Unlocking the Complex Flavors of Dysgeusia after Hematopoietic Cell Transplantation

Abstract

Dysgeusia is a frequently encountered symptom for patients after hematopoietic cell transplantation that has important long-term effects on physical, nutritional, and immunologic recovery as well as quality of life. Despite the relevance of this symptom, there has been limited study of dysgeusia in patients undergoing hematopoietic cell transplantation, in part due to its complexity. In this article, we review normal taste function and its clinical evaluation, discuss how dysgeusia uniquely affects patients undergoing hematopoietic cell transplantation, and examine distinct, transplantation-related contributors to dysgeusia that may help elucidate strategies to ultimately reduce this symptom burden after transplantation.

Introduction:

Taste disturbance, known as dysgeusia, is an often-reported, yet underappreciated sequela of cancer therapy that can markedly affect patients’ everyday quality of life (QoL).¹ While dysgeusia is not unique to the field of hematopoietic-cell transplantation (HCT), this complication may be most pertinent in the early post-transplantation period when direct conditioning regimen-related mucosal injury impairs taste and flavor perception, nutritional absorptive capacity, and when myelosuppression and delayed immune recovery affect mucosal immunity and oropharyngeal microbiome biodiversity.^2-6 Moreover, distinct transplantation-related complications such as graft-versus-host disease (GVHD) can further negatively affect taste perception.^7,8 All of these contributing factors impede the adequate nutrition necessary to promote physical and emotional recovery as well as adequate immune reconstitution.

While practicing transplanters find themselves discussing taste disturbances with their patients frequently, the pathophysiology of dysgeusia is poorly understood, and to our knowledge, it has not been widely evaluated in prospective HCT clinical trials. As the number of annual transplantations performed continues to grow, and the number of older long-term survivors increases, we feel it is essential to bring attention to this complication.^9,10 In this article, we will review normal taste function and how it is evaluated, discuss unique transplantation-related factors that contribute to dysgeusia, and examine potentially novel strategies to both study and mitigate dysgeusia in this patient population.

Review of Taste Function

At its fundamental level, the sense of taste evolved to allow an individual to appraise ingested items as nutritious food or noxious material. It also allows us to derive satisfaction and pleasure from the experience of eating.¹¹ As such, taste plays a critical role both in our nutritional status and QoL. Human flavor perception is a highly regulated and multicomponent sensorial system that involves neuronal pathways, the sense of olfaction, and adequate saliva production.⁸ At the time of food consumption, salivary enzymes dissolve taste molecules that are delivered to taste receptors. Multiple taste receptor cells contained within taste buds of the tongue, palate, and oropharynx function as neuro-receptors. Three distinct types of taste receptor cells are thought to transduce specific taste stimuli. All of these subtypes turn over after about 10 to 14 days when they undergo apoptosis and are continually renewed.¹² Stimulation by molecules of ingested food leads to signaling that is mediated by G-protein-coupled receptors and nerve depolarization through sensory afferent pathways of cranial nerves VII (facial), IX (glossopharyngeal), and X (vagus) and a portion of the mandibular branch of V (trigeminal), that converge upon the nucleus tractus solitarius of the medulla and through parabrachial nucleus.^1,11,13 Subsequently, they connect in the thalamus, amygdala, and insular cortex of the brain where this complex system is integrated into a gustotopic map with distinct neuronal areas that correspond to specific taste qualities.^14,15 A schematic of the basic taste pathway is illustrated in Figure 1. Further complexity is added to this neuronal system with the contributions of orthonasal and retronasal olfaction during mastication, which is easily identifiable clinically by any person who has previously experienced flavor disturbances with a loss of the sense of smell.^16,17 The intricacies of these neuronal networks help explain some of the difficulty treating dysgeusia, given the numerous potential etiologies that can affect taste perception along any of these pathways.¹

Figure 1. Schematic of Basic Taste Pathway.

This simple schematic (not every aspect of this complex pathway is shown) shows the basic taste pathway. Taste molecules stimulate taste receptors, located on taste buds in the oropharynx. These taste signals are carried by afferent nerve fibers of cranial nerves (CN) with branches converging at the nucleus tractus solitarius (NTS). The gustatory signal then projects to the parabrachial nucleus (PBN) in the pons. From there, connections are made in the thalamus, amygdala, and insular cortex of the brain where this complex system is integrated into a gustotopic map corresponding to specific taste qualities (Adapted from references 11, 13, and 18).

There are at least five basic human taste qualities which identify unique chemical qualities in food: sweetness, bitterness, saltiness, sourness, and a more recently described taste known as umami that recognizes savory, glutamate-rich foods. Less well-defined taste qualities such as spiciness and oleogustus (“fattiness”), among others, can add flavor depth to the experience along with the contributions of retro-olfaction as mentioned above.^1,11,18,19 Patients treated for cancer can report loss of specific taste qualities; however, they often describe a chronic bitter or metallic taste that affects the flavor of all ingested foods and liquids.²⁰

Causes of Taste Disorders in Patients with Cancer

Taste disorders in patients with cancer are often have multiple etiologies.¹⁹ Patients with head and neck cancer undergoing multi-modality treatment with surgery, chemotherapy and radiotherapy (RT) are the most well studied population.²¹ The incidence of taste disturbances in this population has been reported as high as 75 to 100% in several series with some patients reporting taste changes even prior to the beginning of treatment, suggesting a direct impact from the tumor.²² In a mouse model developed by Nguyen et al., in which taste buds were disrupted by radiation exposure, the primary mechanism of taste disturbance after RT was direct injury to taste-receptor progenitor cells that impeded normal cell turnover.¹² In addition, RT damages salivary glands resulting in hyposalivation and in often painful naso-oropharyngeal mucositis that may exacerbate taste dysfunction.²³ Along with direct injury to the oral mucosa and tongue epithelium, surgery and RT can also affect taste through injury to the larger cranial nerves described above. These multi-factorial mucosal effects are often further compounded by concurrent cytotoxic and targeted chemotherapies, as well as supportive medications that damage rapidly diving taste receptor cells, impact salivation, and cause neuropathy.^24-26 Moreover, numerous supportive medications with different mechanisms of action have been reported to cause reversible taste disorders including antimicrobials, diuretics, anti-hypertensives, which are all frequently used after HCT.^27-29

Unique Aspects of Taste Disturbances in Patients Undergoing HCT

Conditioning Regimens

The contributors of dysgeusia may be different in recipients of autologous stem-cell transplantation (ASCT) versus allogeneic hematopoietic-cell transplantation (allo-HCT).^{30, 31} Early taste disturbances after ASCT are largely caused by direct conditioning-regimen related oral mucosal and salivary gland injury from chemotherapy with or without RT. A patient’s underlying disease often dictates the conditioning regimen of choice, which in turn variably affects the severity and duration of dysgeusia and decreased saliva production. The most common indications for ASCT are multiple myeloma and non-Hodgkin lymphoma for which high-dose melphalan and combination chemotherapy regimens such as carmustine, etoposide, cytarabine and melphalan (BEAM) remain widely utilized.^{32, 33} A recent retrospective analysis of patients with lymphoma and myeloma undergoing a BEAM-like regimen and high-dose melphalan, respectively, demonstrated that combination chemotherapy conditioning regimens and the development of oral mucositis were both independent risk factors for dysgeusia. Patients with myeloma who utilized oral preventive cryotherapy prior to high-dose melphalan were at less risk of significant taste disturbances.³⁴ No other patient or transplant characteristics were found to modulate the risk of developing dysgeusia. Moreover, nutritional intake measurements confirmed that patients who developed dysgeusia had lower total caloric intake and more frequently required total parenteral nutrition (TPN). Late effects on taste after ASCT appear to be largely a function of residual conditioning regimen effects, unwanted side effects of supportive medications, and other ordinary causes of smell loss and dysgeusia in patients with chronic disease.^2,8

For patients undergoing allo-HCT, dysgeusia appears to be a longer-lasting and more complex problem due, perhaps due to the more intense conditioning regimens, exposure to immunosuppressants, and the increased frequency of infections and the allo-reactive complications unique to this type of transplantation.³⁰ While most chemotherapy-only myeloablative conditioning regimens pose a similar risk for taste disturbances and anorexia as they do for patients undergoing ASCT, total-body irradiation (TBI) based conditioning is more often used in allo-HCT and is associated with more profound mucosal injury. A common GVHD prophylaxis regimen employs methotrexate, which has well-known mucosal toxicity.³⁵ Even in the absence of methotrexate-containing GVHD prophylaxis regimens, TBI-based regimens are associated with mucositis rates of up to 64%.³⁶

Graft-versus-Host Disease

Several pro-inflammatory cytokines, including interleukin (IL)-2, IL-6 and tumor necrosis factor-alpha have been reported to negatively affect symptoms such as appetite in cancer patients.³⁷ In a study of patients after myeloablative conditioning and allo-HCT, these cytokines were markedly increased in the early post-transplantation period, coincident with decreased oral intake. Interestingly, patients with persistent fever had the most significant reductions in measured oral intake.³⁸ In contrast, a study by Mattsson and colleagues found a significant correlation between the number of days without oral intake, which may reflect the severity of mucositis, and the development of severe GVHD. Based on their findings and previous studies, the authors suggested that promoting enteral nutrition after allo-HCT might represent an opportunity to reduce the production of gut-associated pro-inflammatory cytokines, thus potentially improve oral intake.³⁹ While these studies support the association of GVHD with anorexia and reduced oral intake, it is unclear whether these effects are at all mediated through taste disturbances. Taste acuity measured prospectively in three groups of patients at different time points after allo-HCT surprisingly showed no association between taste disturbances and salivary output with concurrent incidence of chronic oral GVHD, though there were clear changes in taste perception that persisted as far as 3 years after allo-HCT in some patients.⁸ These data highlight the need for further inquiry regarding the role of GVHD in affecting normal taste.

Dysgeusia and Malnourishment

Taste disturbances can have profound, objective effects on dietary intake and certain indicators of nutritional status after HCT such as albumin. Hypoalbuminemia is a reflection of multiple factors including liver synthetic function, the inflammatory cytokine milieu, and losses through proteinuria or protein-losing enteropathy, with nutritional status representing only one key component.⁴⁰ However, multiple studies have demonstrated an association between pre- and post-transplantation albumin levels and the development of GVHD, non-relapse mortality (NRM), and overall survival.^40-42 Hypoalbuminemia also contributes to post-transplantation volume overload, which is now recognized as an important adverse event with serious implications on NRM.⁴³ A deleterious cycle of intravascular fluid loss and marked interstitial edema due to hypoalbuminemia and impaired vascular tone clinically influences the use and overuse of intravenous (IV) fluids after transplantation further exacerbating the problem, even in the absence of sepsis or overt critical illness.^44,45 In a study of 48 patients undergoing high-dose therapy and ASCT, 24 patients (42%) reported dysgeusia. These patients had poorer nutrition, with longer periods of decreased oral intake and more days requiring parenteral nutrition than those not reporting taste disturbances.³⁴ The presence of mucositis and the intensity of the conditioning regimen were independent risk factors for developing dysgeusia. These studies underline associations between taste disturbances and poor dietary intake, and suggest that dysgeusia may play an integral role in contributing to this cycle of poor nutrition, GVHD, and NRM.

Similarly, by decreasing the desire for oral intake, dysgeusia likely affects other surrogate measures of nutritional status after HCT, such as weight loss and body-mass index (BMI). Patients considered malnourished using these surrogate measures after HCT have inferior overall survival in patients considered malnourished.⁴⁶ A large study reported by Navarro et al. using data from the Center for International Blood and Marrow Transplant Research reported an increased risk of all-cause death among underweight patients as compared to normal-weight patients.⁴⁷ It should be noted that while weight and BMI are often used as surrogates of nutritional state, they imperfectly reflect the full biological assessment of nourishment. This may be particularly true as we develop a more robust understanding of the role of cardiopulmonary health, muscle mass, and physical conditioning on post-transplantation recovery and outcomes.^46,48 Diminished post-transplantation oral intake and progressive weight loss often necessitate provision of nutrition support. Recent consensus guidelines from the United States and Europe have more clearly specified the importance of enteral nutrition (EN) over parenteral nutrition (PN) in patients after HCT.^46,49 An observational study using propensity score adjustment showed that patients fed via EN had improved overall survival and lower rates of acute GVHD when compared to patients receiving PN.⁵⁰ In a similar study, while Guieze and colleagues found no overall survival difference, patients receiving EN had fewer days of fever, a reduced need for anti-fungal therapy, and less risk of transfer to a higher level of care.⁵¹ A highly relevant, prospective, randomized study comparing NRM rates between patients with hematologic malignancies receiving EN versus PN after allo-HCT is currently ongoing ().⁵² Whether reductions in taste disturbances could further influence improvements in post-transplantation oral intake in patients has not been studied prospectively and requires investigation.

Immune Recovery

By influencing appetite and nutritional intake, dysgeusia also indirectly impacts immunity, as there are well-recognized relationships between malnutrition and weight loss, impaired healing, and ineffective innate and adaptive immune responses.⁵³ In the early post-transplantation time period, immune recovery represents a critical step in avoiding life-threatening infections and risk of disease relapse.⁵⁴ The thymus maintains effective immune function, and thymic atrophy from malnourishment suppresses T-cell maturation and function. This is particularly relevant in older adults that naturally have thymic involution with advancing age, and in the context of conditioning regimen- and GVHD-related thymic injury after HCT.^55-58 Nutritional formulas designed to improve immune responses, also known as immunonutrition, have been studied in multiple populations, such as critically ill patients, with mixed and sometimes negative results.^59-61 Interestingly, anorexia during infection is a widely recognized phenomenon, and is thought by some to represent an adaptive response that upregulates and improves autophagy in immune and non-immune cells.⁶² Whether optimal timing of our nutritional efforts could maximize immune function after allo-HCT requires further inquiry.

The Unique Role of the Microbiome

Recent advances in sequencing technology have allowed renewed investigations into the multifaceted and integral role of the human intestinal microbiota in health and disease.⁶³ Patients undergoing allo-HCT represent a distinctive group in which to study the intestinal microbiota given the intense nutritional disturbances and antibiotic exposures. Conditioning regimens result in marked colonic mucosal injury, which allows for resulting gut translocation of microorganisms or their products such as lipopolysaccharide, as well as poor nutritional intake and dysgeusia.⁶⁴ GVHD-prophylaxis medications, prolonged exposure to antibiotics, and donor-host immunologic interactions all contribute to these complex interactions.⁶⁵ Reductions in intestinal flora diversity and the abundance of specific species within the intestinal lumen have been linked to post-transplantation outcomes such as: GVHD, pulmonary complications, bacteremia, Clostridium difficile infection, relapse, and overall survival.^5,66-70 This is of particular interest given the burgeoning literature linking the impact of the human diet on modifying the gut microbiome and how these micro-organisms in turn influence nutritional habits and behavior.^71,72

While most microbiome studies in the transplantation setting have focused on intestinal microbiota, the changes that occur in the oral microbiome during transplantation and what role they may play in dysgeusia or other transplantation outcomes has not been well studied. Pilot data from our institution (reported in abstract form) suggests that oral bacterial biomass declines early after transplantation and increases following hospital discharge, and that most patients experience a significant shift in oral bacterial composition over the course of transplantation.⁷³ The role of oropharyngeal microbiota in affecting the oral environment, specifically oral mucositis and dysgeusia remains unclear.^74,75 Given the immense diversity of the oropharyngeal flora and the known effects of the gastrointestinal microbiota, it stands to reason that the oropharyngeal microbiota plays a role in both mucositis and taste disturbances, and may play a role in oral chronic GVHD.⁷⁶ Previous studies evaluating the role of oral microbes in the development of mucositis are confounded by patient, disease and methodological heterogeneity.^77,78 The paucity of data regarding the role of oropharyngeal microbiota in affecting taste disturbances, nutrition and outcomes highlights the need for further inquiry.

Quality of Life

Only a few studies have quantified the symptom burden of dysgeusia. Sonis and colleagues prospectively examined physical, emotional, and social function in 56 patients in their first year after HCT and found that 20% of patients reported dysgeusia that impacted QoL.² Campagnaro et al. prospectively evaluated the symptom burden of patients undergoing high-dose melphalan-based ASCT within the first 30 days using a previously developed MD Anderson Symptom Inventory – Blood and Marrow Transplantation (MDASI-BMT) and found that the most common early post-transplant symptoms included fatigue, weakness, anorexia/nausea, diarrhea, and insomnia.⁷⁹ Importantly, these symptoms were associated with decreased frequency of physical activity and QoL. While many of toxicities in this prospective study are interrelated, dysgeusia likely contributed in part to these symptom clusters.^80,81 Table 2 includes a summary of selected published trials of dysgeusia and related factors after hematopoietic cell transplantation

Table 2.

Selected Published Trials of Dysgeusia and Related Factors after Hematopoeitic Cell Transplantation

Study	Study Type	Type of HCT (No. of patients)	Outcome/Findings
Dysgeusia and/or Oral Mucositis
Marinone et al. (2001)30	Retrospective	ASCT (8) Allo-HCT (15) Normal subjects (20)	Allo-HCT: hypogeusia for salt; no variations for sweet and bitter ASCT: no variation for sweet, salt, sour
Cutler et al.(2005)35	Retrospective	Allo-HCT: MTX-based GVHD ppx (24) Non-MTX-based GVHD ppx (30)	Mild, moderate, and severe mucositis (%) MTX group: 8%, 42%, 50% Non-MTX group 37%, 57%, 7% Less TPN, less narcotic use in non-MTX group, shorter hospitalizations
Okada et al. (2016)34	Retrospective	ASCT (48)	20 (42%) patients had dysgeusia TPN rates higher in those with dysgeusia Combination chemo and oral mucositis risk factors for dysgeusia Oral cryotherapy reduced dysgeusia
Dysgeusia/Nutrition & GVHD
Boer et al. (2010)8	Prospective	Allo-HCT	Measured taste perception, salivation and oral pathologies Taste alterations noted over long-term follow-up 31 patients had cGVHD No correlation between taste dysfunction and oral cGVHD Salivation was lower in 16% of patients
Malone et al. (2007)38	Prospective	Allo-HCT (147)	Determined oral intake, assessed cytokines levels and correlation with anorexia Oral caloric intake reduced in 92% Plasma cytokines (IL2, IL6, TNF-a) abnormally elevated early post-HCT Patients with persistent fever had greatest reduction in oral intake
Mattsson et al. (2006)39		Allo-HCT (231)	Studied nutritional history of patients after allo-HCT Patients with high-grade GVHD received more PN than low grade GVHD Correlation found between number of days without oral intake and incidence of aGVHD. >9 days without oral intake associated with high-grade GVHD [OR 7.66 (CI 1.44-40.7), p=0.016]
Dysgeusia & Anorexia/Malnourishment
Seguy et al. (2006)50		Allo-HCT (45): Received EN (22) Received PN (23)	Those who received EN v. PN had less high-grade aGVHD (18% v. 35%, p=0.011). EN group had lower infection-related mortality
Navarro et al.(2010)47	Retrospective	ASCT & Allo-HCT(4215)	Patients total compared based on BMI: Increased risk of death for underweight patients in related donor allo-HCT No other major differences in outcome
Rezvani et al.(2011)42	Retrospective	Allo-HCT (401)	≥0.5 g/dL decrease in serum albumin from baseline until aGVHD was 69% sensitive and 73% specific predictive for aGVHD ≥0.5 g/dL decrease in serum albumin associated with poorer OS after aGVHD
Kharfan-Dabaja et al. (2011)41	Retrospective	Allo-HCT (163)	Serum albumin <3 g/dL and KPS <80 at day +90 independently predicted for poorer NRM and OS
Sivgin et al.(2013)40	Retrospective	Allo-HCT (102)	Serum albumin < 3.2 g/dL lower OS and DFS compared to patients with ≥3.2 g/dL
Dysgeusia & Quality of Life (QoL)
Sonis et al.(2001) 2	Prospective	ASCT & Allo-HCT (92)	Measured oral mucositis using OMAS early post-HCT and relationship between post-HCT toxicities. Peak OMAS scores associated with: Additional days with fever, TPN and opioid use Longer length of hospital stay Increase in risk of day-100 mortaliy
Epstein et al. (2002)3	Prospective	Allo-HCT (50)	QoL surveys with oral symptom, taste and smell assessments administered 3 months post-HCT: Abnormalities in taste were noted, particularly sour and bitter taste Females taste perception affected more than males Increased smell sensitivity noted
Campagnaro et al. (2008)79	Prospective	ASCT 64 patients	Evaluation of symptom burden after ASCT for multiple myeloma using MDASI: High MDASI scores early post-HCT that returned to baseline by day +30 in most patients. Women and those with prolonged time to ASCT had higher baseline MDASI scores.

The Assessment of Taste Dysfunction

A detailed patient history assessing the onset and quality of symptoms, medication review, and a comprehensive head and neck physical examination are invaluable tools in identifying the etiology of taste disturbances. Commercially available kits such as the University of Pennsylvania Smell Identification Test (UPSIT) have been used to evaluate the contribution of olfactory disturbances to dysgeusia.^1,82 Relevant laboratory testing for electrolyte disturbances and for hepatic and renal function may also be indicated in certain cases. For example, hyperuricemia is known to be associated with appetite suppression.⁸³

Given the importance of flavor on QoL and adequate nutritional intake, it is essential to integrate both subjective and objective data in assessing dysgeusia after HCT. Several scoring systems have been used to quantify and quality dysgeusia: the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Scale of Subjective Total Taste Acuity (STTA).^{84, 85} Table 1 summarizes two clinician-based tools for assessing taste disturbances, the CTCAE version 4.0 and STTA scoring systems. Additionally, taste abnormalities can be obtained with patient-reported outcomes (PRO) instruments such the National Cancer Institute (NCI)-PRO CTCAE, which can further compliment standard clinician toxicity reporting.⁸⁵ Chemical gustometry represents an objective and standardized testing instrument to assess taste function. In whole-mouth gustometric testing, patients first rinse their mouth with room temperature water. Then, small amounts of specific chemical reagents at various concentrations that test the above-reviewed 5 taste senses are swished around their mouths or applied directly throughout the tongue and mouth by soaked filter paper/applicators or droppers. Similarly, spatial taste testing allows the tester to compare taste changes on different areas of the oral cavity.¹

Table 1:

Scoring Systems for Assessing Taste Disturbances

	CTCAE v. 4.0	Scale of Subjective Total Taste Acuity (STTA)
Grade 0	None	No change in taste acuity from baseline
Grade 1	Altered taste, no change in diet	Mild loss of taste acuity, but not inconvenient in daily life
Grade 2	Altered taste with change in diet (e.g., oral supplements); noxious or unpleasant taste; loss of taste	Moderate loss of taste acuity, and sometimes inconvenient in daily life
Grade 3	--	Severe loss of taste acuity, and frequently inconvenient in daily life
Grade 4	--	Almost complete or complete loss of taste acuity

Adapted from references 84 and 85.

Given the known contributions of salivation on taste disturbances, additional complementary patient evaluations include salivary measurements, which objectively estimate the stimulated and unstimulated salivary flow rate. Boer and colleagues evaluated oral examinations, taste changes, and salivary flow rate in 61 patients after allo-HCT in the largest prospective study of chemical gustometry. They noted definitive taste alterations over an extended period of time post-HCT, which highlights the notion that these changes often do not correlate with oral mucosal injury related to chronic GVHD and/or changes in salivary function.⁸ This study established the proof-of-principle that chemical gustometry and salivation rates can be studied systematically and prospectively, but it also highlighted the difficulty in understanding specific pre- and post-HCT patient characteristics that may contribute to oral pathology given the heterogeneity of patients and diseases. Mucosal sensitivity that may represent mucosal atrophy or neuropathy, particularly of C-fibers, may affect diet.¹⁹ Further oral evaluation includes assessment of oral hygiene and levels of dental plaque.

Prevention and Treatment

There are no specific and effective treatments for patients with dysgeusia. Several published studies of zinc supplementation have demonstrated modest improvements in taste disturbances, particularly for patients with known zinc deficiency, though zinc supplementation is rarely used in practice.^86-89 Most treatment strategies in this area have largely focused on prevention of oropharyngeal mucositis (OPM). Attempts to prevent or alleviate OPM with agents such as keratinocyte growth factor (KGF), free-radical reducers such as amifostine, pentoxifylline, or topical/systemic analgesics have yielded mixed results.^90,91 Three main strategies have shown consistent efficacy in certain patient populations: systemic KGF in patients undergoing TBI-based myeloablative conditioned HCT, topical cryotherapy in patients receiving high-dose melphalan and ASCT for multiple myeloma, and photomodulation with low level laser light therapy (LLLT) in various chemotherapy and RT protocols.^36,90,92-94 Each of these strategies has potential advantages and limitations including variable clinical utility and effectiveness in specific populations as well as cost considerations.^92,95-97 Good oral hygiene, addressing dental/oral disease and hyposalivation, should be recognized as important in taste management. Potential additional approaches for dysgeusia may include treatment trials of megestrol, cannabinoids, and Synsepalum dulcificum (Miracle Berry), which have limited evidence of benefit.⁹⁸ Studies of these agents in patients undergoing HCT are needed.

Conclusions and Future Directions

Dysgeusia in patients undergoing HCT is a complex syndrome. A better understanding of its etiology and pathobiology, and the preventative or therapeutic strategies that could be developed would likely have a major positive impact on QoL and possibly on other outcomes such as NRM. As our biological understanding of contributing factors towards dysgeusia broadens and deepens, it is essential to design innovative and multi-modal studies that incorporate our growing knowledge of the interactions between host and microbiota, nutrition and dietary intake, personalized approaches to conditioning regimen administration, immune recovery, and novel preventive strategies such as photomodulation with LLLT. This will open the door to impactful prospective studies that attempt to minimize confounding variables by selecting homogeneous patient populations, diseases, and conditioning platforms. The prospective strategies chosen must include patient-reported-outcomes data and should evaluate whether the studied approach is clinically and economically effective. High-quality data from well-defined and carefully selected patient populations may be applicable across HCT platforms and may inform strategies to reduce the incidence, severity, and symptom burden of dysgeusia. Moreover, the information gained through this work may be relevant in the care of patients undergoing cytotoxic therapy for other malignancies.

Highlights.

• Dysgeusia is a pervasive and complex complication of hematopoietic-cell transplantation.

• It has an impact upon many factors such as oral diet, quality of life, physical, and immunologic recovery.

• Innovative studies are required to understand its pathobiology, and to manage dysgeusia after HCT.