Introduction
Hematopoietic stem cell transplantation (HCT) constitutes a potentially curative modality for patients with hematologic malignancies, especially leukemias [ 1 ]. Nevertheless, the requisite high-dose conditioning regimens frequently precipitate profound myelosuppression and injury to rapidly proliferating tissues in the oral and gastrointestinal mucosa [ 2 , 3 ]. Oral ulcerative mucositis (OUM) emerges as one of the most prevalent and debilitating complications, manifesting as inflammation, erythema, and painful ulceration of the oral mucosa [ 4 , 5 ]. Reported incidence varies by transplant modality; in autologous HCT, OUM afflicts 40–60% of recipients, whereas in allogeneic HCT, rates increase to 70–99%, which is attributable to intensified conditioning and graft-versus-host disease (GVHD) prophylaxis incorporating methotrexate [ 6 ].
Severe OUM significantly compromises patients’ quality of life through various mechanisms, including intractable oral pain, impaired nutritional intake, dysphagia, and dysarthria [ 7 , 8 ]. These manifestations often necessitate escalation of analgesic interventions, including opioids, and dependence on total parenteral nutrition (TPN) to sustain caloric requirements [ 1 , 7 ]. Additionally, OUM disrupts mucosal integrity, creating a portal for translocation of oral commensals and pathogens during neutropenia and thereby increasing risks of febrile neutropenia, bacteremia, and sepsis [ 9 – 12 ]. Seminal investigations have elucidated that severe mucositis confers a nearly fourfold elevation in infectious complications [ 12 , 13 ]. This increased risk has economic ramifications, including incremental hospital charges surpassing $42,000 per episode, predominantly driven by protracted hospitalizations and intensified supportive care [ 1 , 14 , 15 ].
Hospital length of stay (LOS), delineated by discharge timing (discharge date minus admission date), represents a critical clinical and resource utilization metric in HCT [ 16 , 17 ]. Autologous recipients are typically discharged within 10–20 days, whereas allogeneic cohorts often require 20–25 days or greater, owing to protracted engraftment, donor type, GVHD surveillance, and toxicity management [ 18 , 19 ]. Delayed discharge frequently reflects underlying complications, such as severe OUM or infections, while concurrently heightening nosocomial exposure. This engenders a reciprocal dynamic: severe OUM may defer discharge via symptomatic burden and incipient infections, while prolonged hospitalization exacerbates toxicity through sustained immunosuppression and environmental pathogen exposure [ 11 , 12 ].
Current literature mainly evaluates outcomes longitudinally or without stratification by discharge timing tailored to transplant type [ 10 ]. This makes it difficult to identify complication clustering in delayed-discharge cohorts. Stratifying by discharge timing—10–19 vs. 20–29 days in autologous HCT and 15–24 vs. 25–34 days in allogeneic HCT—creates an innovative lens to investigate whether protracted discharge signals increased systemic morbidity among those affected with OUM [ 10 , 12 ].
Utilizing nationally representative discharge data, the present investigation characterizes OUM in HCT recipients stratified by discharge timing. We hypothesized that prolonged discharge cohorts (20–29 days for autologous and 25–34 days for allogeneic) would exhibit substantially elevated rates of both healthcare-associated complications such as septicemias and modality-specific morbidities, including coagulopathies, hypertension, and congestive heart failure, persisting after covariate adjustment. By prioritizing discharge-based stratification, this inquiry generates novel perspectives on the temporal aggregation of oral-systemic sequelae, informing precision supportive care to expedite safe discharge and reduce morbidity. This retrospective cohort study aimed to evaluate, among HCT recipients with documented OUM, whether prolonged hospital discharge timing—used as a pragmatic proxy for extended length of stay (LOS)—is associated with increased systemic complications. By focusing exclusively on patients who developed OUM and stratifying them by discharge timing, we sought to determine whether prolonged hospitalization identifies a high-risk subset of OUM patients with greater systemic morbidity.
To consider professionally-delivered oral care regimens as the gold standard for preventing systemic infections after HCT, a number of important questions must be addressed:
To what extent does prolonged hospital discharge timing—serving as a proxy for extended LOS—correlate with increased systemic complications, such as septicemia and healthcare-associated infections, among HCT recipients diagnosed with OUM? Are there transplant-specific differences in the association between delayed discharge and adverse outcomes in patients with OUM? Does the clustering of systemic morbidities (e.g., coagulopathies, hypertension, congestive heart failure) in prolonged-discharge cohorts persist after adjustment for demographic factors and comorbidity burden, suggesting a complication-driven prolongation of hospitalization? Can discharge timing stratification (earlier vs. later) within a cohort of patients with documented OUM reveal patterns of morbidity that are obscured in unstratified comparisons?
Methods
This retrospective cohort investigation utilized discharge abstracts from the 2021 National Inpatient Sample (NIS), the preeminent all-payer inpatient repository in the United States curated by the Healthcare Cost and Utilization Project (HCUP) under the Agency for Healthcare Research and Quality. The NIS implements a stratified probability sampling framework to yield nationally representative estimates, encompassing circa 20% of annual U.S. community hospital discharges. De-identification of records obviated institutional review board oversight.
Study Population
Adult patients (≥ 18 years) hospitalized with leukemia or multiple myeloma undergoing autologous or allogeneic HCT complicated by ulcerative mucositis were identified via pertinent International Classification of Diseases, Tenth Revision (ICD-10) codes. Patients were then stratified according to discharge timing into modality-specific LOS categories: autologous HCT, discharged 10–19 vs. 20–29 days, and allogeneic HCT, discharged 15–24 vs. 25–34 days. Shorter discharges (0–10 days) served as referential comparators, devoid of adverse events. Baseline covariates abstracted from discharge records encompassed age, sex, race/ethnicity (White, Black, Hispanic, Asian/other), ZIP code-derived median household income quartile, primary payer (Medicare, Medicaid, private, self-pay/other), residence per the National Center for Health Statistics urban-rural schema, and comorbidity burden quantified by the weighted Elixhauser Comorbidity Index. Principal endpoints comprised systemic morbidities: healthcare-associated complications that comprise infectious complications (ICD codes provided) including septicemias (ICD codes provided), isolated septicemia (ICD codes provided), coagulopathies, hypertension, and congestive heart failure, identified through corresponding ICD-10 codes. Details of all ICD-10 codes used for cohort identification and outcome definition are provided in Supplementary Table S1 .
Inclusion and exclusion criteria
Inclusion criteria were (1) age ≥ 18 years, (2) diagnosis of leukemia or multiple myeloma, (3) autologous or allogeneic HCT procedure, and (4) documented diagnosis of oral ulcerative mucositis. Exclusion criteria included age < 18 years, absence of HCT procedure code, absence of oral ulcerative mucositis diagnosis, and discharges with missing key variables (rare in the NIS). Thus, no control group of patients without OUM was added.
Comorbidity Assessment
Comorbidity burden was assessed using the weighted Elixhauser Comorbidity Index, a validated measure based on 30 comorbidity categories derived from administrative data [ 20 , 21 ]. Higher scores indicate greater comorbidity burden.
Analyses accommodated NIS survey design, integrating stratification, clustering, and weighting for unbiased national inference. Descriptive metrics included weighted frequencies/percentages for categorical variables and means ± standard deviations for continuous variables. Inter-strata disparities were interrogated via survey-adjusted chi-square and weighted t-tests.
Multivariable survey-weighted logistic regression modeled adjusted odds ratios (aOR) with 95% confidence intervals for endpoints in prolonged vs. abbreviated discharge strata (the latter as the referent), adjusted for covariates age, sex, race/ethnicity, income quartile, payer, urban-rural designation, and Elixhauser score. Robust quasi-binomial variance estimation was applied. Computations employed R (version 3.6.1) with the survey package. The statistical significance threshold was bilateral, p < 0.05. Missing data, minimal in core NIS elements, underwent no imputation [ 20 ].
Results
In autologous HCT recipients with OUM (weighted n = 1290), 78.3% ( n = 1010) were discharged between 10 and 19 days and 21.7% ( n = 280) between 20 and 29 days. The mean age was ~ 55 years in both groups ( p = 0.61), but there were more females (51.8% vs. 40.6%; p = 0.17), and Asians/others (24.1% vs. 12.0%; p = 0.121) in the prolonged discharge cohort. Socioeconomic proxies (income, payer) and urban-rural distribution aligned ( p > 0.4). The Elixhauser score was nonsignificantly elevated in prolonged discharge (17.0 vs. 15.0; p = 0.1) (Table 1 ).
Table 1 Baseline characteristics of autologous transplant ulcerative mucositis patients stratified by discharged patients for 10–19 days and 20–29 days Autologous transplant ulcerative mucositis patients discharged (10–19 days) (weighted) Autologous transplant ulcerative mucositis patients discharged (20–29 days) (weighted). P -value n 1010 (78.29%) 280 (21.7%) AGE (mean (SD)) 55.86 (13.74) 54.50 (15.62) 0.61 Sex (%) 0.17 Female 410 (40.6) 145 (51.8) RACE (%) 0.12 White 610 (61.0) 140 (51.9) Black 165 (16.5) 30 (11.1) Hispanic 105 (10.5) 35 (13.0)35 (13.0) Asian & Others 120 (12.0) 65 (24.1) Median household income (based on current year) 0.4 0-25th percentile 185.0 (18.6) 70.0 (25.0) 26th to 50th percentile 250.0 (25.1) 50.0 (17.9) 51st to 75th percentile 275.0 (27.6) 60.0 (21.4) 76th to 100th percentile 285.0 (28.6) 100.0 (35.7) Expected primary payer (%) 0.79 Medicare 350.0 (34.8) 80.0 (28.6) Medicaid 100.0 (10.0) 35.0 (12.5) Private insurance 515.0 (51.2) 150.0 (53.6) Self-pay, No charge and other 40.0 (4.0) 15.0 (5.4) Patient Location: NCHS Urban-Rural Code (%) 0.52 “Central” counties of metro areas of > = 1 million population 350 (34.8) 80 (28.6) “Fringe” counties of metro areas of > = 1 million population 320 (31.7) 60 (21.4) Counties in metro areas of 250,000-999,999 population. 205 (20.3) 55 (19.6) Counties in metro areas of 50,000-249,999 population. 65 (6.4) 15 (5.4) Micropolitan counties & Not metropolitan or micropolitan counties 115 (11.4) 40 (14.3) Weighted Elixir score mean (SD) 14.98 (6.93) 17.02 (7.60) 0.1 Healthcare-associated complications (that include septicemias (%)) 110 (10.9) 70 (25.0) 0.003 Septicemia (%) 60.0 (5.9) 55.0 (19.6) 0.001 Congestive Heart Failure (%) 20.0 (2.0) 40.0 (14.3) < 0.001 Abbreviations: SD Standard deviation, NCHS National Center for Health Statistics, $ United States’ Dollar, UM Ulcerative mucositis Note: All frequencies and percentages are weighted
Table 1
Baseline characteristics of autologous transplant ulcerative mucositis patients stratified by discharged patients for 10–19 days and 20–29 days
Abbreviations: SD Standard deviation, NCHS National Center for Health Statistics, $ United States’ Dollar, UM Ulcerative mucositis Note: All frequencies and percentages are weighted
| Autologous transplant ulcerative mucositis patients discharged (10–19 days) (weighted) | Autologous transplant ulcerative mucositis patients discharged (20–29 days) (weighted). | P -value | |
| n | 1010 (78.29%) | 280 (21.7%) | |
| AGE (mean (SD)) | 55.86 (13.74) | 54.50 (15.62) | 0.61 |
| Sex (%) | 0.17 | ||
| Female | 410 (40.6) | 145 (51.8) | |
| RACE (%) | 0.12 | ||
| White | 610 (61.0) | 140 (51.9) | |
| Black | 165 (16.5) | 30 (11.1) | |
| Hispanic | 105 (10.5) | 35 (13.0)35 (13.0) | |
| Asian & Others | 120 (12.0) | 65 (24.1) | |
| Median household income (based on current year) | 0.4 | ||
| 0-25th percentile | 185.0 (18.6) | 70.0 (25.0) | |
| 26th to 50th percentile | 250.0 (25.1) | 50.0 (17.9) | |
| 51st to 75th percentile | 275.0 (27.6) | 60.0 (21.4) | |
| 76th to 100th percentile | 285.0 (28.6) | 100.0 (35.7) | |
| Expected primary payer (%) | 0.79 | ||
| Medicare | 350.0 (34.8) | 80.0 (28.6) | |
| Medicaid | 100.0 (10.0) | 35.0 (12.5) | |
| Private insurance | 515.0 (51.2) | 150.0 (53.6) | |
| Self-pay, No charge and other | 40.0 (4.0) | 15.0 (5.4) | |
| Patient Location: NCHS Urban-Rural Code (%) | 0.52 | ||
| “Central” counties of metro areas of > = 1 million population | 350 (34.8) | 80 (28.6) | |
| “Fringe” counties of metro areas of > = 1 million population | 320 (31.7) | 60 (21.4) | |
| Counties in metro areas of 250,000-999,999 population. | 205 (20.3) | 55 (19.6) | |
| Counties in metro areas of 50,000-249,999 population. | 65 (6.4) | 15 (5.4) | |
| Micropolitan counties & Not metropolitan or micropolitan counties | 115 (11.4) | 40 (14.3) | |
| Weighted Elixir score mean (SD) | 14.98 (6.93) | 17.02 (7.60) | 0.1 |
| Healthcare-associated complications (that include septicemias (%)) | 110 (10.9) | 70 (25.0) | 0.003 |
| Septicemia (%) | 60.0 (5.9) | 55.0 (19.6) | 0.001 |
| Congestive Heart Failure (%) | 20.0 (2.0) | 40.0 (14.3) | < 0.001 |
Morbidity escalated markedly in prolonged discharge: healthcare-associated complications including septicemias (25.0% vs. 10.9%; p = 0.003), isolated septicemia (19.6% vs. 5.9%; p = 0.001), and congestive heart failure (14.3% vs. 2.0%; p < 0.001). No events emerged in the 0–10 day discharge cohort (Table 2 ).
Table 2 Oral ulcerative mucositis outcomes among the length of stay groups, 10–19 LOS and 20–29 days (autologous transplant patients) OUM-associated outcomes and other risks Outcome estimates* (in the 20–29 days, compared to 10–19 days). OUM-associated risk (unadjusted) of outcomes in the 10–19 and 20–29 days (number, percentage, and p -value) OUM-associated risk (unadjusted) of outcomes during 0 days of admission and 10 days (number and percentages) 10–19 Days 20–29 Days P value 0 LOS 10 LOS Healthcare-associated complications that include septicemias aOR: 3.09; 95%CI: 1.45–6.59 110 (10.9) 70 (25.0) 0.003 0 (0) 0 (0) Septicemias alone aOR: 4.68; 95% CI: 1.83–11.96 60.0 (5.9) 55.0 (19.6) 0.001 0 (0) 0 (0) Other risks—developing congestive heart failure aOR: 1.68; 95% CI: 2.44–11.58 20.0 (2.0) 40.0 (14.3) < 0.001 0 (0) 0 (0) Abbreviations: *Multivariate regression analysis ( aOR adjusted odds ratio, 95% CI 95% confidence interval) OUM Oral ulcerative mucositis
Table 2
Oral ulcerative mucositis outcomes among the length of stay groups, 10–19 LOS and 20–29 days (autologous transplant patients)
Abbreviations: *Multivariate regression analysis ( aOR adjusted odds ratio, 95% CI 95% confidence interval) OUM Oral ulcerative mucositis
| OUM-associated outcomes and other risks | Outcome estimates* (in the 20–29 days, compared to 10–19 days). | OUM-associated risk (unadjusted) of outcomes in the 10–19 and 20–29 days (number, percentage, and p -value) | OUM-associated risk (unadjusted) of outcomes during 0 days of admission and 10 days (number and percentages) | |||
| 10–19 Days | 20–29 Days | P value | 0 LOS | 10 LOS | ||
| Healthcare-associated complications that include septicemias | aOR: 3.09; 95%CI: 1.45–6.59 | 110 (10.9) | 70 (25.0) | 0.003 | 0 (0) | 0 (0) |
| Septicemias alone | aOR: 4.68; 95% CI: 1.83–11.96 | 60.0 (5.9) | 55.0 (19.6) | 0.001 | 0 (0) | 0 (0) |
| Other risks—developing congestive heart failure | aOR: 1.68; 95% CI: 2.44–11.58 | 20.0 (2.0) | 40.0 (14.3) | < 0.001 | 0 (0) | 0 (0) |
Adjusted regression confirmed the findings. Prolonged discharge conferred increased odds of healthcare-associated complications, including septicemias (aOR 3.09, 95%CI: 1.45–6.59), isolated septicemia (aOR 4.68, 95%CI 1.83–11.96), and congestive heart failure (aOR 1.68, 95% CI: 2.44–11.58) (Table 2 ).
Among allogeneic HCT recipients with OUM (weighted n = 885), 45.8% ( n = 405) were discharged between 15 and 24 days and 54.2% ( n = 480) between 25 and 34 days. Mean age was relatively similar between the cohorts (50 vs. 52 years; p = 0.43), although the prolonged discharge group had greater female representation (43.7% vs. 34.6%; p = 0.17) and a lower proportion of Whites (60.0% vs. 74.7%; p = 0.063). The Elixhauser score was significantly increased in prolonged discharge (7.7 vs. 5.7; p = 0.03) (Table 3 ).
Table 3 Baseline characteristics of allogeneic transplant ulcerative mucositis patients stratified by discharged patients for 15–24 days and 25–34 days Allogeneic transplant ulcerative mucositis patients discharged during 15–24 days (weighted) Allogeneic transplant ulcerative mucositis patients discharged during 25–34 days (weighted) P -value n 405 (45.76%) 480 (54.24%) AGE (mean (SD)) 49.84 (13.16) 51.59 (15.50) 0.43 Sex (%) 0.17 Female 140 (34.6) 210 (43.7) RACE (%) 0.06 White 295 (74.7) 285 (60.0) Black 5 (1.3) 40 (8.4) Hispanic 65 (16.5) 90 (18.9) Asian & Others 30 (7.6) 60 (12.6) Median household income (based on current year) 0.66 0-25th percentile 70.0 (17.3) 95.0 (19.8) 26th to 50th percentile 85.0 (21.0) 95.0 (19.8) 51st to 75th percentile 155.0 (38.3) 150.0 (31.2) 76th to 100th percentile 95.0 (23.5) 140.0 (29.2) Expected primary payer (%) 0.08 Medicare 45.0 (11.3) 130.0 (27.1) Medicaid 50.0 (12.5) 75.0 (15.6) Private insurance 300.0 (75.0) 245.0 (51.0) Self-pay, No charge and other 5.0 (1.3) 30 (6.3) Patient Location: NCHS Urban-Rural Code (%) 0.296 “Central” counties of metro areas of > = 1 million population 100 (24.7) 175 (36.5) “Fringe” counties of metro areas of > = 1 million population 115 (28.4) 130 (27.1) Counties in metro areas of 250,000-999,999 population. 90 (22.2) 85 (17.7) Counties in metro areas of 50,000-249,999 population. 50 (12.3) 30 (6.3) Micropolitan counties & Not metropolitan or micropolitan counties 50 (12.3) 60 (12.5) Weighted Elixir score mean (SD) 5.7 (6.36) 7.69 (7.39) 0.03 Healthcare associated complications that includes septicemias (%) 30.0 (7.4) 85.0 (17.7) 0.04 Coagulopathies (%) 30.0 (7.4) 100.0 (20.8) 0.02 Hypertension (%) 120.0 (29.6) 220.0 (45.8) 0.01 Abbreviations: SD Standard deviation, NCHS National Center for Health Statistics, $ United States’ Dollar, UM Ulcerative mucositis Note: All frequencies and percentages are weighted
Table 3
Baseline characteristics of allogeneic transplant ulcerative mucositis patients stratified by discharged patients for 15–24 days and 25–34 days
Abbreviations: SD Standard deviation, NCHS National Center for Health Statistics, $ United States’ Dollar, UM Ulcerative mucositis Note: All frequencies and percentages are weighted
| Allogeneic transplant ulcerative mucositis patients discharged during 15–24 days (weighted) | Allogeneic transplant ulcerative mucositis patients discharged during 25–34 days (weighted) | P -value | |
| n | 405 (45.76%) | 480 (54.24%) | |
| AGE (mean (SD)) | 49.84 (13.16) | 51.59 (15.50) | 0.43 |
| Sex (%) | 0.17 | ||
| Female | 140 (34.6) | 210 (43.7) | |
| RACE (%) | 0.06 | ||
| White | 295 (74.7) | 285 (60.0) | |
| Black | 5 (1.3) | 40 (8.4) | |
| Hispanic | 65 (16.5) | 90 (18.9) | |
| Asian & Others | 30 (7.6) | 60 (12.6) | |
| Median household income (based on current year) | 0.66 | ||
| 0-25th percentile | 70.0 (17.3) | 95.0 (19.8) | |
| 26th to 50th percentile | 85.0 (21.0) | 95.0 (19.8) | |
| 51st to 75th percentile | 155.0 (38.3) | 150.0 (31.2) | |
| 76th to 100th percentile | 95.0 (23.5) | 140.0 (29.2) | |
| Expected primary payer (%) | 0.08 | ||
| Medicare | 45.0 (11.3) | 130.0 (27.1) | |
| Medicaid | 50.0 (12.5) | 75.0 (15.6) | |
| Private insurance | 300.0 (75.0) | 245.0 (51.0) | |
| Self-pay, No charge and other | 5.0 (1.3) | 30 (6.3) | |
| Patient Location: NCHS Urban-Rural Code (%) | 0.296 | ||
| “Central” counties of metro areas of > = 1 million population | 100 (24.7) | 175 (36.5) | |
| “Fringe” counties of metro areas of > = 1 million population | 115 (28.4) | 130 (27.1) | |
| Counties in metro areas of 250,000-999,999 population. | 90 (22.2) | 85 (17.7) | |
| Counties in metro areas of 50,000-249,999 population. | 50 (12.3) | 30 (6.3) | |
| Micropolitan counties & Not metropolitan or micropolitan counties | 50 (12.3) | 60 (12.5) | |
| Weighted Elixir score mean (SD) | 5.7 (6.36) | 7.69 (7.39) | 0.03 |
| Healthcare associated complications that includes septicemias (%) | 30.0 (7.4) | 85.0 (17.7) | 0.04 |
| Coagulopathies (%) | 30.0 (7.4) | 100.0 (20.8) | 0.02 |
| Hypertension (%) | 120.0 (29.6) | 220.0 (45.8) | 0.01 |
There were clear disparities between the allogenic HCT cohorts. Particularly, there were increased rates within the prolonged discharge group of healthcare-associated complications including septicemias (17.7% vs. 7.4%; p = 0.04), coagulopathies (20.8% vs. 7.4%; p = 0.02), and hypertension (45.8% vs. 29.6%; p = 0.01). There were no incidences of OUM in the 0–10 day allogenic discharge group (Table 4 ).
Multivariable modeling supported these findings. Prolonged discharge associated with OUM increased odds of healthcare-associated complications, including septicemias (aOR 3.3, 95%CI: 1.19–9.12), coagulopathies (aOR 3.47, 95%CI: 1.33–9.03), and hypertension (aOR 2.00, 95%CI: 1.05–3.82) (Table 4 ).
Table 4 Oral ulcerative mucositis-associated outcomes among the length of stay groups, 15–24 LOS and 25–35 days (allogeneic transplant patients) OUM-associated outcomes and other risks Outcome estimates* (in the 25–35 days, compared to 15–24 days). OUM-associated risk (unadjusted) of outcomes in the 15–24 and 25–34 days (number, percentage, and p -value) OUM-associated risk (unadjusted) of outcomes during 0 days of admission and 10 days (number and percentages) 15–24 Days 25–34 Days P value 0 LOS 10 LOS Healthcare-associated complications that include septicemias aOR: 3.3; 95% CI: 1.19–9.12 30.0 (7.4) 85.0 (17.7) 0.04 0 (0) 0 (0) coagulopathies aOR: 3.47; 95% CI: 1.33–9.03 30.0 (7.4) 100.0 (20.8) 0.02 0 (0) 0 (0) Hypertension aOR: 2.00; 95% CI: 1.05–3.82 120.0 (29.6) 220.0 (45.8) 0.01 0 (0) 0 (0) Abbreviations: *Multivariate regression analysis ( aOR adjusted odds ratio, 95% CI 95% confidence interval) OUM Oral ulcerative mucositis
Table 4
Oral ulcerative mucositis-associated outcomes among the length of stay groups, 15–24 LOS and 25–35 days (allogeneic transplant patients)
Abbreviations: *Multivariate regression analysis ( aOR adjusted odds ratio, 95% CI 95% confidence interval) OUM Oral ulcerative mucositis
| OUM-associated outcomes and other risks | Outcome estimates* (in the 25–35 days, compared to 15–24 days). | OUM-associated risk (unadjusted) of outcomes in the 15–24 and 25–34 days (number, percentage, and p -value) | OUM-associated risk (unadjusted) of outcomes during 0 days of admission and 10 days (number and percentages) | |||
| 15–24 Days | 25–34 Days | P value | 0 LOS | 10 LOS | ||
| Healthcare-associated complications that include septicemias | aOR: 3.3; 95% CI: 1.19–9.12 | 30.0 (7.4) | 85.0 (17.7) | 0.04 | 0 (0) | 0 (0) |
| coagulopathies | aOR: 3.47; 95% CI: 1.33–9.03 | 30.0 (7.4) | 100.0 (20.8) | 0.02 | 0 (0) | 0 (0) |
| Hypertension | aOR: 2.00; 95% CI: 1.05–3.82 | 120.0 (29.6) | 220.0 (45.8) | 0.01 | 0 (0) | 0 (0) |
Different systemic outcomes were examined in autologous and allogeneic HCT cohorts based on clinical plausibility and the patterns observed in the data. In autologous HCT, congestive heart failure emerged as a significant complication associated with prolonged discharge, whereas in allogeneic HCT, coagulopathies and hypertension were more prominent. This distinction reflects known differences in treatment exposures: autologous recipients often have greater prior exposure to cardiotoxic agents, while allogeneic recipients experience prolonged immunosuppression and higher rates of endothelial injury and drug-related toxicities.
Further, discharges within 0–10 days were analyzed as a separate reference category because this group had zero events for all examined systemic outcomes, consistent with rapid and uncomplicated recovery. Due to complete separation in the data, these cases were not included in the primary multivariable logistic regression models comparing 10–19/15–24 days versus prolonged discharge groups (Tables 2 and 4 ).
Collectively, these observations suggest an unfortunate reciprocal interplay between length of hospitalization and complications wherein HCT patients with OUM who have prolonged hospitalizations are at greater risk of complications, which can further increase their length of stay.
Discussion
This nationally representative discharge-centric inquiry shows the significant morbidity associated with delayed discharge timing in HCT recipients afflicted by OUM [ 7 , 8 ]. Across autologous and allogeneic modalities among patients with oral ulcerative mucositis (OUM), prolonged discharge timing (as a proxy for extended length of stay) is independently associated with higher rates of systemic complications, with adjusted odds ratios spanning 1.68–4.68 [ 12 ].
The autologous HCT group demonstrated escalation of septicemia-related complications and congestive heart failure within the prolonged discharge cohort (20–29 days) compared to the shorter one (10–19 days) [ 18 , 22 ]. The near quintupling of isolated septicemia odds (aOR 4.68, 95%CI: 1.83–11.96) may highlight mucosal barrier compromise as a potential conduit for pathogen translocation amid neutropenia—a paradigm corroborated by meta-analytic synthesis demonstrating nearly fourfold infectious risk amplification [ 12 , 23 ]. However, infections originating from origins other than the oral cavity or conditioning regimens may also increase hospital LOS and septicemias. The reason for increased odds of congestive heart failure remains unclear, as it is a relatively rare event, although it may be related to conditioning chemotherapy, impaired glucose tolerance, pre-existing cardiovascular risk factors, sepsis-mediated myocardial dysfunction, arrythmias such as atrial fibrillation, or TPN-associated fluid dysregulation in protracted oral intolerance [ 18 , 24 ].
The transplant-specific differences in associated complications are noteworthy. Congestive heart failure in autologous HCT may be driven by anthracycline-related cardiotoxicity, fluid shifts from parenteral nutrition, or sepsis-induced cardiomyopathy in the setting of prolonged hospitalization. In allogeneic HCT, the higher incidence of coagulopathies and hypertension likely reflects endothelial damage from intensive conditioning, prolonged exposure to calcineurin inhibitors and corticosteroids, and the effects of graft-versus-host disease prophylaxis. These findings highlight that while septicemia-related complications are common to both groups, the additional morbidities associated with prolonged discharge differ by transplant type and underlying treatment exposures.
Interestingly, a greater proportion of allogeneic recipients required prolonged hospitalization, with over half not discharged until at least 25 days compared to 78% of autologous recipients being discharged within 10–19 days. This discrepancy is likely due to differences in time to engraftment and GVHD complications between the modalities. Prolonged discharge independently tripled septicemia-inclusive complications and coagulopathies while doubling hypertension [ 19 , 22 ]. Increased coagulopathy is likely secondary to conditioning-induced endothelial perturbation, cytokine dysregulation, and infection-consumptive coagulopathy. The reason for increased hypertension is less clear but is perhaps driven by conditioning agents and immunosuppressants such as tacrolimus and cyclosporine, which promote fluid retention, vasoconstriction, and potential kidney damage [ 19 , 24 ].
Central to this discussion is the interplay between OUM, length of hospitalization, and risk of complications. Severe OUM impedes timely discharge due to increased symptom burden and increased infection risk. Prolonged hospitalization, in turn, further intensifies nosocomial vulnerability and risk of complications [ 16 , 17 ]. These relationships become more clear in a study such as this, which stratifies according to discharge time [ 16 ], and the inter-strata demographic similarity of this study serves to strengthen the relationship between discharge prolongation and related complications. Despite trends toward females, minority ethnicity, and comorbidity accrual in prolonged discharge, multivariable adjustment demonstrates robust associations [ 25 , 26 ]. The lack of outcomes in short discharges within 0–10 days further substantiates the link between length of hospitalization and complication risk [ 10 , 14 ].
Consistent with prior spending, standard pharmacoeconomic evaluations found nearly $42,000 in additional costs, mainly due to longer hospital stays [ 1 , 14 ]. Interventional trials have shown that palifermin and photobiomodulation can improve severe OUM by 40–60%, which could possibly expedite discharge. Present data suggest that such interventions, along with intensified oral hygiene and preemptive microbials, should be prioritized for those with the potential for prolonged hospitalizations [ 11 , 27 ]. Multidisciplinary algorithms integrating hematology, oral medicine, infectious diseases, and nutrition may improve LOS and therefore morbidity. Measures to prevent or lessen the severity of OUM would also financially benefit the healthcare system, and quality metric bundling of supportive modalities may catalyze their dissemination.
The post-transplant phase following HCT represents a prolonged period of immunological vulnerability, marked by gradual hematopoietic reconstitution, lingering mucosal fragility, and persistent susceptibility to opportunistic pathogens. The present investigation, which reveals substantially elevated systemic complications among patients with OUM experiencing delayed discharge, highlights the critical need for comprehensive, multidisciplinary oral care that extends well beyond neutrophil engraftment. Although pre-transplant dental evaluation and sanitation may minimize preexisting infectious foci, the post-transplant period requires systematic oral management to preserve mucosal barrier integrity, ameliorate mucositis sequelae, and hopefully reduce morbidity [ 22 , 23 ].
Current clinical practice guidelines from the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) strongly advocate for structured basic oral care protocols as the cornerstone of mucositis prevention and mitigation in those undergoing HCT [ 28 ]. These protocols involve daily gentle mechanical cleansing with ultra-soft toothbrushes, use of alcohol-free fluoride-containing rinses, and application of moisturizing agents to counteract xerostomia—a common post-conditioning sequela that exacerbates ulceration and facilitates microbial overgrowth [ 29 , 30 ]. Meta-analyses of randomized trials confirm that multifaceted basic oral care regimens, incorporating saline or sodium bicarbonate rinses, significantly reduce mucositis severity, pain scores, and secondary infection rates in HCT recipients, supporting the need for integrated multi-disciplinary care teams [ 29 , 30 ].
Emerging therapeutic modalities offer additional promise for post-transplant oral stewardship [ 11 , 27 ]. Photobiomodulation therapy (PBMT), also known as low-level laser therapy, has received strong guideline endorsement for prophylactic use in high-risk conditioning regimens. By promoting epithelial proliferation, modulating inflammatory cytokines, and enhancing tissue repair, PBMT reduces the incidence and duration of severe mucositis, with sustained benefits observable into the early post-engraftment phase. Similarly, oral cryotherapy—administration of ice chips during cytotoxic infusions—reduces mucositis in melphalan-containing protocols, producing protective effects that persist post-transplant [ 1 , 11 ]. Professional dental engagement remains indispensable before, during, and after engraftment. While profound neutropenia precludes invasive interventions, periodic oral examinations by trained dental hygienists or oral medicine specialists enable timely identification of secondary infections, oral candidiasis, or herpes virus reactivation, which are frequent complications in the immunocompromised host [ 12 ]. Population-based studies suggest that structured peri-transplant oral care correlates with reduced post-HCT infectious events, although direct effects on mucositis duration remain variable. In allogeneic recipients, where chronic graft-versus-host disease (cGVHD) commonly manifests with oral lichenoid changes, sclerotic features, or salivary gland dysfunction months to years post-transplant, ongoing oral care and dental surveillance is essential to prevent secondary caries, periodontal progression, mucosal fibrosis, and rare but serious secondary malignancies [ 9 , 24 ].
Patient-centered education forms an integral component of effective post-transplant oral care. Empowering recipients with individualized hygiene guidance tailored to thrombocytopenia, GVHD-related fragility, and xerostomia fosters adherence and self-management [ 29 , 30 ]. Dietary counseling emphasizing soft, bland, non-acidic foods minimizes mechanical irritation, and multimodal analgesia, including topical agents such as doxepine or lidocaine formulations (benzydamine in countries where available) alleviates discomfort, promotes oral intake, and potentially reduces reliance on total parenteral nutrition [ 31 ]. Despite compelling evidence, barriers to optimal post-transplant oral care persist, including inconsistent protocol implementation across centers, limited access to specialized oral medicine services, and variable reimbursement structures. Implementation science studies, particularly in pediatric HCT populations, demonstrate that bundled evidence-based oral care interventions enhance compliance and clinical outcomes. Seamless integration of oral care into multidisciplinary transplant care pathways—involving hematologists, nursing staff, infectious disease specialists, and dental professionals—holds potential to interrupt the vicious cycle of mucositis, infection, and hospitalization prolongation observed in this study [ 28 , 29 ].
Given our findings of clustered morbidity in prolonged-discharge cohorts, intensified post-transplant oral interventions warrant prioritization in patients exhibiting delayed recovery [ 32 ]. Such strategies may not only mitigate systemic complications but also facilitate earlier safe discharge and have implications throughout survivorship. Prospective clinical trials evaluating comprehensive oral care bundles—incorporating PBMT, professional monitoring, and enhanced patient education—with endpoints encompassing infection incidence, quality-of-life measures, and healthcare utilization are needed. These efforts will translate observational insights into actionable improvements, ultimately refining supportive care paradigms and reducing the substantial burden of post-HCT oral morbidity [ 12 , 27 ].
The study’s deliberate restriction to patients with documented OUM—and its comparison of outcomes between earlier versus later discharge timing within this affected group—represents a methodologically robust and clinically meaningful design choice, rather than a limitation. This approach strengthens the inference that prolonged hospitalization (delayed discharge) reflects complication severity and clustering in mucositis-afflicted patients, rather than merely comparing mucositis-positive versus mucositis-negative cases [ 10 – 12 ].
Focused examination of mucositis-related morbidity burden — By including only patients with OUM, the study isolates the subpopulation most vulnerable to systemic complications. Non-ulcerative mucositis (e.g., grades 1–2, manifesting as erythema or mild soreness without frank ulceration) typically entails less severe pain, preserved oral intake, and minimal infection risk through intact mucosal barriers. In contrast, ulcerative mucositis (grades 3–4) breaches epithelial integrity, serving as a direct portal for bacterial translocation during neutropenia—a key driver of septicemia, healthcare-associated infections, and secondary organ dysfunction [ 33 , 34 ]. Including non-ulcerative cases would dilute effect sizes and obscure the specific, high-impact sequelae of barrier-disrupting ulceration, which the study explicitly targets [ 22 , 23 ]. Discharge timing as a proxy for complication-driven hospital prolongation — The core hypothesis posits a bidirectional relationship: severe OUM contributes to delayed discharge (via pain, nutritional failure, and infections), while prolonged hospitalization exacerbates nosocomial risks and cumulative toxicity [ 16 , 17 ]. Stratifying within OUM-positive patients by discharge timing (earlier vs. later) directly tests whether more severe or complicated mucositis courses manifest as extended stays. This yields greater clinical relevance than a simple mucositis-present-versus-absent comparison, which would conflate mild (non-ulcerative) cases with severe ones and fail to capture temporal clustering of morbidity. The observed 3–4.7-fold adjusted risks for septicemia and other outcomes in prolonged-discharge OUM patients strongly support that delayed discharge serves as a real-world marker of mucositis severity and complication accrual [ 22 , 35 ]. Avoidance of confounding by mild or asymptomatic cases — Non-ulcerative mucositis often resolves rapidly with basic supportive care and rarely precipitates systemic events or hospitalization extensions. Including such cases would introduce heterogeneity, potentially attenuating associations and underestimating the true burden in the high-risk ulcerative subgroup [ 36 ]. Administrative data (e.g., NIS ICD-10 coding) further justify this exclusion: codes for mucositis typically capture clinically significant (often ulcerative) disease warranting documentation, whereas mild erythema may be undercoded or omitted. Thus, the cohort inherently enriches for impactful cases [ 10 – 12 ]. Alignment with clinical and research priorities — Supportive care guidelines (MASCC/ISOO) and interventional trials (e.g., palifermin, photobiomodulation) prioritize prevention/mitigation of severe/ulcerative mucositis due to its dominant contribution to morbidity, costs, and quality-of-life impairment. By focusing on this subgroup and using discharge timing to stratify severity indirectly, the study generates actionable insights for resource-intensive patients most likely to benefit from intensified oral care, infection prophylaxis, or early intervention—precisely those with prolonged stays [ 12 , 14 ].
Thus, our examination sharpens the focus on the clinically dominant severe phenotype, leverages discharge timing as a pragmatic severity proxy, minimizes confounding by mild disease, and enhances translational relevance for high-burden scenarios in HCT supportive care [ 37 ].
Study Design Considerations
The present study was deliberately restricted to patients with documented oral ulcerative mucositis rather than comparing OUM-positive versus OUM-negative patients. This approach was chosen because ulcerative mucositis constitutes the biologically and clinically most relevant phenotype, directly disrupting the mucosal barrier and facilitating bacterial translocation during neutropenia. Milder (non-ulcerative) or absent mucositis cases generally carry a substantially lower risk of systemic complications and rarely result in prolonged hospitalization. By focusing exclusively on patients with OUM and stratifying them according to discharge timing, the analysis tests whether prolonged hospitalization serves as a real-world marker of greater complication severity and clustering within this high-risk subgroup. Although evaluating OUM as an independent predictor of prolonged LOS (followed by LOS as a predictor of complications) would be a valuable complementary analysis, such a stepwise approach was outside the scope of this manuscript. Future studies may usefully address this broader question.
Limitations warrant acknowledgment. NIS retrospective architecture hinges on administrative coding, potentially under-identifying subclinical mucositis or omitting severity gradation (e.g., WHO criteria). Inferential causality remains constrained; unmeasured confounding (e.g., regimen specifics, prophylaxis) persists despite adjustment. Inpatient confinement precludes post-discharge sequelae. Select estimates evince interval breadth, reflective of strata dimensionality notwithstanding weighting.
Study merits include expansive national representativeness facilitating modality-specific discharge stratification—infrequent in unicentric cohorts—and stringent survey analytics mitigating bias. Discharge timing as a pragmatic endpoint augments translational fidelity. Prospective avenues encompass clinical gradation validation, regimen granularity incorporation, and randomized protracted-discharge interventional trials. Early OUM biomarker/machine learning prognostication could enable bespoke risk stratification and prophylaxis. Further future examination through all grade non-mucositis cases might provide execellent comparisons to mitigate oral-systemic associations.
In conclusion, delayed discharge timing in ulcerative mucositis-complicated HCT robustly prognosticates—and likely propagates—severe oral-systemic complications. These findings impel discharge-stratified supportive paradigms to improve modifiable hazards, hasten safe discharge, and optimize clinical/fiscal outcomes in this susceptible population.
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Author contributions
Contribution: SR contributed to the revision of the manuscript; KM contributed to the design, conception, interpretation of data, drafting, and critical revision of the manuscript; SJMVL contributed critical revision of the manuscript; LVG contributed critical revision of the manuscript; LR contributed critical revision of the manuscript; JE contributed critical revision of the manuscript; RP contributed critical revision of the manuscript; NB contributed critical revision of the manuscript; SK contributed to the design, conception, acquisition, interpretation of data, drafting, and critical revision of the manuscript.
Funding
This study received no funding. Poolakkad S. Satheeshkumar received funding from Kaleida Troup Funding (Kaleida Troup Funding, 030GRT00000091). All other authors have not received any funding for this work.
Data availability
We used data from the United States’ 2021 National Inpatient Sample database obtained from Healthcare Cost and Utilization Project (HCUP) of the Agency for Healthcare Research and Quality (AHRQ).
Code availability
Not applicable.
Declarations
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Consent to participate
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Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
References
1. Sonis ST Oster G Fuchs H Bellm L Bradford WZ Edelsberg J Hayden V Eilers J Epstein JB LeVeque FG Miller C Peterson DE Schubert MM Spijkervet FK Horowitz M Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation J Clin Oncol 2001 19 8 2201 2205 10.1200/JCO.2001.19.8.2201 11304772 Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, Hayden V, Eilers J, Epstein JB, LeVeque FG, Miller C, Peterson DE, Schubert MM, Spijkervet FK, Horowitz M (2001) Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19(8):2201–2205. 10.1200/JCO.2001.19.8.2201 11304772 10.1200/JCO.2001.19.8.2201
2. Gyurkocza B Sandmaier BM Conditioning regimens for hematopoietic cell transplantation: one size does not fit all Blood 2014 124 3 344 353 10.1182/blood-2014-02-514778 24914142 PMC4102707 Gyurkocza B, Sandmaier BM (2014) Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 124(3):344–353. 10.1182/blood-2014-02-514778 24914142 10.1182/blood-2014-02-514778 PMC4102707
3. Riley P Glenny AM Worthington HV Littlewood A Fernandez Mauleffinch LM Clarkson JE McCabe MG Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors Cochrane Database Syst Rev 2017 11 11 CD011990 10.1002/14651858.CD011990.pub2 29181845 PMC6486203 Riley P, Glenny AM, Worthington HV, Littlewood A, Fernandez Mauleffinch LM, Clarkson JE, McCabe MG (2017) Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors. Cochrane Database Syst Rev 11(11):CD011990. 10.1002/14651858.CD011990.pub2 29181845 10.1002/14651858.CD011990.pub2 PMC6486203
4. Blakaj A Bonomi M Gamez ME Blakaj DM Oral mucositis in head and neck cancer: Evidence-based management and review of clinical trial data Oral Oncol 2019 95 29 34 10.1016/j.oraloncology.2019.05.013 31345391 Blakaj A, Bonomi M, Gamez ME, Blakaj DM (2019) Oral mucositis in head and neck cancer: Evidence-based management and review of clinical trial data. Oral Oncol 95:29–34. 10.1016/j.oraloncology.2019.05.013 31345391 10.1016/j.oraloncology.2019.05.013
5. Franco P Martini S Di Muzio J Cavallin C Arcadipane F Rampino M Ostellino O Pecorari G Garzino Demo P Fasolis M Airoldi M Ricardi U Prospective assessment of oral mucositis and its impact on quality of life and patient-reported outcomes during radiotherapy for head and neck cancer Med Oncol 2017 34 5 81 10.1007/s12032-017-0950-1 28386836 Franco P, Martini S, Di Muzio J, Cavallin C, Arcadipane F, Rampino M, Ostellino O, Pecorari G, Garzino Demo P, Fasolis M, Airoldi M, Ricardi U (2017) Prospective assessment of oral mucositis and its impact on quality of life and patient-reported outcomes during radiotherapy for head and neck cancer. Med Oncol 34(5):81. 10.1007/s12032-017-0950-1 28386836 10.1007/s12032-017-0950-1
6. Chaudhry HM Bruce AJ Wolf RC Litzow MR Hogan WJ Patnaik MS Kremers WK Phillips GL Hashmi SK The Incidence and Severity of Oral Mucositis among Allogeneic Hematopoietic Stem Cell Transplantation Patients: A Systematic Review Biol Blood Marrow Transpl 2016 22 4 605 616 10.1016/j.bbmt.2015.09.014 26409924 Chaudhry HM, Bruce AJ, Wolf RC, Litzow MR, Hogan WJ, Patnaik MS, Kremers WK, Phillips GL, Hashmi SK (2016) The incidence and severity of oral mucositis among allogeneic hematopoietic stem cell transplantation patients: a systematic Review. Biol Blood Marrow Transpl 22(4):605–616 10.1016/j.bbmt.2015.09.014 26409924
7. Murphy BA Clinical and economic consequences of mucositis induced by chemotherapy and/or radiation therapy J Support Oncol 2007 5 9 Suppl 4 13 21 18046994 Murphy BA (2007) Clinical and economic consequences of mucositis induced by chemotherapy and/or radiation therapy. J Support Oncol 5(9 Suppl 4):13–21 18046994
8. Peterson DE Lalla RV Oral mucositis: the new paradigms Curr Opin Oncol 2010 22 4 318 322 10.1097/CCO.0b013e32833a9fab 20485169 PMC3716390 Peterson DE, Lalla RV (2010) Oral mucositis: the new paradigms. Curr Opin Oncol 22(4):318–322. 10.1097/CCO.0b013e32833a9fab 20485169 10.1097/CCO.0b013e32833a9fab PMC3716390
9. Shouval R Kouniavski E Fein J Danylesko I Shem-Tov N Geva M Yerushalmi R Shimoni A Nagler A Risk factors and implications of oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation Eur J Haematol 2019 103 4 402 409 10.1111/ejh.13299 31332836 Shouval R, Kouniavski E, Fein J, Danylesko I, Shem-Tov N, Geva M, Yerushalmi R, Shimoni A, Nagler A (2019) Risk factors and implications of oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation. Eur J Haematol 103(4):402–409. 10.1111/ejh.13299 31332836 10.1111/ejh.13299
10. Nakagaki M Kennedy GA Gavin NC Clavarino A Whitfield K The incidence of severe oral mucositis in patients undergoing different conditioning regimens in haematopoietic stem cell transplantation Support Care Cancer 2022 30 11 9141 9149 10.1007/s00520-022-07328-4 36008731 PMC9410738 Nakagaki M, Kennedy GA, Gavin NC, Clavarino A, Whitfield K (2022) The incidence of severe oral mucositis in patients undergoing different conditioning regimens in haematopoietic stem cell transplantation. Support Care Cancer 30(11):9141–9149. 10.1007/s00520-022-07328-4 36008731 10.1007/s00520-022-07328-4 PMC9410738
11. Nguyen DT Shayani S Palmer J Dagis A Forman SJ Epstein J Spielberger R Palifermin for prevention of oral mucositis in allogeneic hematopoietic stem cell transplantation: a single-institution retrospective evaluation Support Care Cancer 2015 23 11 3141 3147 10.1007/s00520-015-2688-7 25791390 Nguyen DT, Shayani S, Palmer J, Dagis A, Forman SJ, Epstein J, Spielberger R (2015) Palifermin for prevention of oral mucositis in allogeneic hematopoietic stem cell transplantation: a single-institution retrospective evaluation. Support Care Cancer 23(11):3141–3147. 10.1007/s00520-015-2688-7 25791390 10.1007/s00520-015-2688-7
12. Eichhorn S Rudin L Ramasamy C Varsani R Padhi P Nassour N Meleveedu K Epstein JB Semegran B Pili R Satheeshkumar PS Elevated Likelihood of Infectious Complications Related to Oral Mucositis After Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis of Outcomes and Risk Factors Cancers (Basel) 2025 17 16 2657 10.3390/cancers17162657 40867286 PMC12384372 Eichhorn S, Rudin L, Ramasamy C, Varsani R, Padhi P, Nassour N, Meleveedu K, Epstein JB, Semegran B, Pili R, Satheeshkumar PS (2025) Elevated Likelihood of Infectious Complications Related to Oral Mucositis After Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis of Outcomes and Risk Factors. Cancers (Basel) 17(16):2657. 10.3390/cancers17162657 40867286 10.3390/cancers17162657 PMC12384372
13. Trotti A Bellm LA Epstein JB Frame D Fuchs HJ Gwede CK Komaroff E Nalysnyk L Zilberberg MD Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review Radiother Oncol 2003 66 3 253 262 10.1016/s0167-8140(02)00404-8 12742264 Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, Komaroff E, Nalysnyk L, Zilberberg MD (2003) Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 66(3):253–262. 10.1016/s0167-8140(02)00404-8 12742264 10.1016/s0167-8140(02)00404-8
14. Vera-Llonch M Oster G Ford CM Lu J Sonis S Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies Support Care Cancer 2007 15 5 491 496 10.1007/s00520-006-0176-9 17139495 Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S (2007) Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Support Care Cancer 15(5):491–496. 10.1007/s00520-006-0176-9 17139495 10.1007/s00520-006-0176-9
15. Elting LS Cooksley CD Chambers MS Garden AS Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies Int J Radiat Oncol Biol Phys 2007 68 4 1110 1120 10.1016/j.ijrobp.2007.01.053 17398022 Elting LS, Cooksley CD, Chambers MS, Garden AS (2007) Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 68(4):1110–1120. 10.1016/j.ijrobp.2007.01.053 17398022 10.1016/j.ijrobp.2007.01.053
16. Stewart S Robertson C Pan J Kennedy S Haahr L Manoukian S Mason H Kavanagh K Graves N Dancer SJ Cook B Reilly J Impact of healthcare-associated infection on length of stay J Hosp Infect 2021 114 23 31 10.1016/j.jhin.2021.02.026 34301393 Stewart S, Robertson C, Pan J, Kennedy S, Haahr L, Manoukian S, Mason H, Kavanagh K, Graves N, Dancer SJ, Cook B, Reilly J (2021) Impact of healthcare-associated infection on length of stay. J Hosp Infect 114:23–31. 10.1016/j.jhin.2021.02.026 34301393 10.1016/j.jhin.2021.02.026
17. Jeon CY Neidell M Jia H Sinisi M Larson E On the role of length of stay in healthcare-associated bloodstream infection Infect Control Hosp Epidemiol 2012 33 12 1213 1218 10.1086/668422 23143358 PMC3510977 Jeon CY, Neidell M, Jia H, Sinisi M, Larson E (2012) On the role of length of stay in healthcare-associated bloodstream infection. Infect Control Hosp Epidemiol 33(12):1213–1218. 10.1086/668422 23143358 10.1086/668422 PMC3510977
18. Gul Z Bashir Q Cremer M Yusuf SW Gunaydin H Arora S Slone S Nieto Y Sherwani N Parmar S Shah N Dinh YT Hosing CM Popat UR Kebriaei P Shpall EJ Giralt SA Champlin RE Qazilbash MH Short-term cardiac toxicity of autologous hematopoietic stem cell transplant for multiple myeloma Leuk Lymphoma 2015 56 2 533 535 10.3109/10428194.2014.926346 24882259 Gul Z, Bashir Q, Cremer M, Yusuf SW, Gunaydin H, Arora S, Slone S, Nieto Y, Sherwani N, Parmar S, Shah N, Dinh YT, Hosing CM, Popat UR, Kebriaei P, Shpall EJ, Giralt SA, Champlin RE, Qazilbash MH (2015) Short-term cardiac toxicity of autologous hematopoietic stem cell transplant for multiple myeloma. Leuk Lymphoma 56(2):533–535. 10.3109/10428194.2014.926346 24882259 10.3109/10428194.2014.926346
19. Majhail NS Challa TR Mulrooney DA Baker KS Burns LJ Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic cell transplantation Biol Blood Marrow Transpl 2009 15 9 1100 1107 10.1016/j.bbmt.2009.05.010 19660723 Majhail NS, Challa TR, Mulrooney DA, Baker KS, Burns LJ (2009) Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl 15(9):1100–1107. 10.1016/j.bbmt.2009.05.010 10.1016/j.bbmt.2009.05.010 19660723
20. van Walraven C Austin PC Jennings A Quan H Forster AJ A modification of the Elixhauser comorbidity measures into a point system for hospital death using administrative data Med Care 2009 47 6 626 633 10.1097/MLR.0b013e31819432e5 19433995 van Walraven C, Austin PC, Jennings A, Quan H, Forster AJ (2009) A modification of the Elixhauser comorbidity measures into a point system for hospital death using administrative data. Med Care 47(6):626–633. 10.1097/MLR.0b013e31819432e5 19433995 10.1097/MLR.0b013e31819432e5
21. Moore BJ White S Washington R Coenen N Elixhauser A Identifying Increased Risk of Readmission and In-hospital Mortality Using Hospital Administrative Data: The AHRQ Elixhauser Comorbidity Index Med Care 2017 55 7 698 705 10.1097/MLR.0000000000000735 28498196 Moore BJ, White S, Washington R, Coenen N, Elixhauser A (2017) Identifying increased risk of readmission and in-hospital mortality using hospital administrative data: the AHRQ elixhauser comorbidity index. Med Care 55(7):698–705. 10.1097/MLR.0000000000000735 28498196 10.1097/MLR.0000000000000735
22. Dandoy CE Kim S Chen M Ahn KW Ardura MI Brown V Chhabra S Diaz MA Dvorak C Farhadfar N Flagg A Ganguly S Hale GA Hashmi SK Hematti P Martino R Nishihori T Nusrat R Olsson RF Rotz SJ Sung AD Perales MA Lindemans CA Komanduri KV Riches ML Incidence Risk Factors, and Outcomes of Patients Who Develop Mucosal Barrier Injury-Laboratory Confirmed Bloodstream Infections in the First 100 Days After Allogeneic Hematopoietic Stem Cell Transplant JAMA Netw Open 2020 3 1 e1918668 10.1001/jamanetworkopen.2019.18668 31913492 PMC6991246 Dandoy CE, Kim S, Chen M, Ahn KW, Ardura MI, Brown V, Chhabra S, Diaz MA, Dvorak C, Farhadfar N, Flagg A, Ganguly S, Hale GA, Hashmi SK, Hematti P, Martino R, Nishihori T, Nusrat R, Olsson RF, Rotz SJ, Sung AD, Perales MA, Lindemans CA, Komanduri KV, Riches ML, Incidence (2020) Risk factors, and outcomes of patients who develop mucosal barrier injury-laboratory confirmed bloodstream infections in the first 100 days after allogeneic hematopoietic stem cell transplant. JAMA Netw Open 3(1):e1918668. 10.1001/jamanetworkopen.2019.18668 31913492 10.1001/jamanetworkopen.2019.18668 PMC6991246
23. See I Iwamoto M Allen-Bridson K Horan T Magill SS Thompson ND Mucosal barrier injury laboratory-confirmed bloodstream infection: results from a field test of a new National Healthcare Safety Network definition Infect Control Hosp Epidemiol 2013 34 8 769 776 10.1086/671281 23838215 See I, Iwamoto M, Allen-Bridson K, Horan T, Magill SS, Thompson ND (2013) Mucosal barrier injury laboratory-confirmed bloodstream infection: results from a field test of a new National Healthcare Safety Network definition. Infect Control Hosp Epidemiol 34(8):769–776 23838215 10.1086/671281
24. Mikulska M Gualandi F Anserini P Early and late complications of hematopoietic stem cell transplantation Handb Clin Neurol 2024 202 135 151 10.1016/B978-0-323-90242-7.00010-9 39111905 Mikulska M, Gualandi F, Anserini P (2024) Early and late complications of hematopoietic stem cell transplantation. Handb Clin Neurol 202:135–151. 10.1016/B978-0-323-90242-7.00010-9 39111905 10.1016/B978-0-323-90242-7.00010-9
25. Mielcarek M Gooley T Martin PJ Chauncey TR Young BA Storb R Torok-Storb B Effects of race on survival after stem cell transplantation Biol Blood Marrow Transpl 2005 11 3 231 239 10.1016/j.bbmt.2004.12.327 15744242 Mielcarek M, Gooley T, Martin PJ, Chauncey TR, Young BA, Storb R, Torok-Storb B (2005) Effects of race on survival after stem cell transplantation. Biol Blood Marrow Transpl 11(3):231–239. 10.1016/j.bbmt.2004.12.327 10.1016/j.bbmt.2004.12.327 15744242
26. Sorror ML Storb RF Sandmaier BM Maziarz RT Pulsipher MA Maris MB Bhatia S Ostronoff F Deeg HJ Syrjala KL Estey E Maloney DG Appelbaum FR Martin PJ Storer BE Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation J Clin Oncol 2014 32 29 3249 3256 10.1200/JCO.2013.53.8157 25154831 PMC4178523 Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, Bhatia S, Ostronoff F, Deeg HJ, Syrjala KL, Estey E, Maloney DG, Appelbaum FR, Martin PJ, Storer BE (2014) Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 32(29):3249–3256 25154831 10.1200/JCO.2013.53.8157 PMC4178523
27. de Kauark-Fontes E Jr de Migliorati CA Epstein JB Treister NS Alves CGB Faria KM Palmier NR Rodrigues-Oliveira L Pauli Paglioni M Gueiros LAM Conceição Vasconcelos KGM Castro G Leme AFP Lopes MA Prado-Ribeiro AC Brandão TB Santos-Silva AR Extraoral photobiomodulation for prevention of oral and oropharyngeal mucositis in head and neck cancer patients: interim analysis of a randomized, double-blind, clinical trial Support Care Cancer 2022 30 3 2225 2236 10.1007/s00520-021-06625-8 34708311 PMC8550910 Kauark-Fontes E, Migliorati CA, Epstein JB, Treister NS, Alves CGB, Faria KM, Palmier NR, Rodrigues-Oliveira L, de Pauli Paglioni M, Gueiros LAM, da, Conceição Vasconcelos KGM, de Castro G Jr, Leme AFP, Lopes MA, Prado-Ribeiro AC, Brandão TB, Santos-Silva AR (2022) Extraoral photobiomodulation for prevention of oral and oropharyngeal mucositis in head and neck cancer patients: interim analysis of a randomized, double-blind, clinical trial. Support Care Cancer 30(3):2225–2236. 10.1007/s00520-021-06625-8 34708311 10.1007/s00520-021-06625-8 PMC8550910
28. Elad S, Cheng KKF, Lalla RV, Yarom N, Hong C, Logan RM, Bowen J, Gibson R, Saunders DP, Zadik Y, Ariyawardana A, Correa ME, Ranna V, Bossi P, Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) (2020). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. ;126(19):4423–4431. 10.1002/cncr.33100. Epub 2020 Jul 28. Erratum in: Cancer. 2021;127(19):3700. doi: 10.1002/cncr.33549. PMID: 32786044; PMCID: PMC7540329 10.1002/cncr.33100 PMC7540329 32786044
29. Hong CHL Gueiros LA Fulton JS Cheng KKF Kandwal A Galiti D Fall-Dickson JM Johansen J Ameringer S Kataoka T Weikel D Eilers J Ranna V Vaddi A Lalla RV Bossi P Elad S Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Systematic review of basic oral care for the management of oral mucositis in cancer patients and clinical practice guidelines Support Care Cancer 2019 27 10 3949 3967 10.1007/s00520-019-04848-4 31286232 Hong CHL, Gueiros LA, Fulton JS, Cheng KKF, Kandwal A, Galiti D, Fall-Dickson JM, Johansen J, Ameringer S, Kataoka T, Weikel D, Eilers J, Ranna V, Vaddi A, Lalla RV, Bossi P, Elad S, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) (2019) Systematic review of basic oral care for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer 27(10):3949–3967. 10.1007/s00520-019-04848-4 31286232 10.1007/s00520-019-04848-4
30. McGuire DB Fulton JS Park J Brown CG Correa ME Eilers J Elad S Gibson F Oberle-Edwards LK Bowen J Lalla RV Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Systematic review of basic oral care for the management of oral mucositis in cancer patients Support Care Cancer 2013 21 11 3165 3177 10.1007/s00520-013-1942-0 24018908 McGuire DB, Fulton JS, Park J, Brown CG, Correa ME, Eilers J, Elad S, Gibson F, Oberle-Edwards LK, Bowen J, Lalla RV, Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) (2013) Systematic review of basic oral care for the management of oral mucositis in cancer patients. Support Care Cancer 21(11):3165–3177. 10.1007/s00520-013-1942-0 24018908 10.1007/s00520-013-1942-0
31. Cheng KK Leung SF Liang RH Tai JW Yeung RM Thompson DR Severe oral mucositis associated with cancer therapy: impact on oral functional status and quality of life Support Care Cancer 2010 18 11 1477 1485 10.1007/s00520-009-0771-7 19916030 Cheng KK, Leung SF, Liang RH, Tai JW, Yeung RM, Thompson DR (2010) Severe oral mucositis associated with cancer therapy: impact on oral functional status and quality of life. Support Care Cancer 18(11):1477–1485. 10.1007/s00520-009-0771-7 19916030 10.1007/s00520-009-0771-7
32. Mohan MP Pili R Epstein JB Rudin L Eichhorn S Satheeshkumar PS Cancer treatment-induced ulcerative mucositis serves as a significant predictor of burden of illness including dysphagia, and associated disparities among hospitalized cancer patients Support Care Cancer 2024 33 1 22 10.1007/s00520-024-09071-4 39666090 Mohan MP, Pili R, Epstein JB, Rudin L, Eichhorn S, Satheeshkumar PS (2024) Cancer treatment-induced ulcerative mucositis serves as a significant predictor of burden of illness including dysphagia, and associated disparities among hospitalized cancer patients. Support Care Cancer 33(1):22. 10.1007/s00520-024-09071-4 39666090 10.1007/s00520-024-09071-4
33. Vasbinder A Hoeger CW Catalan T Anderson E Chu C Kotzin M Xie J Kaakati R Berlin HP Shadid H Perry D Pan M Takiar R Padalia K Mills J Meloche C Bardwell A Rochlen M Blakely P Leja M Banerjee M Riwes M Magenau J Anand S Ghosh M Pawarode A Yanik G Nathan S Maciejewski J Okwuosa T Hayek SS Cardiovascular Events After Hematopoietic Stem Cell Transplant: Incidence and Risk Factors JACC CardioOncol 2023 5 6 821 832 10.1016/j.jaccao.2023.07.007 38205002 PMC10774793 Vasbinder A, Hoeger CW, Catalan T, Anderson E, Chu C, Kotzin M, Xie J, Kaakati R, Berlin HP, Shadid H, Perry D, Pan M, Takiar R, Padalia K, Mills J, Meloche C, Bardwell A, Rochlen M, Blakely P, Leja M, Banerjee M, Riwes M, Magenau J, Anand S, Ghosh M, Pawarode A, Yanik G, Nathan S, Maciejewski J, Okwuosa T, Hayek SS (2023) Cardiovascular Events After Hematopoietic Stem Cell Transplant: Incidence and Risk Factors. JACC CardioOncol 5(6):821–832. 10.1016/j.jaccao.2023.07.007 38205002 10.1016/j.jaccao.2023.07.007 PMC10774793
34. Blijlevens NM Donnelly JP De Pauw BE Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview Bone Marrow Transpl 2000 25 12 1269 1278 10.1038/sj.bmt.1702447 PMC7091624 10871732 Blijlevens NM, Donnelly JP, De Pauw BE (2000) Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transpl 25(12):1269–1278. 10.1038/sj.bmt.1702447 10.1038/sj.bmt.1702447 PMC7091624 10871732
35. Kumar G Ahmad S Taneja A Patel J Guddati AK Nanchal R Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators Severe sepsis in hematopoietic stem cell transplant recipients* Crit Care Med 2015 43 2 411 421 10.1097/CCM.0000000000000714 25599465 Kumar G, Ahmad S, Taneja A, Patel J, Guddati AK, Nanchal R, Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators (2015) Severe sepsis in hematopoietic stem cell transplant recipients*. Crit Care Med 43(2):411–421. 10.1097/CCM.0000000000000714 25599465 10.1097/CCM.0000000000000714
36. van der Velden WJ Herbers AH Netea MG Blijlevens NM Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis Br J Haematol 2014 167 4 441 452 10.1111/bjh.13113 25196917 van der Velden WJ, Herbers AH, Netea MG, Blijlevens NM (2014) Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol 167(4):441–452. 10.1111/bjh.13113 25196917 10.1111/bjh.13113
37. Ali M Kerio AA Khattak TA Hussain M Khan MA Abbas Y Oral Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplantation J Coll Physicians Surg Pak 2023 33 7 804 808 10.29271/jcpsp.2023.07.804 37401225 Ali M, Kerio AA, Khattak TA, Hussain M, Khan MA, Abbas Y (2023) Oral Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplantation. J Coll Physicians Surg Pak 33(7):804–808. 10.29271/jcpsp.2023.07.804 37401225 10.29271/jcpsp.2023.07.804