The Basic Documentation for Psycho-Oncology in Pediatric Stem Cell Transplantation Recipients: Ratings of Parents and Staff and the Profile of Salivary α -Amylase

Background . Hematopoietic stem cell transplantation (HSCT) is a curative treatment option for malignant and nonmalignant diseases that is highly distressing, especially for children. A valid assessment of pediatric patients’ distress that is independent from their language skills would be benefcial. Research regarding HSCT-specifc self-reporting or rater-reporting instruments is scarce. Method . In this single-center prospective study, pediatric patients and young adolescents undergoing HSCT were screened for mental and somatic distress using PO-Bado (Basic Documentation for Psycho-Oncology) ratings from parents and medical caregivers on eight observations days before, during, and up to 200days after HSCT. Additionally, the stress biomarkers cortisol and α -amylase were monitored on the same observation days. Results . A total of 39 pediatric and young adult patients with a median age of 9.3years (range 0.5–19.0), with 18 females (46%) and 21 males, were enrolled. Te perceptions of the patients’ somatic and mental distress of parents and medical caregivers of patients were signifcantly correlated (mental subscale (( r (276) � 0.31, p < 0 . 001., 95% CI of the correlation: (0.20, 0.41)) and somatic subscale (( r (284) � 0.46, p < 0 . 001., 95% CI of the correlation: 0.36, 0.54)). Te time period between the days of transplantation until day +10 was rated as the most mentally and somatically distressing. Conclusions . While the somatic burden declined over time, the mental distress in the patients remained at a stable level, emphasizing the importance of further psychological and psycho-oncological support in these patients. Te use of salivary α -amylase as a suitable distress detection marker in pediatric patients undergoing HSCT should be further investigated.


Introduction
Hematopoietic stem cell transplantation (HSCT) is a curative treatment option for malignant and nonmalignant diseases that is performed over 400 times per year in children in Germany (2019: 349 allogeneic HSCTs and 96 autologous HSCTs) [1]. Given the persistent burden of a life-threatening disease and its likewise potentially life-threatening cure, the patients experience high psychological and somatic distress when undergoing this intense treatment. Tey are at particularly high risk of depression, posttraumatic stress disorders, anxiety, and an impaired emotional well-being and quality of life, not only in the acute transplantation period but also in the following years [2][3][4][5][6].
Basic or-if indicated-intensifed psychosocial support for pediatric and adolescent patients undergoing HSCT is recommended by the German national S3 Guideline "Psychosocial care in childhood and adolescent oncology" [7]. Research regarding HSCT-specifc self-reporting or raterreporting instruments assessing the children's perceived emotional or physical stress or their health-related quality of life during and after HSCT is scarce and often includes rather punctual observations with a long time lag, e.g. before and six or twelve months after HSCT [8][9][10][11][12]. Te data are often limited to older children and their ability to understand and communicate their mental and physical well-being or stress. External observers-i.e., parents and caregivers-might be a benefcial resource in the comprehensive assessment of the mental or somatic condition in this specifc patient cohort, especially in younger children and infants. Te parents have a thorough understanding of their child's physical and emotional constitution, and the medical stafs (physicians and nurses) have usually a profound experience with many patients undergoing HSCTand its individual burdensome aspects. Both may provide useful information, potentially enabling a reliable identifcation of patients with a need for further psychooncological support and psychosocial care. However, only few works address multirater perspectives and an evaluation of the specifc inter-rater diferences [8,[12][13][14].
Pediatric allogeneic and autologous HSCT is performed in specialized treatment centers usually afliated to university hospitals and it integrates the treatment of international and culturally diverse patients. Tis can be accompanied by challenges in communicating with the patients and parents, potentially complicating the screening of the patients' need for further support [15]. A valid assessment of patient distress that is independent from their language skills would therefore be benefcial.
In our prospective investigation, we analyzed the mental and somatic distress of a total of 39 pediatric and young adult patients undergoing allogeneic or autologous HSCT as perceived by the patients' parents and their medical caregivers, as well as the patients' blood and salivary stress biomarkers. Tese studies were conducted at short intervals during the in-patient stay during HSCT and at follow-up until day +200 after HSCT, i.e., the day of in-patient admission (baseline; day −10 before HSCT), on day 0 (day of HSCT), day +10, day +20, day +30, day +60, day +100, and day +200 after HSCT. Te primary objective was to describe the course of the mental and somatic distress of pediatric patients before, during, and after HSCTand analyze the inter-rater diferences of the external observers. Furthermore, we evaluated age as an infuencing factor and the measure of agreement between the distress ratings and stress biomarkers.

Study Background and Design.
In this prospective study, patients of the stem cell transplantation unit of the University Children's Hospital Tübingen were recruited between 2019 and 2020. Te inclusion criteria were an age between 0.5 and 20 years at the time of study enrollment and an upcoming allogeneic or autologous HSCT. Te exclusion criteria were a diagnosis of a mental disorder according to the ICD-11 (International Classifcation of Disease-11) before study enrollment [16]. After written informed consent was obtained from the patients and their legal guardians, the patients were enrolled. Te observation period started on the day of in-patient admission prior to the commencement of HSCT and ended on day +200 after HSCT. Te patients' parents and medical caregivers answered questionnaires and the patients were screened for laboratory markers on a total of eight observation days, i.e., the day of in-patient admission (baseline; day −10 before HSCT), on day 0 (day of HSCT), day +10, day +20, day +30, day +60, day +100, and day +200 after HSCT.

Questionnaires.
Te perceived mental and somatic distress of the patients was rated on the specifc observation days by the medical staf and one of their parents. Te mental and somatic distress was assessed with the standard version of the PO-Bado (Basic Documentation for Psycho-Oncology) cancer-specifc screening instrument, developed by Herschbach and colleagues [17][18][19].

Laboratory Analyses.
On the observation days, the patients were tested for salivary α-amylase and blood levels of cortisol as markers of the stress response, thyroidfunction parameters, thyroid-stimulating hormone (TSH), free triiodothyronine (fT 3 ), and free thyroxine (fT 4 ). Blood collection was performed around 7 a.m. on the observation days. Measurements obtained during phases of conditioning in which steroids were substituted, as well as during steroid therapies in case of acute GvHD, were excluded from the analyses of cortisol measurements. Normal blood concentrations of the parameters were defned as follows: cortisol 125-400 nmol/L (nanomole per liter), TSH 0.3-4.0 mU/L (milliunits per liter), fT 3 3.5-6.5 pmol/L (picomole per liter), and fT 4 13-26 pmol/L.

Statistical
Analysis. PO-Bado scores for the subscales somatic distress and mental distress were calculated from the ratings done by staf and parents for each participant and point in time according to the manual. For primary analyses, we conducted a baseline correction, subtracting the baseline PO-Bado score (day −10) from the scores of the following days. Te baseline-corrected data were then used to ft a linear mixed model [20]. Te equation used to ft the model can be described by score ijk � β 0j + β 1j * day k + ϑ 0i + ϑ 1i + ε ijk . In this model equation score ijk denotes the baseline corrected PO-Bado score of Patient i � 1, . . ., 39, in rating group j � 1 (somatic distress rated by staf), 2 (mental distress rated by staf), 3 (somatic distress rated by parents), or 4 (mental distress rated by parents), at day k � 0, . . ., 200 after HSCT. β 0j and β 1j denote the fxed efects, where β 0j is the intercept estimate (i.e., the baseline corrected PO-Bado score at day 0 after HSCT) and β 1j is the slope estimate (i.e., how much the baseline corrected PO-Bado score decreases or increases each day) for the respective rating group j. ϑ 0i and ϑ 1i describe the individual-specifc random intercepts and slopes, while ε ijk is the error term [21][22][23].

Patient Characteristics.
A total of 39 pediatric and young adult patients with a median age of 9.3 years (range 0.5-19.0), with 18 females (46%) and 21 males, were enrolled in this prospective analysis. Of these patients, eight patients (21%) underwent an autologous and 31 patients (79%) underwent an allogeneic HSCT. Detailed patient characteristics can be found in Table 1.

Course of Mental and Somatic Distress during HSCT.
Te results of the linear mixed model analysis show signifcant positive estimates for the intercepts of somatic distress rated by staf and parents, as well as mental distress rated by staf. Te intercept estimates for the baseline corrected PO-Bado score signify that there was a signifcant increase in the rating of distress from baseline to day 0 for those rating groups. Te intercept estimates of mental distress rated by parents did not yield a signifcant result, meaning the distress did not increase nor decrease signifcantly from the baseline to day 0. For slope estimates-which indicate how much the baseline corrected PO-Bado score decreases each day after HSCT-only the parameter estimates for somatic distress were signifcant, while the slope estimates for mental distress did not reach signifcance. Tis implies that while the rating of baseline-corrected somatic distress decreased after HSCT, the rating of baselinecorrected mental distress did not change signifcantly (Table 2, Figure 1).
In order to identify age as an infuencing factor, the interactions of age as a continuous variable and subscalerater combinations were added to the mixed linear model as fxed efects. It was shown that age was not an infuencing factor in any of the subscale-rater combinations of somatic staf ( Figure 1(c)), somatic parents ( Figure 1(d)), mental staf ( Figure 1(e)), and mental parents ( Figure 1(f )), considering a 95% CI. For a clearer depiction in the graphs, age is categorized in groups of 0-5 years, 6-12 years, and ≥13 years.

Inter-Rater Diferences of Parents and Medical Staf.
Correlation analyses of the mental and somatic subscales between the ratings of the parents and medical staf showed a signifcant correlation of both the mental subscale ((r(276) � 0.31, p < 0.001., 95% CI of the correlation: (0.20; 0.41)) and the somatic subscale ((r(284) � 0.46, p < 0.001., 95% CI of the correlation: (0.36, 0.54)). Given that the subscale scores are a combination of items that may be rated diferently by staf or parents but still result in the same mean score, the inter-rater reliability was additionally analyzed at the item level with a weighted Cohen's Kappa for each patient and both subscales. Subsequent t-tests showed that the inter-rater reliability was signifcantly higher for the somatic subscale (M � 0.38) when compared to the mental subscale (M � 0.18; t (76) � 4.53; p < 0.001) ( Figure 2).

Stress and Tyroid
Biomarkers. All children six years of age and older were able to reliably provide saliva samples, while only just under one-third (28.6%) of those under six years of age generated evaluable saliva samples. In the following analyses, all correctly obtained saliva samples are taken into account, so that the results are representative of all children aged six years and older, but only to a limited extent for the group of children up to 5 years. Salivary α-amylase continuously increased from day −10 before HSCT (baseline) (mean 61.6 ± 11.3 units per liter (U/ L), range 3.9-225.8 U/L) to an overall peak on day +10 after HSCT (mean 142.1 ± 57.2 U/L, range 5.2-1105 U/L). Given the wide range of results, the mean levels between baseline and day +10 after HSCT were not signifcantly diferent (p � 0.68). Te levels declined until day +20 (mean 52.9 ± 9.6 U/L, range 4.1-138.8 U/L) and continuously increased until day +200 after HSCT (mean 115.5 ± 32.5, range 3.0-467.7 U/L) (Figure 3(a)). At present, there are no reference values for salivary α-amylase, and hence, a description of the detected concentration can only be relative. Based on previous studies, it is recommended to measure the respective relative increase of alpha-amylase of the subject compared to a baseline level instead of considering absolute values [24].
Serum cortisol levels continuously and signifcantly increased from a mean baseline level of 262.5 ± 24.8 nmol/L (range 14.0-501.0 nmol/L) to a peak value of 489.8 ± 42.6 nmol/L on day +60 after HSCT (p � 0.0012). Tereafter, the mean cortisol concentrations decreased to 326.1 ± 48.3 nmol/L (range 54.0-1117 nmol/L) on day +200. A signifcant increase of the mean cortisol levels beyond the upper normal limit (420 nmol/L) was not reached on any of the observation days (Figure 3(b)).
Te TSH blood levels remained similar throughout the whole observation period. Baseline levels started at a mean of 4.4 ± 1.4 mU/L (range 0.1-48.4 mU/L) and slightly and insignifcantly (p � 0.56) decreased to a mean of 2.6 ± 0.3 (range 0.1-6.6 mU/L) on day +10 after HSCT. None of the determined TSH levels decreased or increased beyond the normal limits (6.3 mU/L) (Figure 3(c)).
European Journal of Cancer Care

Correlation of Somatic and Mental Distress with Blood
Biomarkers. Te analyses showed that mental distress as rated by parents and medical staf was rather constant throughout the whole observation period, while somatic distress increased from baseline to peak values between day 0 and day +10 and subsequently decreased over time. Correlation analyses between the ratings of the parents and medical staf showed a signifcant correlation between both the mental and the somatic subscales, with a higher interrater reliability of the latter. To identify correlations of the    Symbols directly below or above data points indicate signifcant decreases beyond the normal limits. Indication of the following symbols are * p < 0.05; * * p < 0.01; * * * p < 0.001; and * * * * p < 0.0001.

Discussion
Psycho-oncological support holds strong importance in complementing cancer therapy [25]. In the past two decades, the assessment of the health-related quality of life in pediatric cancer patients has gained considerably in importance [9]. Especially in these patients, a reliable external observer rating provides important data to detect patients at need of further support. Te results of this prospective study show that the somatic burden was rated similarly by parents and medical staf, with worsening at the time of transplantation until day +10 after HSCT. Te scores were not signifcantly diferent between the two raters, with an overall high degree of alignment over the entire observation period. Although the inter-rater reliability of the mental distress subscale (item-based analysis) was lower when compared to the somatic distress scores, the results of both rater-groups were also not signifcantly diferent over the observation period. Contrary to our expectations, patient age was not an infuencing factor in these analyses.
Although there were alignments of the somatic and mental distress-especially in the early posttransplant period-the slope estimate analyses of both showed that while the somatic burden declined over time after HSCT, the mental burden of the patients did not signifcantly change. Tis implies that the somatic burden of the transplantation is a relevant-but not exclusive-factor in the extent of the mental distress. Tis clearly shows that the decrease of the individual disease burden does not automatically lead to a decrease of mental distress up to day +200 after HSCT. In a multicenter, prospective study with a total of 165 children undergoing HSCT, the feasibility and the benefts of a multirater assessment of the health-related quality of life as experienced by the patients or rated by parents and nurses were demonstrated. In contrast to our results, the somatic and mental distresses were associated with a higher patient age. Although ratings difered by several factors-e.g., perceptions of the somatic burden-the authors demonstrated the beneft and feasibility of a multirater assessment of the quality of life of pediatric HSCT patients [12]. While quality of life in pediatric patients is mainly due to somatic impairment within the early posttransplantation period, i.e., within the frst 30 days after HSCT, mental distress mainly comprises the frst 6 months after HSCT. Previous data show a short-term deterioration in quality of life one month after HSCT, followed by improvement as early as 3 months after transplantation to levels better than pretransplant baseline and stability until one year after HSCT [26,27]. Te quality of life in autologous stem cell transplanted adults is higher compared with adults who had an allogeneic stem cell transplant [28]. In pediatric patients with leukemia, distress after induction therapy shows that children with standard-risk ALL experience signifcant impairment in health-related quality of life at the end of induction but improve rapidly. However, many still sufer from physical and social distress 3 months after therapy, suggesting that family support and physical functioning play a supporting role [29]. Certain infuential factors seem to play a role in pediatric patients with ALL with regard to the assessment of quality of life. In high-risk ALL, girls and older children had a poorer quality of life. For standard-risk ALL, those with lower household income and unmarried parents had a poorer quality of life [30]. In addition, interviewed fathers appeared to have lower quality of life perceptions compared with interviewed mothers [31].
Te hypothalamus-pituitary-adrenal (HPA) axis and the hypothalamus-pituitary-thyroid (HPT) axis are interdependent key regulators of neurological, neuroendocrine, endocrine, psychological, and immunological functioning [32,33]. Tese axes can be signifcantly altered due to stress disorders, cancer, or infammation [34][35][36][37][38][39][40][41]. In contrast to alpha-amylase and cortisol, thyroid hormone concentrations can decrease with increased exercise [32,42]. In the present study, TSH and fT4 showed descriptively lower values between day 0 and day 30 and increased-as did fT3-towards the end of the observation period. Although we identifed a signifcant increase of T4 with a peak on day +60 after HSCT, relevant increases or decreases beyond the normal levels of the thyroid-function markers were not observed. Previous works have described the efects of the conditioning regimen on the gonads and the hypothalamopituitary-gonadal control of pediatric and adolescent patients [21][22][23]. Although hypothyroidism is a known long-term consequence of HSCT in childhood, to date there are no published data on thyroid hormone changes in the frst 30 days after HSCT for either adults or children [43][44][45].
Both salivary α-amylase and cortisol are suggested as useful biomarkers for detecting acute and chronic physical and psychological stress [46][47][48][49][50][51]. In the present analysis, the levels of the stress biomarker cortisol increased over time and peaked on day +60 after HSCT. In contrast to the cortisol, a peak of the salivary α-amylase levels occurred on day +10 after HSCT, followed by a drop on day +20 after HSCT and then a subsequent and constant increase until the end of the observation period. Accordingly, reference data for the concentration profle of salivary α-amylase during pediatric HSCT were not found in the existing literature.
During allogeneic HSCT, salivary α-amylase levels of 41 adults were signifcantly higher after one-month posttransplant in comparison to pretransplant baseline levels [52]. During autologous HSCTof 25 adult myeloma patients, a signifcant diference of the salivary α-amylase levels was not observed between day −3 pretransplant and day +7 posttransplant, which was identifed as the day of the maximum severity of oral mucositis [53].

Conclusions
Te perceptions of the somatic and mental distress of parents and medical caregivers of pediatric patients undergoing HSCT were signifcantly correlated and not dependent on the patient's age. Te time period between the days of transplantation until day +10 was rated as the most mentally and somatically distressing. While the somatic burden declined over time, the mental distress in the patients remained at a stable level until the end of the observation period (6 months after HSCT), emphasizing the importance of further psychological and psycho-oncological support in these patients. Te use of salivary α-amylase as a suitable distress detection marker in pediatric patients undergoing HSCT should be further investigated.

Data Availability
Te data that support the fndings of this study are available upon reasonable request from the corresponding author. Te data are not publicly available due to privacy or ethical restrictions.

Ethical Approval
Te prospective study was performed in accordance with the Helsinki Declaration adopted by the 18th WMA General

Consent
Written informed consent to participate in this study and for publication of the data were obtained from all participants and, if necessary, their parents/legal representatives.

Conflicts of Interest
All the authors declare that they have no conficts of interest.

Authors' Contributions
MD, KMCS, and ST were responsible for the conception and design of this study. All authors collected the data. ST, JX, DW, KMCS, and MD analyzed and interpreted the data. KMCS, MD, ST, and JX wrote the manuscript. All authors were substantially involved in the drafting and/or critical revision of the manuscript. All authors have read and approved the fnal manuscript.