
Sarah Mubaraki,Sharat Chandra Pani,Amal Alseraihy,Hassan Abed,Zikra Alkhayal
Special Care in Dentistry. 2020;
[Pubmed] | [DOI]


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