Key words : Quality of life, Symptom management, Taste alteration

Introduction

Hematopoietic stem cells are made by the bone marrow. They are the origin of different blood cells, including platelets, red blood cells, and white blood cells. Sources of stem cells include the umbilical cord blood, bone marrow, and peripheral blood stem cells.¹ Hematopoietic stem cells transplant (HSCT) is used as a preventive and curative treatment for hematologic pathologies.² The most common case is HSCT treatment following a conditioning procedure, such as chemotherapy or radiotherapy, in leukemia.³ Goals of conditioning procedures are to eradicate malignant cells that have multiplied and to promote graft take-up by reducing host immune cells to suppress the immune response, ensuring successful engraftment of transplanted cells. There are 2 types of HSCT: allogeneic and autologous. In allogeneic, cells come from a donor contrary to patient’s own cells in the latter case.^1,3,4 Allogeneic HSCT carries a risk of graft-versus-host disease (GVHD), whereas autologous has a lower risk of this complication but might not be effective against all types of diseases due to the reinfusion of potential malignant cells. The number of people undergoing HSCT and the number of survivors have increased.^3,5 Worldwide activity per year has risen steadily, from 10?000/year in 1991 to 82?718 first HSCTs in 2016, with a global increase of more than 7%.⁶ In addition to this general increase, it is estimated that there will be 5 times more transplant survivors in 2030 (500?000) than in 2009 in the United States.⁷

Dysgeusia is a taste distortion, described as a modification of taste and the 5 fundamental qualities of taste (sweet, bitter, salted, acidic, and umami), that affects taste buds on the tongue surface.8 It differs from ageusia (loss of taste) and hypogeusia (reduced taste sensitivity) because it involves not just alterations in the intensity of taste sensations but also potentially experiencing unpleasant taste. Dysgeusia is frequently associated with HSCT and can be present 3 to 6 months after the procedure in adults, with final recovery taking, on average, 1 year after HSCT.^5,7 Dysgeusia decreases quality of life, producing an appetite reduction and therefore weight loss, responsible for health deterioration. These side effects reduce treatment efficiency and patient motivation.⁹

Dysgeusia is often transitory, but can persist over time. Many factors influence the persistence or the type of taste distortions after HSCT (such as treatment, buccal lesions, malnutrition) and thus the pathology and the treatment. In HSCT cases, dysgeusia can start on salty and sour tastes.^10,11 In a qualitative and exploratory study based on semi-structured interviews applied during hospitalization for HSCT, patients had alterations of salty, sweet, and metallic tastes (especially with meat, chocolate, and juice or tea).¹²

Enhancement of both quality of life and treatment efficacy underlines the significance of research of dysgeusia.¹³ Dysgeusia has been shown to increase risk of morbidity in patients and affect their chance of recovery, most notably by requiring more intensive treatment.¹⁴ Moreover, the rising number of HSCTs further emphasizes the relevance of these studies.⁹ In this review, we aimed to consolidate information pertaining to dysgeusia and HSCT, synthesizing quantitative data available.

Materials and Methods

We conducted an extensive literature review on dysgeusia in HSCT studies up to November 2023 through systematic review. We aimed to syste-matically review the frequency of dysgeusia in HSCT recipients. We followed the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) statement. We registered the method on Prospero (November 11, 2023; CRD42023472377) before analysis, to enhance transparency and reduce bias.

Search strategy and selection criteria
We selected articles based on their relevance, focusing on key themes such as dysgeusia, HSCT, cancer treatment, and side effects. We considered studies from 1992 to 2023, to capture the evolution of dysgeusia understanding in HSCT recipients. For this purpose, we used PubMed, PMC-PubMed, and Web of Science databases. We included different types of studies to gather as much information as possible by employing broad selection criteria, including both qualitative and quantitative studies. The search strategies are listed in Table 1. Both authors conducted the initial selection of studies, with discrepancies resolved through discussion.

Data extraction
RD reviewed the compiled studies, which were organized using Zotero software for reference management and organization. Essential data were gathered using a predefined table, which included details about the study topic, design (longitudinal or cross-sectional), key findings (frequency of dysgeusia), characteristics of the study population (age distribution, HSCT type), data collection methods (interview, self-administered questionnaire, or gustatory test), author information, and year of publication.

Assessment of risk of bias
We evaluated each study for its risk of bias based on five criteria: data collection method (gustatory test being the most reliable), data collection time frame (precision to the day being the best, and lack of precision being the worst), inclusion of short-term results, inclusion of long-term results, and inclusion of graft type information. A customized scale was developed to assess these biases.

Results

To address the central question of our study (How prevalent is dysgeusia among patients undergoing hematologic stem cell transplant?), we screened 94 articles, leading us to identify 14 articles through adherence to inclusion criteria. The Ferreira paper contributed 2 studies as it presents 2 distinct data sets, leading to a total of 15 studies.^10-13,15-24 These selected studies are reported in a flowchart (Figure 1).

Of the studies, 8 were longitudinal studies and 7 were cross-sectional studies. However, the latter represented a larger population on average (110 people compared with 55.25). The mean sample size was 80.8 (range, 9-502) and both children and adults, for a total of 1212 patients. The dysgeusia frequency varied significantly, from 6% to 95%, with the research periods differing across studies, from the time of grafting to several years posttransplant. All frequencies and samples sizes are summarized in Figure 2.

Data collection methods included gustatory tests (n = 3), interviews (n = 5), and self-administered questionnaires (n = 7). Although the sample size precluded a robust statistical comparison, preliminary analysis of the data suggested that the methodology of data collection did not significantly affect the reported frequency of dysgeusia. The findings presented intervals of 0.214 to 0.300 with a weighted mean of 0.25 for gustatory tests, 0.33 to 0.95 with a weighted mean of 0.51 for interviews, and 0.20 to 0.64 with a weighted mean of 0.53 for self-administered questionnaires. Of note, gustatory tests, which appeared to report a lower frequency of dysgeusia, had a smaller subset of the data (comprising only 3 studies). This limited representation necessitates a cautious interpretation of the apparent lower frequency observed with gustatory test methodo-logies.

In studies that reported frequencies of dysgeusia, the value proximal to a 2-week interval was preferentially selected for inclusion in subsequent averaging processes. This selection criterion was underpinned by the rationale that this period postoperatively strikes an optimal balance for evaluation. It is sufficiently distanced from the immediate postsurgical phase to mitigate direct postoperative influences, yet not so delayed as to encroach on the time frame conducive to the natural resolution of dysgeusia symptoms. In addition, this methodological approach aimed to enhance the homogeneity of the dataset, thereby facilitating a more rigorous and standardized comparison across studies. Included studies are described in Table 2.

We considered other aspects, such the lack of short-term and long-term findings. Similarly, the kind of transplant examined (autograft or allograft) lowered the possibility of bias in this study. A large number of studies withheld results for >1 year or a given term of data collection (only 3 papers shared long-term results). Likewise, the number of patients included in each study must be considered. The degree of uncertainty will also depend on sample size. Sampling error is decreased as sample size is increased. Our analysis highlighted a small predominance of research focusing on AL (3 AL vs 2 AT). However, 30% of studies did not report the type of graft or did not represent the 2 types (AL + AT).

Findings indicated notably higher frequency of dysgeusia at the start of treatment, which decreased over time. Of the 15 articles, only 8 specified an exact period for data collection. This variability in the data collection time frame may affect the precision of the findings, particularly in determining the specific timing and duration of dysgeusia symptoms following HSCT. Furthermore, dietary issues are most prevalent after HSCT, where dysgeusia is a leading symptom. Of note, however, a considerable number of studies covered a wide range of data collection periods.

Only 3 of 15 studies evaluated dysgeusia in pediatric populations. The range of systemic frequency was smaller, with values ranging from around 3% to 6%. Despite the lower number of data, the largest study in terms of population was a pediatric study with 502 participations. Each study corresponded to 1 of the 3 data collection methods we encountered in the systematic review, and 2 of 3 were cross-sectional studies.

The evaluation of bias, including data collection method, data collection time frame, short-term and long-term results, and graft type definition, is shown in Figure 3.

Discussion

Dysgeusia is a common and variable condition experienced by patients undergoing HSCT. Mucositis and various oral lesions significantly contribute to its onset. The type of transplant, conditioning regimen, and use of radiation can all affect oral complications during HSCT. Allogeneic HSCT tends to exhibit higher rates of dysgeusia compared with autologous HSCT, possibly because of increased risk of GVHD and the need for more intensive immunosuppression in allogeneic transplants. The conditioning regimen also plays a critical role in the development of oral complications. Ablative regimens, which are typically more intense, can increase the risk of oral mucositis and dysgeusia compared with nonmyeloablative regimens. The use of radiation in transplant regimens can further exacerbate these complications, damaging oral tissues and affecting taste perception.25 Understanding these factors can guide interventions to manage or prevent dysgeusia and improve quality of life.

Dysgeusia is a frequent and variable pathology. The lowest frequency was explained by the analysis of severe dysgeusia combined with a long time frame postprocedure (90-100 days in this case).¹⁶ The highest frequency was explained by the broad definition of dysgeusia provided by the authors.¹² With regard to objectivity of data method, the gustatory test avoids errors such as forgetting or mixing, thus explaining a slightly decreased frequency of dysgeusia (questionable since the difference between frequency of dysgeusia did not appear to be significant). We also found more cross-sectional articles with interviews than gustatory tests, as the latter method is more complicated to implement.

Most of the studies suggested that dysgeusia during HSCT is a multifactorial process, particularly in the context of chemotherapy. Dysgeusia, primarily attributed to the cytotoxic effects of chemotherapy drugs,^8,12,26 is also recognized as a sporadic side effect of this treatment.13 Dysgeusia is believe to be caused by alterations in the taste buds, affecting their renewal process.^2,27 Wong and colleagues estimated that 50% to 75% of dysgeusia cases in HSCT recipients can be attributed to chemotherapy.²⁸ Similar observations have been made with radiotherapy treatments and their radioactive effects on cells. The primary mechanism behind taste disturbances after radiation exposure is believed to be the death of precursor cells of taste receptors.8 This observation also accounted for the higher number of publications that reported a short-term frequency of dysgeusia (14 articles) versus studies with long-term frequency (3 articles). The pronounced effect of treatment during the initial stages is believed to contribute to the peak of dysgeusia around the time of conditioning and transplantation. Of note, we must consider the potential bias in long-term studies, which may lose more patient perspectives and yield less significant results. Consequently, an effective yet minimal dose has been recommended to reduce side effects associated with HSCT, including dysgeusia.²⁹

Immunosuppressive therapies, commonly used in the context of transplant, can contribute to the development of dysgeusia and oral infections.²¹ Medications such as anticholinergics or antihista-mines may play a role by reducing salivary secretion, which increases the risk of dysgeusia, or by directly causing dysgeusia as a side effect.¹³ The adverse effects of various antibiotics or antirejection medica-tions on taste perception has been reported.³⁰

Another contributing factor to dysgeusia is the presence of tumors and their associated inflammatory mechanisms.^3,12,31 Individuals with cancer or inflam-matory conditions often experience alterations in their sense of taste. One prevailing theory suggests that the heightened concentration of tumor necrosis factor, a result of the inflammatory processes and cancerous diseases, could lead to lowered thresholds for detecting certain tastes and odors. This change in sensory perception is a significant aspect of how tumors and inflammation can impact taste. Systemic inflammation and the resultant alterations in interferon pathways and toll-like receptors negatively affect the renewal of gustatory brain cells, thereby contributing to the development of dysgeusia. One effect of inflammation, particularly induced by lipopolysaccharides, is the reduced proliferation of taste progenitor cells and an extended lifespan of taste bud stem cells.²⁷ Furthermore, high levels of interleukins, such as interleukin 6, during tumor development also appear to influence taste perception. In a study that focused on symptoms in patients with myeloma, 46% experienced dysgeusia.²⁹ This finding has led to treatment approaches for dysgeusia that involve blocking interleukin 6 pathways, highligh-ting the connection between inflammatory processes and taste alterations.²⁹

Mucositis and various oral lesions are major contributors to the onset of dysgeusia.^3,8,13 They affect 40% to 80% of patients undergoing anticancer therapy, with a higher severity often observed in those receiving HSCT.³² A link has been noted between the type of chemotherapy, the development of mucositis, and the frequency of dysgeusia.¹³ These factors are explained by the cytotoxicity of treatments that follow conditioning treatments. In the event of strict dental hygiene, the frequency of dysgeusia may be reduced by 70%, even throughout the healing period.⁴ Addressing mucositis is therefore an important focus in both the prevention and treatment of dysgeusia. However, drawbacks to treating mucositis occasionally occur. Palifermin (marketed as Kepivance), for example, was taken off the market as a result of number of adverse effects, including dysgeusia.

Hyposalivation, characterized by a reduction in salivary flow, can also lead to alterations in the oral flora, which in turn affects the various tastes detected by humans.^3,8 The precise mechanisms behind this are still under investigation.¹ Both the quality and quantity of saliva play a major role in dysgeusia; of note, treatments have an effect on taste buds. Hyposalivation is considered to be one of the causes of dysgeusia, as previously indicated.^2,8,26,31,33 Numerous factors, often variable and altered, affect the functioning of salivary glands. These include hydration levels, body weight, time of day, season, sex, and the size of the glands. Such factors can influence the quantity, quality, viscosity, and composition of proteins or ions in saliva.²³ Boer and colleagues reported that ~16% of patients are likely to experience a reduced salivary flow.31 Consequently, a treatment strategy to address this issue might involve the use of sialogogues, which stimulate saliva production, ensuring adequate hydration throughout the treatment process.³

Malnutrition has been identified as another potential source of dysgeusia. Previous work has established a link between dysgeusia and weight loss.18 This link may be due to a refusal to eat or a decrease in the nutritional quality of food consumed.^17,18,26 Both weight loss and reduced calorie intake have been associated with dysgeusia, potentially leading to a decline in quality of life.^13,34,35 Dysgeusia can cause severe malnutrition, as it may lead to food aversion, induce nausea, or even result in vomiting.^1,2,5,10,29 The studies that we analyzed showed that weight loss is both a consequence of dysgeusia and mucositis and a perpetuating factor. However, because the duration of mucositis is generally shorter than that of weight loss, mucositis may be considered a less important factor.¹³ A negative correlation between malnutrition and survival has been established, linking malnutrition with adverse clinical outcomes.³⁶ In response, nutritional supplements can be prescribed to prevent malnutrition by addressing dysgeusia indirectly, rather than managing it directly.³⁷

Dietary guidelines are often recommended during HSCT to mitigate issues with dysgeusia and malnutition,^12,29,38 which are aimed at providing balanced nutrition and helping manage symptoms associated with dysgeusia. Generally, individuals affected by dysgeusia exhibit 1 of 3 responses: increased food intake to compensate for the loss of flavor, decreased food intake due to a loss of enjoyment in eating, or maintained diet, adhering to their typical eating habits.¹⁷ This variation in responses underscores the complex interplay of physical, social, and emotional aspects in the experience of dysgeusia. During HSCT treatments, patients experiencing dysgeusia tend to have a lower nutritional intake compared with those who do not develop dysgeusia. This alteration in taste significantly influences food choices.⁵

The prescription of growth factors has been considered as a potential treatment option for managing dysgeusia during HSCT.⁸ This approach suggests a medical intervention to mitigate the adverse effects of dysgeusia on patients’ nutrition and overall well-being during treatment.

In the context of transplantation, people who are malnourished face an increased risk of graft rejection and actual rejection events.31 This is particularly important in patients with dysgeusia, who often require prolonged nutritional support via parenteral means.¹³ This is due to a dual effect: the dependence on nutritional assistance resulting from weight loss and the loss of appetite caused by dysgeusia. The heightened risk of rejection in the context of allogeneic HSCT is more prominently reflected in our research, as evident in our table. Of studies reviewed, 3 specifically mentioned this risk in the context of allogeneic HSCT, compared with 2 that discussed it in relation to autografts. This disparity highlights the greater challenges faced in managing nutritional issues and rejection risks in scenarios of allogeneic transplant. In autologous transplant cases, the side effects, including dysgeusia, appear less pronounced.³⁰ However, in allogeneic transplant, a potential for selection bias must be considered because of increased likelihood of secondary effects. This bias could potentially reinforce the perceived connection between dysgeusia and HSCT.

Exploring the role of the altered microbiome in dysgeusia is also insightful. The presence of a less diverse oral flora, coupled with medication residues in saliva, can affect the tongue’s capacity to accurately perceive taste.^1,8,12 This effect is mediated through the lingual papillae, which are responsible for taste sensation.²⁹ The balance of the oral microbiome is crucial, as it can either stimulate or inhibit taste reception, indicating a major link between oral health, medication use, and taste perception in dysgeusia.

Taste alterations are observed during episodes of apoplexy.³⁹ Changes in blood composition can also affect oral health and, consequently, taste perception.³ For example, in one study, 21.4% of patients experienced dysgeusia following the onset of neutropenia.¹⁸ This highlights the influence of hematological changes on the oral environment and taste sensation.

Other contributing factors to dysgeusia include GVHD,^3,4,8,40 which is an immune response of donor cells against the host’s cells. Symptoms associated with GVHD, such as dysgeusia, xerostomia, infections, and oral pain, further complicate the condition.^39,41 In addition, social and emotional factors are also found to influence dysgeusia.

In the pediatric context, one study suggests that children undergoing cancer treatment who expe-rience vomiting and nausea are more prone to dysgeusia compared with others. Similarly, children who are not native English speakers also exhibit a higher susceptibility to dysgeusia, an observation that may be associated with genetic or cultural factors.⁴² In contrast, school-aged children and those undergoing treatment for acute lymphoblastic leukemia seem to have a lower chance of developing dysgeusia, unlike hospitalized children with acute myeloid leukemia receiving anticancer therapy.¹¹ These findings imply that the social environment plays a role in the development of dysgeusia. Pediatric studies, as shown in the table, typically present short-term results, with slightly lower rates among children than in adults. Long-term studies in the pediatric population suggest not only a faster recovery rate but also potential challenges in conducting extended research in this demographic. However, the long-term data might affect our understanding of dysgeusia’s long-term effect on children.

The frequency of dysgeusia in children is influenced by various factors, such as the time elapsed since the graft, the presence of oral mucositis, sex, age, nutritional status before HSCT, diagnostic outcomes, and the presence of infections. Infections are common and distressing in the context of cancer treatment. Dysgeusia also tends to manifest around the time of the conditioning therapy. The prevailing hypothesis suggests that the faster cellular regene-ration in children, particularly in the development of gustatory receptors, plays a substantial role.²⁹ Therefore, it appears that children recover more quickly. The limited number of pediatric studies (only 3 of the 15) poses a challenge in thoroughly analyzing results within this specific population group. Of note, the lowest rate of dysgeusia in this population was represented by the gustatory test (0.3 vs 0.603 for questionnaire and 0.4 for interview).

Dysgeusia has been observed to heighten the risk of morbidity in patients and affect their likelihood of recovery, notably by extending the duration of hematological care required.¹⁴ This underscores the importance of researching and implementing effective preventive or therapeutic strategies to address this secondary effect, which has significant repercussions for patient well-being and recovery. Addressing dysgeusia promptly and effectively is crucial because of effects on patient outcomes and the overall treatment process.

In addressing dysgeusia treatments, effectiveness largely depends on the treatment’s rapidity of action.⁹ One frequently discussed option is oral cryotherapy, which has been shown to prevent the onset of dysgeusia.^3,9,13,28,29 Its effectiveness is attributed to vasoconstriction and the resultant decrease in blood flow, which reduces the concentration of medications in the buccal mucosa.¹³ This principle is based on the analgesic effects of cold. In addition, maintaining good oral hygiene is crucial.^3,8 This includes a thorough examination of the oral condition before starting HSCT, with 87% of centers surveyed requiring dental clearance beforehand according to a recent survey of transplant sites in the Eastern Mediterranean region.¹⁴ Another approach targets the taste buds directly, with zinc sulfate sup-plementation aiding in their development.^2,8,38 Lastly, enhancing flavors using spices, acidity, or enco-uraging snacks to increase appetite can also be of benefit. Regular rotation of foods during meals can prevent the gustatory cells from adapting, and slow chewing can enhance flavor perception.28 These diverse strategies highlight the multifaceted approach needed to effectively manage dysgeusia in patients undergoing treatment.

Conclusions

The frequency of dysgeusia varies considerably across studies, with a notable spike observed approximately 7 days after HSCT. The findings present intervals of 0.214 to 0.300 with a weighted mean of 0.25 for gustatory tests, 0.33 to 0.95 with a weighted mean of 0.51 for interviews, and 0.20 to 0.64 with a weighted mean of 0.53 for self-administered questionnaires. The limited number of studies necessitates a cautious interpretation of the apparent lower frequency obser-ved with gustatory test methodologies. Allogeneic transplants, particularly in the adult population, tend to exhibit higher rates of dysgeusia. Influencing factors such as time since HSCT, mucositis, sex, nutritional state, diagnosis, and infections underscore its multifactorial nature. Treatment strategies like oral cryotherapy, zinc sulfate supplementation, dental hygiene, and flavor enhancement have been explored, with their effectiveness often depending on the speed of implementation.

Dysgeusia can affect nutritional status, leading to weight loss and potentially diminished quality of life. A direct link has been observed between malnutrition and decreased survival rates. In addition, social and emotional factors play a role in the onset of dysgeusia. Ultimately, dysgeusia not only increases the risk of morbidity but also extends the duration of hematological care. Continued research is urgently needed on effective preventive and therapeutic measures to combat this challenging secondary effect.

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