Application of the NCCN-distress thermometer in pediatric patients during autologous and allogeneic HSCT and relationship to blood parameters of the stress axis

doi:10.21203/rs.3.rs-2462213/v1

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Research Article

Application of the NCCN-distress thermometer in pediatric patients during autologous and allogeneic HSCT and relationship to blood parameters of the stress axis

https://doi.org/10.21203/rs.3.rs-2462213/v1

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Purpose

Hematopoietic stem cell transplantations (HSCT) are extremely stressful procedures for pediatric patients. The activation of the Hypothalamic pituitary adrenocortical axis (HPA) can influence the immune system negatively and therefore the overall outcome. A screening instrument should be established to detect elevated stress levels.

Methods

In this prospective study, a distress thermometer with attached problem list was used in 40 pediatric patients and their parents. The patients were aged 10 to 18 years and received a HSCT. Furthermore, the patients' cortisol, thyroid stimulating hormone, free triiodothyronine and Thyroxine levels were measured regularly during the inpatient stay.

Results

After admission to the hospital, the stress levels of the pediatric patients and their parents increased and reached their maximum on the day of HSCT. The overall stress values of the parents were higher than those of the children, with a significant difference on the day of HSCT. The mean cortisol values of the pediatric patients also increased after admission, reaching significant elevated levels above the upper norm limit one week after HSCT and on discharge day. While the pediatric patients experienced mainly exhaustion, especially on the day of transplantation, their parents mainly felt worry and anxiety. Interestingly, the rate of worry among children increased in the posttransplant period and reached its maximum on the day of discharge.

Conclusions

These results confirm the need for early and continuous psycho-oncological intervention with the pediatric patients and their parents, especially up to the day of HSCT.

distress thermometer

pediatric patients

stress hormones

hematopoietic stem cell transplantation

cortisol

psychological burden

Hematopoietic stem cell HSCT (HSCT) is the only curative therapy for multiple malignant and non-malignant diseases [1]. The psychological impact on children receiving HSCT is similar to that of children receiving chemotherapy [2, 3]. In both cases, children have to cope for a long period of time with the fact that they are not in their familiar home environment, they cannot maintain the same social contacts as previously, and they also have to endure the side effects associated with the treatment. Especially in the case of malignant primary diseases, the fear of death or a relapse represent further psychological stress [4, 2]. This psychological stress can lead to anxiety and depression, which can worsen both the quality of life and the survival rate of patients [5, 6]. Psychoneuroimmunological studies provide evidence that depression and anxiety can negatively affect the function of the immune system [7]. Thus, psychological stress during HSCT could directly influence the outcome by delaying the regeneration of the immune system. There is evidence that severely experienced anxiety and depression short time after initial diagnosis can lead to persistence of these symptoms [8]. In addition, the psychological burden during HSCT can cause negative long-term effects especially in adolescent patients, and can lead to health impairment and unhealthy behavior even years after the disease has been overcome [9, 5]. Intensified psycho-oncological care is therefore strongly indicated immediately during or after the occurrence of such high psychological stress.

Because uniform guidelines for early assessment of stress in hemato-oncology pediatrics are still missing, anxiety and depression are often diagnosed and treated too late in pediatric patients [3]. For this reason, a screening test for mental distress that can be easily implemented in everyday clinical practice should be established in the field of pediatric oncology. [10, 3]. The NCCN-distress thermometer was developed according to these needs and allows a quick and easy to perform survey of distress. Previous studies have shown that its use is reliable, valid and acceptable in pediatric patients. [11, 6]. With the help of the distress thermometer, the child can classify his or her subjectively experienced stress on a visual analog scale with the subdivisions 0 (no stress) to 10 (extreme stress) [6]. In both adult and pediatric oncology patients, this test has been used successfully in the daily routine to identify those patients who should be evaluated in more detail [12, 13, 6].

In this prospective single center study, the distress thermometer was used to assess distress before, during, and after allogeneic HSCT in 40 pediatric patients, adolecents, and young adults with malignant and non-malignant diseases, aged 10 to 18 years [14]. The aim of the study was to assess the psychological distress of both pediatric patients, adolecents, young adults and their parents during the course of HSCT up to discharge. In addition, we investigated whether the psychological stress follows a certain temporal pattern in the course of HSCT and which subjective reasons for an increased stress load were given at certain points in time. Hereby, it was investigated whether it is possible to determine potential critical time points and external factors in the course of HSCT. This could further increase the rate of early diagnosis of mental distress in children and early initiation of appropriate psychotherapeutic support.

Study conception and design

In this prospective monocentric study, 40 children, adolescents, and young adult HSCT patients between 10 and 18 years of age, and one parent of each patient, were prospectively and consecutively enrolled at admission for scheduled HSCT between January 2019 and December 2020.

Patients were excluded if they were under 10 years of age, or if the patients and/or their parents did not have sufficient German or English language skills to apply the questionnaires used in this study. Furthermore, patients were excluded from the study if they had already been diagnosed with a mental illness prior to HSCT.

The observation period was defined as the period from one day before start of the conditioning regimen until the date of discharge after HSCT.

The Distress Thermometer

The NCCN-distress thermometer (DT) is a screening tool for assess distress in patients with hemato-oncological malignancies, developed by the United States National Comprehensive Cancer Network (NCCN). It is a single item screening instrument with an eleven-point visual analogue scale on which the subjectively experienced stress level can be rated from 0 (no stress) to 10 (extreme stress) [15]. A cut-off score ≥ 5 is internationally recommended as an indicator for a distressed patient. Additionally, a modified problem list identifies potential sources of distress. The German version of the NCCN DT and the corresponding problem list were used for this study, with the DT changed to a more child-friendly representation [14].

The children and one parent per child were given a distress diary with the DT and the problem lists were handed out every five days to analyze the stress level and the possible cause of distress of both the patients and one part of their parents. Using these stress diaries with the DT and the problem list, the reported stress levels were recorded and evaluated during the time period on the ward on the day of admission, five days before HSCT, the day of HSCT (day 0), day + 7, day + 14, day + 21, day + 28, day + 35, day + 42, day + 50, day + 60 after HSCT and the day of inpatient discharge.

Determination of blood parameters

The stress parameters cortisol, the thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and thyroxine (fT4) were determined in the blood of the pediatric patients and adolescents at the same time points for analysis of the DTs in order to compare the results. TSH, as well as fT3 and fT4 are quantified in heparinized peripheral blood using enzyme immunoassays, i.e. the ADVIA Centaur® XPT Immunoassay-System (Siemens-Healthcare GmbH, Erlangen, Germany).

Cortisol is a hormone of the stress response and recruits energetic compounds and molecules through activating catabolic processes. Cortisol was determined in the blood plasma using the corticosterone (Rat/Mouse 9 ELISA Kit from DRG Instruments GmbH, Marburg, Germany DRG Instruments GmbH, Marburg, Germany). The sampling and preparation of the peripheral blood taken from routine blood sampling was performed according to the manufacturer information, including the determination of negative and positive control samples.

All blood parameters were determined from blood samples taken as part of routine diagnostics, which took place daily in the morning between 6 and 7 am. Results were determined in the blood of the pediatric patients and adolescents at the same time points for analysis of the DTs in order to compare the results.

Statistical methods

All data were tested for normal distribution using the Shapiro-Wilk test. Because of significant deviations from normality, data were then tested with the Kruskal-Wallis-Test and, if significant, the p-value was then finally determined using the Dunn’s multiple comparison test. All p-values were adjusted for multiple testing. P values of < 0.05 (*), p < 0.01 (**), p < 0.001 (***), and p < 0.0001 (****) were defined as statistically significant.

The collection of laboratory data was performed using the laboratory information system Swisslab LAURIS (version 16.10.05.5, Roche Diagnostics IT Solutions GmbH, Berlin, Germany). All medical reports derived from the SAP-system of the University Children’s Hospital Tübingen (SAP Netweaver SAP GUI for Windows, Version 7300.3.10.1084, SAP SE, Walldorf, Germany). The data were collected using Microsoft Excel (Microsoft Excel 2010 Version 14.0 for Windows, Microsoft Germany GmbH, Munich, Germany). Graphs and statistical tests were created with GraphPad Prism for Windows, version 9.4, 2022 (GraphPad Software Inc., La Jolla, CA, USA).

Patients characteristics:

Patients characteristics are summarized in Table 1. The patient group consisted of 40 pediatric patients, adolescents, and young adults who received a HSCT because of a hematologic-oncologic malignant or non-malignant underlying disease. From these patients, 22 patients (55.0%) were male, 18 patients (45.0%) were female. The median age was 14.6 years (range 10 - 18 years). Patients received graft from matched sibling donors (MSD; n=13; 32.5%), matched unrelated donors (MUD; n=15; 37.5%), mismatched family donors (MMFD; n=7; 17.5%), and themselves (autologous; n=5; 12.5%). The conditioning regimen was in 37 out of 40 patients myeloablative (92.5%) and in three cases intensity reduced (7.5%), composite in one case of cyclophosphamide (4 x 50 milligram per kilogram (mg/kg)) and anti-thymocyte globulin (ATG; 3 x 10 mg/kg), in one case of fludarabine (3 x 40 milligram per square meter (mg/m²)), thiotepa (15 milligram per kilogram (mg/kg)), total lymphoid irradiation (TLI, 1 x 7 Gray (Gy)) and ATG (2 x 15 mg/kg) and in the third case of fludarabine (5 x 30 mg/m²), total body irradiation (TBI; 4 Gy), Thiotepa (2 x 5 mg/kg), ATG (6 mg/kg) and post-transplant cyclophosphamide (2 x 50 mg/kg). Out of 40 patients, 17 (42.5%) suffered from acute leukemia or myelodysplastic syndrome and four patients (10.0%) had a lymphoma. Furthermore, seven patients (17.5%) were diagnosed with a non-hematologic solid tumor and twelve patients (30.0%) had a non-malignant underlying disease. During the clinical course 17 patients each (42.5%) suffered from sepsis or systemic inflammatory response syndrome (SIRS) and viremia. An acute graft-versus-host disease (aGvHD) grade 1 occurred in eleven patients (27.5%). There was no case of higher grade aGvHD during the observation period. A veno-occlusive disease (VOD) was diagnosed in seven patients (17.5%) within the clinical course and three patients (7.5%) had a graft failure.

The median observation period was 51.5 days (range 24-155 days).

Table 1: Patient characteristics

Patient characteristic	Number (%)

Sex
male	22 (55.0)
female	18 (45.0)
Age [years]
Median (range)	14 (10.0 – 18.0)
HSCT donor
Matched sibling donor	13 (32.5)
Matched unrelated donor	15 (37.5)
Mismatched family donor	7 (17.5)
Autologous	5 (12.5)
Diagnosis
Malignant diseases
Acute lymphoblastic leukemia and relapse	9 (22.5)
Acute myeloid leukemia and relapse	5 (12.5)
Ewing`s sarcoma	3 (7.5)
Myelodysplastic syndromes	3 (7.5)
Morbus Hodgkin	2 (5.0)
Neuroblastoma	2 (5.0)
Osteosarcoma	1 (2.5)
Nephroblastoma	1 (2.5)
Anaplastic large cell lymphoma	1 (2.5)
Peripheral T cell lymphoma	1 (2.5)
Non-malignant diseases
Sickle cell anemia	7 (17.5)
Thalassemia	2 (5.0)
Severe aplastic anemia	2 (5.0)
Severe combined immunodeficiency	1 (2.5)
Conditioning regime
Reduced-intensity conditioning	3 (7.5)
Myeloablative conditioning	37 (92.5)
Complications after HSCT
Sepsis/SIRS	17 (42.5)
aGvHD Grade 1-2	11 (27.5)
aGvHD Grade 3-4	0 (0.0)
VOD	7 (17.5)
Viremia	17 (42.5)
Graft failure	3 (7.5)

Abbreviations: aGvHD – acute graft-versus-host disease | HSCT – hematopoietic stem cell transplantation | n – sample size | SIRS – systemic inflammatory response syndrome | VOD – veno-occlusive disease

Analysis of the distress thermometer

The mean baseline DT value of the patients was 5.0 (range 3 - 9). On day -5 before HSCT, the patients reported a mean DT value of 6.0 (range 2 - 9, DT day -5 vs. base: p=0.76), a maximum mean value of 6.1 on the day of HSCT (range 2 - 10, DT day 0 vs. base: p=0.76), followed by a downward trend with a mean value of 5.1 one week after HSCT (range 0 - 9, DT day +7 vs. base: p>0.99), 5.2 on day +14 (range 0 - 10, DT day +14 vs. base: p>0.99), 3,7 on day +21 (range 0 - 7, DT day +21 vs. base: p=0.17), 3.5 on day +28 (range 0 - 8, DT day +28 vs. base: p=0.0224), 3.9 on day +35 (range 1 - 9, DT day +35 vs. base: p=0.22), 3.3 on day +42 (range 1 - 10, p=0.0142), 2.7 on day +50 (range 2 - 6, day +50 vs. base: p=0.0057), 2.3 on day +60 (range 1 - 5, day +60 vs. base: p=0.0056) and 1.8 on the day of discharge (range 0 - 4, DT day of discharge vs. base: p<0.0001). The mean values of the DT at the timepoints 4 weeks, 6 weeks, day +50 and day +60 after HSCT and on the day of discharge were significantly below the mean baseline value on the day of admission (Fig. 1a).

The mean baseline DT value of the parent group was 6.4 (range 2 - 9). As in the pediatric patients, the parents show an increasing mean DT value from the day of admission to the day of HSCT, with a maximum on the day of HSCT, followed by a decreasing trend in the mean DT value over the further course of time. The mean DT value of the parents on day -5 was 6.8 (range 2 - 9, DT day -5 vs. base: p>0.99), on the day of the HSCT the mean DT value was a maximum of 8.1 (range 2 – 10, DT day 0 vs. base: p=0.0457), on day +7 it was 6.3 (range 1 – 9, DT day +7 vs. base: p>0.99), two weeks after HSCT it was 5.4 (range 0 – 8, DT day +14 vs. base: p=0.63), 4.4 on day +21 (range 0 – 8, DT day +21 vs. base: p=0.0016), 3.8 on day +28 (range 1 – 8, DT day +28 vs. base: p<0.0001), 3.9 on day +35 (range 1 – 9, DT day +35 vs. base: p<0.0001), 4.1 on day +42 (range 1 – 10, DT day +42 vs. base: p=0.0015), 3.7 on day +50 (range 2 – 6, DT day +50 vs. base: p=0.0025), 3.9 on day +60 (range 2 – 6, DT day +60 vs. base: p=0.0363) and on the day of discharge 2.8 (range 0 - 4, DT day of discharge vs. base: p<0.0001). The mean value of the DT on the day of HSCT was significantly above the mean DT baseline value and from day +21 after HSCT until discharge the mean values of the DT were significantly below the baseline value (Fig. 1b).

Comparing the two groups, the parents of the patients reported higher DT values than the children themselves at all timepoints. On the day of HSCT, the mean DT value of the parents was significantly above the mean DT value of the pediatric patients (mean DT values children 6.1 vs. parents 8.1, p=0.0157). The differences between the mean DT values of the children to their parents at the other time points are not significant (Fig. 1c).

The figure shows the NCCN distress thermometer scores (mean±95% confidence interval, CI) of 40 pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and one parent each collected on the respective observation days before, during and after HSCT. Numbers in the plotted data sets indicate sample size. Base = day of admission, end = day of discharge. Note that most patients were discharged between day +35 and day +42 after HSCT (on day +42, 48% and on day +60, 78% of pediatric patients had already been discharged).

Laboratory analyses

The mean cortisol level of the patients was 449.3 nanomol per liter (nmol/l, range 280.1 nmol/l – 540.4 nmol/l). The mean cortisol value was in the normal range (125 nmol/l - 420 nmol/l) on the day of admission and on the day -5 before HSCT, but exceeded the upper limit value on the day of HSCT and remained above upper limit until discharge with a significant difference from the upper normal value on day +7 after HSCT and on the discharge day (mean cortisol value day +7 (525.0 nmol/l) vs. upper normal value (420.0 nmol/l): p=0.0293; mean cortisol value discharge day (534.2 nmol/l) vs. upper normal value: p=0.0046; Fig. 2a).

The mean TSH level of the pediatric patients during the inpatient stay was 2.602 milli units per liter (mU/l, range 1.506 mU/l – 3.688 mU/l)). The mean values of the stress hormone TSH were never outside the normal range (0.8 mU/l – 5.4 mU/l). They dropped after admission and reached their lowest point on day +7 after HSCT. Subsequently, they showed an increasing trend over time (Fig. 2b).

During the inpatient stay the mean fT3 value was 4.572 picomol per liter (pmol/l, range 4.077 pmol/l – 5.523 pmol/l) and the mean fT4 value was 14.64 pmol/l (range 12.66 pmol/l – 16.68 pmol/l). The mean values of fT3 and fT4 were never outside the normal range (normal range fT3: 3.5 pmol/l – 6.5 pmol/l, normal range fT4: 12pmol/l - 23pmol/l) and also showed no upward or downward trend over time (Fig. 2c, Fig. 2d).

The figure shows the laboratory values (mean±95% confidence interval, CI) of the stress hormones cortisol, thyroid stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) of 40 pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) collected on the respective observation days before, during and after HSCT. Numbers in the plotted data sets indicate sample size. Base = day of admission, end = day of discharge. Note that most patients were discharged between day +35 and day +42 after hematopoietic stem cell transplantation (HSCT) (on day +42, 48% and on day +60, 78% of pediatric patients had already been discharged).

Analysis of the problem lists

In the problem lists handed out, the patients indicated problems in the following areas: exhaustion (problem awareness maximum in 52.5% of the children on the day of HSCT, 10.3% of the parents on the day of discharge), worry (problem awareness maximum in 53.8% of the children on the day of discharge, 67.5% of the parents on the day of HSCT), anxiety (problem awareness maximum in 15.0% of the children on the day of HSCT, 57.5% of the parents on the day of HSCT), nervousness (problem awareness maximum in 15.4% of the children on the day of discharge, 5.0% of the parents on day +14), reference to God (problem awareness maximum in 7.5% of the children on day -7 and day +14, 5.0% of the parents from day -7 until day +21), pain (children's problem awareness maximum 22.5% on day +7 and day +14), nausea (children's problem awareness maximum 72.5% on day -7), sleep (children's problem awareness maximum 37.5% on day +21), appearance (children's problem awareness maximum 40.0% on day -7), inflammation (children's problem awareness maximum 60.0% on day +21), eating (children's problem awareness maximum 25.6% on day of discharge), indigestion (children's problem awareness maximum 30.0% on day +14), constipation (children's problem awareness maximum 17.5% on day +7), diarrhea (children's problem awareness maximum 47.5% on the day of HSCT), changes in urination (children's problem awareness maximum 35.0% on day +7 and +14), fever (children's problem awareness maximum 22.5% on day +14), dry skin (children's problem awareness maximum 42.5% on day +7). In summary, it can be stated that more than half of the children reported problems in the areas of exhaustion, worry, nausea and inflammation. Among the parents, more than 50% reported problems in the areas of worry and anxiety (Fig. 3).

The figure illustrates the areas in which patients and their parents reported problems.

Regarding the problem area of exhaustion over time, it is noticeable that more children reported problems in this area than their parents (problem awareness maximum 52.5% vs. 10.3%). The rate of exhaustion in the pediatric patients increased rapidly until the day of HSCT, after which the curve tended to decline very slowly (Fig. 4a)

Concerning the problem area of worries, it is noticeable that the parents initially indicated more problems in this area than the pediatric patients. However, while the parents' awareness of worries reaches its maximum on the day of HSCT (67.5%) and subsequently drops from day +21 after HSCT onwards, the rate of worries among patients increases over time and is higher than that of the parents at the time of discharge (53.8%) (Fig. 4b).

The awareness of problems in the area of fears was higher among the parents than among the patients over the entire time course (max. problem awareness 15.0% vs. 57.5%). In both groups, the maximum percentage of problem perception was highest on the day of HSCT and subsequently decreased except for the day of discharge, at which time the number of parents perceiving fears increased again (Fig. 4c)

The figure shows the percentage of problem awareness in the areas exhaustion, worries and fears of 40 pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) and one parent each collected on the respective observation days before, during and after HSCT. Note that most patients were discharged between day +35 and day +42 after HSCT (on day +42, 48% and on day +60, 78% of pediatric patients had already been discharged).

In this prospective study, we investigated the psychological distress of pediatric patients who received an HSCT in our hematological-oncological transplant ward by using the DT, a questionnaire regarding problem perception in both physical and psychological areas and the measurement of the stress hormones cortisol, TSH, fT3 and fT4.

At the beginning after admission to the transplant ward, the patients experienced increasing stress and reached their maximum on the day of HSCT with a median DT value of 5.0 (range 2 - 10). Afterwards, the stress decreased over time to a median DT value of 2.0 on the day of discharge (range 0 - 4). Interestingly, the stress perception of the parents was the same; their DT values also increased after admission to the maximum on the day of the HSCT and then decreased again until the day of discharge. However, the median DT values of the parents were higher overall than those of the children, with a significant difference on the day of HSCT (median DT value 8.5 vs. 5.0). This result fits with the fact that in previous studies on pediatric patients undergoing HSCT, the patients generally rated their quality of life higher than their parents [16].

In line with the DT, the stress hormone cortisol also showed an increase from the day of admission. The increase over the upper normal limit reached significant levels on day +7 and on discharge day. This could indicate that discharge is associated with uncertainty, excitement, and stress. The fact that cortisol levels were above the upper normal limit from the day of HSCT until the day of discharge indicates that the HSCT and the posttransplant period are very stressful and drastic times. Studies have shown that the activation of the hypothalamic pituitary adrenocortical (HPA) axis is associated with reduced DNA repair mechanisms, accelerated tumor growth and angiogenesis via increased release of vascular endothelial growth factor and interleukin-6, invasion of malignant cells by an increased production of matrix metalloproteinases and also delayed wound healing [11, 17-19]. Studies have also found that stress and depression reduce the activities of cytotoxic T cells and natural killer cells, so that both the development and progression of tumors appear to be favored by stress [20]. These results indicate that increased stress under HSCT can have a negative impact on post-transplant convalescence and even on the overall prognosis [11, 17, 21].

The mean values of the thyroid hormones TSH, fT3 and fT4 were never outside the normal range. However, compared to the basal values on the day of admission, the decreased TSH values with simultaneously reactively increased fT4 values in the course of the pre-transplant phase fit to the fact that stress correlates laboratory-chemically with an activation of the thyroid hormones [22, 23].

Consistent with the cortisol level, the pediatric patients experienced increasing exhaustion with a maximum on the day of HSCT, after which the rate of exhaustion tended to decline very slowly. Parents experienced less exhaustion than pediatric patients throughout the whole period. However, they felt more worry and anxiety compared to the children especially on the day of HSCT. Interestingly, the rate of worries among the pediatric patients increases over the course of time and is higher than that of the parents at the time of discharge. This difference in perception of worry is consistent with the results of a study, in which the worries of pediatric patients who received HSCT and the worries of their parents were analyzed. It became apparent that the parents and their children worried in different degrees and also worried about different topics. Compared to their children, more parents indicated strong worries and expressed worries about the impact of the HSCT on their families and about a bad outcome. Whereas a larger percentage of children reported no worries or expressed concerns about not getting back to normalcy [24].

Even though only a small proportion of children reported anxiety, the high rate of anxiety among parents should be taken seriously. It was demonstrated in a prospective study of 113 parents of children with leukemia that parental anxiety, especially among mothers, experienced during their children's cancer treatment is predictive of later post-traumatic stress syndrome [25].

It is already known from other studies that high stress and anxiety levels are already felt before and increase towards the day of HSCT and then slowly decrease. Social support is important for patients [4]. Worry, anxiety as well as reduced communication during the acute phase of HSCT have been identified to have a negative impact on health-related quality of life one year after HSCT [26]. It has been shown that the rate of maternal depression correlates with a reduced cognitive and educational outcome of pediatric patients after HSCT [27]. A study on the effects of maternal stress following HSCT of their children reports significantly increased stress and anxiety levels in the mothers compared to the normal values of women of the same age from the normal population. They conclude that this may limit their ability to emotionally support their children and therefore early psychological support for these mothers is necessary [28]. The increased stress levels of the parents do not only lead to parents being less supportive of their children during treatment on the ward. It could be shown that increased stress perception during the children's treatment is associated with post-traumatic stress disorders of the parents after the end of the treatment, so that a stressful family situation also exists afterwards [25].

In a study on the psychological consequences for parents of children who have received an HSCT, a subgroup of parents was found to have increased stress levels even years after the HSCT [29].

In adult breast cancer patients, studies have already shown that concomitant, intensified psychological intervention during therapy reduces the risk of recurrence and also in patients with gastrointestinal cancer, those who received intensified psychotherapeutic treatment during cancer therapy had an improved long-term survival [30-32].

The study results just reported, as well as the results of this current study, clearly demonstrate that psychological intervention must take place as early as possible in this therapeutic context. This applies to both pediatric patients and their parents.

In the present prospective study evaluating stress using the distress thermometer and assessment scales, it was shown that in the pretransplant phase the stress levels of both pediatric patients and their parents increase until the day of HSCT and that the parents experience significantly more stress than their children on that day. Over the course of the post-transplant period, the rate of worry in the children increases and their cortisol levels also remain in a range above the upper normal limit until discharge. These results confirm the need for early and continuous intervention, especially up to the day of HSCT both in psycho-oncological counseling with parents and in intervention with the pediatric patients. Thereby, hopefully, long-lasting psychological problems in the form of PTSD or depression in the pediatric patients or their parents could be counteracted early enough, thus improving the overall outcome. In a prospective study with a larger cohort of pediatric patients and their parents, the rates of stress, exhaustion, worry, and fears after intensified and early psycho-oncological intervention in the patients and their parents should be compared with a control group. Furthermore, in addition to cortisol and thyroid function parameter determination of the patients, these should also be performed in their parents to verify the stress levels by laboratory-chemical methods.

Early psycho-oncological intervention and support of both children and their parents seems to be of great importance for the psychological and cognitive outcome of pediatric patients with severe malignant and non-malignant diseases, especially during such drastic procedures as HSCT.

aGvHD	acute graft versus host disease
ATG	anti-thymocyte globulin
DT	distress thermometer
fT3	free triiodothyronine
fT4	free thyroxine
gy	gray
HPA	hypothalamic pituitary adrenocortical axis
HSCT	hematopoietic stem cell transplantation
mg/kg	milligram per kilogram
mg/m²	milligram per square meter
MMFD	mismatched family donor
MSD	matched sibling donor
MUD	matched unrelated donor
mU/l	milli units per liter
NCCN	National Comprehensive Cancer Network
nmol/l	nanomol per liter
n.s.	not significant
pmol/l	picomol per liter
SIRS	systemic inflammatory response syndrome
TBI	total body irradiation
TLI	total lymphoid irradiation
TSH	thyroid stimulating hormone
VOD	veno-occlusive disease

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Author’s contribution

All authors made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data. All authors drafted the work or revised it critically for important intellectual content. Carmen Isolde Malaval, Michaela Döring and Karin Melanie Cabanillas Stanchi collected and analyzed the data and wrote the manuscript. Michaela Döring was head of the study and responsible for the study design. Dustin Werle and Karin Melanie Cabanillas Stanchi contributed to the study conception and design. Dustin Werle, Stefanie Thiel, Melanie Gansel, Jennifer Svaldi, Peter Lang and Rupert Handgretinger reviewed the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Data availability

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

Compliance with Ethical Standards

This analysis was performed in accordance with the Helsinki declaration adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013. The legal basis for the data processing is Art. 6, 7, 9, 89 of the general data protection regulation (EU) 2016/679 of the EU in combination with §§ 4, 5, 6, 8, 9, 12, 13 of the Landesdatenschutzgesetzes Baden-Württemberg in its current form of May 25th, 2018. Approval for this analysis was granted by the Ethics Committee of the University Hospital Tübingen and the Eberhard Karls University of Tübingen (ID434/2019BO1).

Consent to participate

Written informed consent was obtained from all study participants and/or their legal representatives.

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No competing interests reported.

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Application of the NCCN-distress thermometer in pediatric patients during autologous and allogeneic HSCT and relationship to blood parameters of the stress axis

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Abstract

Purpose

Methods

Results

Conclusions

Figures

Background

Methods

Study conception and design

The Distress Thermometer

Determination of blood parameters

Statistical methods

Results

Patients characteristics:

Analysis of the distress thermometer

Laboratory analyses

Analysis of the problem lists

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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