Abstract
Background
Various kinds of clinical characteristics predispose patients receiving voriconazole therapy to high variability of serum voriconazole level. However, little is known about the predictors of drug level variability among critically ill patients.
Methods
This retrospective study was executed to investigate the associated factors. Between January 2020 and June 2021, all adult patients with invasive pulmonary aspergillosis receiving parenteral voriconazole for more than four days during their stay in intensive care were recruited. The enrolled subjects were classified into within- and beyond-therapeutic group based on their serum voriconazole trough levels.
Results
A total of 34 patients were studied; serum voriconazole levels ranged from < 0.1 to 11.38 mg/L, and 35.3% were categorized as beyond-therapeutic group. The all-cause in-hospital mortality rate was 17.7%. Multivariate logistic regression showed that lower body mass index (BMI) value [odds ratio (OR), 15.16; 95% CI, 2.10–109.51; p = 0.007] and increase in total bilirubin level (OR, 9.23; 95% CI, 1.16–73.21; p = 0.035) were independently associated with variability of serum voriconazole troughs.
Conclusions
Further investigation of appropriate prescribing doses of voriconazole, likely with regards to BMI value, might be needed to attain target drug concentrations to achieve better clinical effectiveness and avoid drug-related toxicity.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12879-025-12221-6.
Keywords: Serum voriconazole trough, Critically ill, Therapeutic, Aspergillosis
Background
Invasive fungal infections are commonly encountered in immunocompromised populations, including critically ill patients and those with hematological malignancies, which raise global concerns due to their high mortality rate [1]. Several factors predispose critically ill patients to acquiring invasive fungal infections, including destruction of biological barriers, extensive use of antimicrobials, poor bowel peristalsis, and complex invasive procedures [2]. Voriconazole, a newer triazole antifungal, is recommended by Infectious Diseases Society of America (IDSA) as drug of choice for treatment of invasive aspergillosis [3] because it has broad-spectrum coverage, including candidemia, pulmonary cryptococcosis, invasive aspergillosis, and fusariosis [4, 5]. On the basis of prescribing information of voriconazole package leaflet [6], one weight-based maintenance dose of 4 mg/kg twice per day should be administered to achieve appropriate voriconazole serum target level at a steady state (a trough concentration ≧ 1 mg/L and < 5.5 mg/L) to guarantee optimal clinical efficacy and minimal adverse events, including neurotoxicity, impaired liver function, and visual disturbance [7, 8]. Nevertheless, the non-linear pharmacokinetic properties characterized voriconazole, prolifically metabolized hepatically by the cytochrome P450 (CYP) family enzymes, as greater inter- and intra-individual differences in the pharmacokinetic profiles [9, 10]. Furthermore, critically ill patients often experiencing specific physiological changes, such as hepatic dysfunction, hemodynamic instability, and malnourishment, accompanied with polypharmacy conditions aggravated so-called variations of serum voriconazole concentration [11, 12]. All the aforementioned issues made therapeutic drug monitoring (TDM) for voriconazole mandatory, which was further supported by Park et al.’s trial [13], and IDSA recommendations [3]. Despite TDM’s merits, its high expenses, inconvenience in clinical application, and inability to offer initial dosing adjustment [14] urged physicians to identify relevant factors associated with serum voriconazole level variation. Age, gender, body weight, genetic polymorphisms of voriconazole-metabolizing CYP isoenzymes, and multiple drug-drug interactions have been identified as associated factors [10, 15, 16]. However, very limited research has been performed on recognition of variables regarding fluctuations of serum voriconazole trough levels in critically ill patients receiving intensive care. Hence, this study aimed to compare the clinical characteristics of critically ill patients acquiring invasive fungal infections with within-therapeutic serum voriconazole trough level to those with beyond-therapeutic level, and to identify the predictors associated with the variability of serum voriconazole trough level.
Methods
Study design and setting
This retrospective study was conducted in one medical and one surgical intensive care unit (ICU) at a regional teaching hospital in northern Taiwan between January 1, 2020, and June 30, 2021. All adult patients aged over 20-years diagnosed with invasive pulmonary aspergillosis concurrently receiving parenteral voriconazole therapy for more than four days under ICU were eligible for recruitment. Patients with allergy or intolerance to voriconazole, concomitant use of other antifungal agents, inaccessibility to blood sampling for monitoring drug levels, and pregnant or lactating women were excluded. A standardized case report form was utilized to collect information on the demographics and clinical characteristics, including the age, sex, Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, body height, body weight, body mass index (BMI), major underlying diseases, laboratory data (hemogram, alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, creatinine, blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR), albumin, and C-reactive protein [CRP]), daily dosing of voriconazole (mg/kg), co-administration of drugs, and all-cause in-hospital mortality. Blood samples collected from every enrolled individual at steady state (five days after continuous administration of voriconazole) underwent serum voriconazole determination using a high-performance liquid chromatography/tandem mass spectrometry system in the research laboratory of Fu Jen Catholic University. On the basis of the above-mentioned serum target level and data of measured voriconazole trough concentration from each patient, all cases were categorized into two groups: within-therapeutic group (Ctrough = 1 to 5.5 mg/L) and beyond-therapeutic group (Ctrough < 1 mg/L or > 5.5 mg/L). The study was approved by the medical ethics committee of Fu Jen Catholic University Hospital, and all clinical investigations were performed following the guidelines of the Declaration of Helsinki.
Definitions
The diagnosis of invasive pulmonary aspergillosis was classified into proven, probable, and possible cases according to the 2008 guidelines from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group Consensus [17]. SOFA score as a prognostic tool for mortality risk [18] and APACHE II score as a predictor of hospital mortality among critically ill patients [19] were applied in our study. According to the laboratory standards in Fu Jen Catholic University Hospital, the normal reference cutoff values of blood tests were as follows: white blood cell (WBC), >4,000 and < 11,000 /µL; hemoglobin (Hb), >11.3 and < 15.3 g/dL in females and >12.3 and < 18.3 g/dL in males; platelet, >150,000 and < 400,000 /µL; ALT and AST, < 40 U/L; total bilirubin, < 1 mg/dL; creatinine, >0.6 and < 1.3 mg/dL; BUN, < 25 mg/dL; eGFR, >60; albumin, >3.5 mg/dL; and CRP, < 0.5 mg/dL. All-cause in-hospital mortality was recorded when a patient died from any cause during hospitalization.
Statistical analyses
Descriptive data for quantitative variables were expressed as mean ± standard deviation and compared using Student’s t-test or Mann–Whitney U test. Categorical variables were presented as counts (%) and compared using the chi-squared test or Fisher’s exact test. Statistical significance was determined using two-tailed testing, and a P-value < 0.05, was considered as the threshold for statistical significance. To identify the independent factors associated with the variability of serum voriconazole trough level, a multivariate logistic regression model was utilized to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curves were used to determine the cut-point of independent variables for predicting the variability of serum voriconazole troughs. All statistical analyses were conducted using SAS statistical software (version 9.4; SAS Institute, Cary, NC, USA).
Results
Baseline characteristics
During the study period, 49 patients with a diagnosis of invasive pulmonary aspergillosis admitted to ICU were recruited, but 15 patients were excluded because of missing clinical data, including 10 with poor voriconazole tolerance, 3 prescribed with other antifungals concurrently, and two with inappropriate blood sampling. Finally, 34 patients were enrolled, with serum voriconazole levels ranging from < 0.1 to 11.38 mg/L and 35.3% (12/34) belonged to the beyond-therapeutic group shown in Fig. 1 (3 as subtherapeutic, 9 as supratherapeutic). Among these patients, approximately 65% were male, and the mean ± standard deviation (SD) of their ages was 71.8 ± 13.9 years (Table 1). The three leading underlying illnesses were end stage renal disease (ESRD) under hemodialysis, type 2 diabetes, and heart failure. Nearly three-tenths (29.4%) of the patients had a relatively low BMI below 19.7 kg/m2, and the mean ± SD of the SOFA and APACHE II scores were 6.94 ± 3.85 and 21.38 ± 9.41, respectively. More than half of the study population displayed abnormalities in various baseline laboratory parameters, including WBC (64.7%), Hb (61.8%), creatinine (55.9%), BUN (73.5%), eGFR (52.9%), albumin (85.3%), and CRP (94.1%). Impaired liver function tests were disclosed in approximately one quarter to one third of the enrolled patients, and more than 40% were found to have concomitant use of proton pump inhibitors and glucocorticoids. The all-cause in-hospital mortality rate in this study was 17.7%.
Fig. 1.
Flow chart of patients with invasive pulmonary aspergillosis included in the analysis
Table 1.
Comparison of demographics and clinical characteristics of patients with within-therapeutic level and beyond-therapeutic level of voriconazole trough concentration
| All, % (n=34) |
Within-therapeutic (n=22) | Beyond-therapeutic (n=12) |
P | |
|---|---|---|---|---|
| Age | 71.84 ± 13.87 | 74.64 ± 11.82 | 66.73 ± 16.31 | 0.113 |
| Gender | 0.465 | |||
| female | 12(35.3) |
9 (40.9) |
3 (25.0) |
|
| male |
22 (64.7) |
13 (59.1) |
9 (75.0) |
|
| SOFA score | 6.94 ± 3.85 | 7.05 ± 3.93 | 6.75 ± 3.86 | 0.835 |
| APACHE II score ( within 24 h) | 21.38 ± 9.41 | 20.45 ± 10.23 | 23.08 ± 7.80 | 0.445 |
| Body height | 161.15 ± 9.18 | 160.82 ± 10.60 | 161.75 ± 6.14 | 0.782 |
| Body weight | 60.50 ± 16.06 | 63.59 ± 17.08 | 54.84 ± 12.76 | 0.131 |
| BMI | 23.19 ± 5.36 | 24.47 ± 5.57 | 20.85 ± 4.21 | 0.058 |
| Diabetes mellitus |
11 (32.4) |
8 (36.4) |
3 (25.0) |
0.705 |
| Hemodialysis |
13 (38.2) |
7 (31.8) |
6 (50.0) |
0.462 |
| Heart failure |
8 (23.5) |
4 (18.2) |
4 (33.3) |
0.410 |
|
WBC (>11000, <4000 /μL) |
22 (64.7) |
13 (59.1) |
9 (75.0) |
0.465 |
| Hb (F, 11.3-15.3; M, 12.3–18.3 g/dL) |
21 (61.8) |
15 (68.2) |
6 (50.0) |
0.462 |
|
Platelet (<150k, >400k /μL) |
14 (41.2) |
9 (40.9) |
5 (41.7) |
1.000 |
| ALT (>40 U/L) |
9 (26.5) |
4 (18.2) |
5 (41.7) |
0.224 |
| AST (>40 U/L) |
11 (32.4) |
4 (18.2) |
7 (58.3) |
0.026 |
| T-bilirubin (>1 mg/dL) |
8 (23.5) |
3 (13.6) |
5 (41.7) |
0.098 |
|
Creatinine (<0.6, >1.3 mg/dL) |
19 (55.9) |
12 (54.6) |
7 (58.3) |
1.000 |
| BUN (>25 mg/dL) |
25 (73.5) |
17 (77.3) |
8 (66.7) |
0.687 |
| eGFR (<60) |
18 (52.9) |
13 (59.1) |
5 (41.7) |
0.475 |
| Albumin (<3.5 g/dL) |
29 (85.3) |
18 (81.8) |
11 (91.7) |
0.635 |
| CRP (>0.5 mg/dL) |
32 94.12 |
20 (90.9) |
12 (100.0) |
0.529 |
| Daily dosing (mg/kg) | 3.60 ± 0.65 | 3.49 ± 0.58 | 3.80 ± 0.75 | 0.193 |
| Concomitant : PPI |
16 (47.1) |
9 (40.9) |
7 (58.3) |
0.475 |
| Concomitant : glucocorticoid |
14 (41.2) |
7 (31.8) |
7 (58.3) |
0.163 |
| All-cause mortality |
6 (17.7) |
3 (13.6) |
3 (25.0) |
0.641 |
*Within-therapeutic : >=1 & <5.5 µg/ml, beyond-therapeutic : <1 or > = 5.5 µg/ml
*Continuous variable : t-test, categorical variable : chi-square test
Comparisons of the demographics and outcomes of patients with within- and beyond-therapeutic voriconazole trough level
The comparisons of the demographics, laboratory data, and clinical outcomes between the within- and beyond-therapeutic groups were also illustrated in Table 1. The mean age and sex distribution were not different between the two groups. More diabetic patients were found in the within-therapeutic group, but the individuals with a diagnosis of ESRD or heart failure were more frequently observed in the beyond-therapeutic group. A higher proportion of patients in the beyond-therapeutic group had lower BMI value (58.3 vs. 13.6%, P = 0.02), but the SOFA and APACHE II scores were similar between the two groups. Laboratory parameters did not differ between the two groups, except that more patients with elevated AST level were noted in the beyond-therapeutic group. Daily dosing of voriconazole and concurrent prescription of medications were not different between the two groups, although there was a non-significant tendency that patients classified as beyond-therapeutic had a higher mortality rate when compared to those classified as within-therapeutic (25.0 vs. 13.6%, P = 0.64). Additionally, we also re-analyzed the data by classifying into sub-therapeutic (< 1.0 µg/mL, n = 3), therapeutic (1.0–5.5 µg/mL, n = 22), and supra-therapeutic (> 5.5 µg/mL, n = 9) levels. Only descriptive statistics, not analytic statistics, were performed because too few case numbers of sub-therapeutic group were recruited. The revised results demonstrated that supra-therapeutic voriconazole troughs tended to occur among patients with lower BMI value, and high total bilirubin levels were associated with serum voriconazole trough levels, consistent with our initial analysis (shown in supplementary files, Table S1).
Factors associated with variability in serum voriconazole trough level ROC curve analysis declared that the area under the curve of BMI was 0.73 (95% CI, 0.54–0.92; p = 0.019), cutoff value 19.7 kg/m2 (sensitivity 58.3%, specificity 86.4%) (Fig. 2). The variable “BMI” was dichotomized using the breakpoint of 19.7 kg/ m2 in subsequent statistics. In the univariate analysis, low BMI value (below 19.7 kg/m2) and elevation of AST level were associated with variations in serum voriconazole trough concentration, and they were subsequently included in the final multivariate logistic regression model (Table 2). Lower BMI value (OR, 15.16; 95% CI, 2.10–109.51; p = 0.007) and rise in total bilirubin level (OR, 9.23; 95% CI, 1.16–73.21; p = 0.035) were found to be independent factors associated with beyond-therapeutic serum voriconazole trough level in the multivariate analysis, but elevated AST level had no statistical significance (Table 2).
Fig. 2.
Receiver operating characteristic (ROC) curve for predicting risk of beyond-therapeutic voriconazole trough level on the basis of body mass index (BMI)
Table 2.
Univariate and multivariate logistic regression analyses of factors associated with beyond-therapeutic voriconazole serum trough level
| Variables | Univariate | Multivariate* | ||||||
|---|---|---|---|---|---|---|---|---|
| coefficients | OR | 95% CI | P | coefficients | OR | 95% CI | P | |
| Age | -0.0432 | 0.96 | 0.91–1.01 | 0.1265 | ||||
| Gender ( vs. female) | 0.7309 | 2.08 | 0.43–9.87 | 0.3581 | ||||
| SOFA score | -0.0207 | 0.98 | 0.81–1.18 | 0.8284 | ||||
| APACHE II score (24hr內) | 0.0304 | 1.03 | 0.96–1.11 | 0.4367 | ||||
| Body height | 0.0115 | 1.01 | 0.94–1.09 | 0.7744 | ||||
| Body weight | -0.0478 | 0.95 | 0.89–1.02 | 0.1465 | ||||
| BMI group ( < = 19.7 as reference) | 2.1823 | 8.87 | 1.66–47.25 | 0.0106 | 1.3593 | 15.16 | 2.10-109.51 | 0.007 |
| Diabetes mellitus | -0.5389 | 0.58 | 0.12–2.80 | 0.5009 | ||||
| Hemodialysis | 0.7621 | 2.14 | 0.51–9.08 | 0.301 | ||||
| Heart failure | 0.8109 | 2.25 | 0.48–11.33 | 0.3256 | ||||
| WBC | 0.7309 | 2.08 | 0.44–9.87 | 0.3581 | ||||
| Hb | -0.7621 | 0.47 | 0.11–1.98 | 0.301 | ||||
| Platelet | 0.0313 | 1.03 | 0.25–4.30 | 0.9658 | ||||
| ALT | 1.1673 | 3.21 | 0.66–15.58 | 0.1472 | ||||
| AST | 1.8405 | 6.30 | 1.3-30.53 | 0.0223 | ||||
| Total bilirubin | 1.5094 | 4.52 | 0.85–24.11 | 0.0771 | 1.1114 | 9.232 | 1.16–73.21 | 0.035 |
| Creatinine | 0.1542 | 1.17 | 0.28–4.84 | 0.8317 | ||||
| BUN | -0.5306 | 0.59 | 0.12–2.80 | 0.5051 | ||||
| eGFR | -0.7041 | 0.50 | 0.12–2.06 | 0.3339 | ||||
| Albumin | 0.8938 | 2.44 | 0.24–24.78 | 0.4494 | ||||
| CRP | 11.8164 | > 999.999 | < 0.001,>999.999 | 0.9719 | ||||
| Daily dosing (mg/kg) | 0.7698 | 2.16 | 0.68–6.86 | 0.1921 | ||||
| Concomitant : PPI | 0.7041 | 2.02 | 0.49–8.43 | 0.3339 | ||||
| Concomitant : glucocorticoid | 1.0986 | 3.00 | 0.70-12.88 | 0.1394 | ||||
*Logistic regression method : stepwise
Discussion
Several previous studies demonstrated that an adequate serum voriconazole level is important but elusive [8, 15, 20]. This study explored the associated factors related to the variations of serum voriconazole trough level among critically ill patients with invasive pulmonary aspergillosis. In the current study, more than one third of individuals were categorized into the beyond-therapeutic group, and the all-cause in-hospital fatality rate was approximately 17.7%. The majority of our study cohort exhibited different kinds of laboratory abnormalities at baseline, including hemogram and biochemistry examinations, but approximately one quarter to one third showed impaired liver function tests. In the present study, lower BMI value and increase in total bilirubin level were independently associated with the beyond-therapeutic serum voriconazole trough level.
Several studies [15, 21–24] attempting to recognize the associated factors with the inter-patient variations of serum voriconazole trough concentration had shown similar findings corroborating our results. The percentage of voriconazole serum trough level outside the therapeutic range was approximately 26.4 to 50% and the mortality rate was 16.7 to 57.9%, versus the 35.3 and 17.7% in our study, respectively. The above discrepancy might be explained by the following reasons. Firstly, enrolled patients varied between different research articles with subsequently distinct blood samples of voriconazole concentration. Secondly, the optimal serum voriconazole trough level employed within those studies was not the same, and particularly appropriate therapeutic range recommended for critically ill patients remained controversial until now [22]. Lastly, diverse patient populations with various disease severities were recruited, and hence a great impact on poor prognosis was observed.
Evidently, severe sepsis or septic shock was common among critically ill patients, thus sepsis-related liver damage due to ischemic hepatitis or cholestasis resulting from impaired bile transport occurred with subsequently elevated bilirubin levels [18, 25]. Furthermore, voriconazole was eliminated primarily via hepatic metabolism, predominantly mediated by CYP2C19, subordinately by CYP3A4 and CYP2C9 [9]. Consequently, it was quite reasonable that hyperbilirubinemia, implicating liver dysfunction, would exert a negative effect on voriconazole clearance making beyond-therapeutic serum voriconazole concentration possible (thereby resulting in a high voriconazole level). On the other hand, several previous studies had verified plasma protein binding as one confounder on the pharmacokinetics of various kinds of antimicrobials [26]– [27], and total bilirubin belonged to highly protein-bound molecules (approximately to 90%) [28], leading to shifting of drugs from albumin with consecutive fluctuation of serum voriconazole levels [25]. Additionally, approximately 40% of critically ill patients developed hypoalbuminemic status, which caused frequent rising of unbound drug levels in serum [25, 27]. The above-mentioned facts could be an explanation as to why the increase in T-bilirubin value was associated with variations of serum voriconazole trough concentration.
Due to absolutely inconstant serum voriconazole troughs, fixed-dose regimens of voriconazole based on actual body weight were likely not appropriate for all patients. Even though Koselke et al. [29] demonstrated that prescription of voriconazole on the basis of ideal body weight or adjusted body weight might be suggested among morbidly obese patients, there was still controversy regarding the optimal dosing strategy for them. Moreover, there were scarce studies illustrating the role of BMI on voriconazole serum concentrations. Lower BMI tending to be associated with higher drug levels was observed in one study [30], which was similar to our results (66.7% of supratherapeutics vs. 33.3% of subtherapeutics among subjects with BMI less than 19.7 kg/m2), and higher BMI was one significant potential predictor for voriconazole related toxicity in another [31]. In contrast, our findings presented that lower BMI values, particularly less than 19.7 kg/m2, were significantly associated with beyond-therapeutic trough concentrations of voriconazole. To the best of our knowledge, this is the first study to definitively clarify the correlation between the cutoff value of BMI and variability of serum voriconazole troughs; lower BMI value was well outside the therapeutic window of voriconazole drug levels noted. A few review articles had raised the concern of higher hospital mortality seen among underweight subjects receiving intensive care [32]– [33]; hence physicians should be cautiously aware of the risk of not attaining voriconazole target levels in those individuals with lower BMI values to improve clinical outcomes.
There were some limitations to our study. First, unavoidable bias and missing data were anticipated due to its retrospective design. Second, this study was conducted in one center, limiting the generalizability of the results, and further analysis of possible variables associated with the fluctuating serum voriconazole concentrations was precluded due to fewer patient numbers and less frequent blood sampling. Third, only a single voriconazole trough level was obtained among all patients, and subsequent drug concentrations while dose modifications indicated were not routinely examined, which might misinterpret pharmacokinetic variability over time. Fourth, small number of outcome events (n = 12) might have a negative effect on model stability and elevated the potential of overfitting. Finally, evaluation of genetic CYP2C19 polymorphisms was not performed, and absence of the above data might make our findings less reliable and valid. Nevertheless, judiciously monitoring serum voriconazole troughs, especially in those with impaired liver function and in relatively underweight individuals, should be kept in mind.
Conclusions
In summary, we reported that a relatively underweight status, that is, a BMI ≦ 19.7 kg/m2, is independently associated with a higher probability of the development of beyond-therapeutic serum voriconazole troughs among critically ill patients. Exploration of optimal dosing regimens of voriconazole, such as based on BMI value, might be mandatory as routine and frequent testing of voriconazole drug levels is troublesome and costly. Likewise, sufficient nutritional support to achieve a proper BMI goal could perhaps avoid fluctuating serum voriconazole concentrations.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Not applicable.
Abbreviations
- BMI
Body mass index
- OR
Odds ratio
- IDSA
Infectious Diseases Society of America
- CYP
Cytochrome P450
- TDM
Therapeutic drug monitoring
- ICU
Intensive care unit
- SOFA
Sequential Organ Failure Assessment
- APACHE II
Acute Physiology and Chronic Health Evaluation II
- ALT
Alanine aminotransferase
- AST
Aspartate aminotransferase
- BUN
Blood urea nitrogen
- eGFR
Estimated glomerular filtration rate
- CRP
C-reactive protein
- WBC
White blood cell
- Hb
Hemoglobin
- CIs
Confidence intervals
- ROC
Receiver operating characteristic
- SD
Standard deviation
- ESRD
End stage renal disease
- PPI
Proton pump inhibitor
Author contributions
YCL, WCK, and WLL contributed to the study conceptualization, investigation and methodology. Data curation and formal analysis were performed by YCC, CFH, JTW, and under the supervision and validation of YLH and JTW. The original draft of the manuscript was written by YCL and WLL. All authors participated in the study design, revised the manuscript, and approved the final version of the manuscript.
Funding
This work was supported by [Fu Jen Catholic University Hospital/CGH-FJCUH108011].
Data availability
The datasets used during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the medical ethics committee of Fu Jen Catholic University Hospital, with written informed consent obtained from all participants.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used during the current study are available from the corresponding author on reasonable request.