Oral foci of infection and their relationship with hospital stay after haematopoietic cell transplantation.

Introduction

Haematopoietic cell transplantation (HCT) is an important treatment modality for many haematological disorders [ 1 ]. HCT involves infusion of haematopoietic cells, either harvested from the patient (autologous HCT) or from a donor (allogeneic HCT). Prior to cell infusion, patients undergo a conditioning regimen consisting of chemotherapy with or without total body irradiation to eradicate cancer and permit donor engraftment [ 1 ]. The intensity of the conditioning regimen can differ considerably based on various factors, including type of HCT and patient’s health status. Historically, myeloablative conditioning was the standard regimen for all patients diagnosed with leukaemia or lymphoma [ 2 ]. The development of non-myeloablative regimens aimed to increase the number of patients who could be considered for transplantation, particularly older patients and those with comorbidities [ 2 ]. Reduced-intensity conditioning serves as an intermediate option. Conditioning regimens induce severe neutropenia and render recipients highly susceptible to infections. A comprehensive oral focus screening is recommended preferably before the start of chemotherapy to minimize dental emergencies, systemic infections and complications during HCT and to reduce the need for invasive dental treatments post-HCT [ 3 ]. Potential oral foci of infection include deep caries lesions, periodontal disease, periapical infections, (partially) impacted or partially erupted teeth not fully covered by bone or showing radiolucency, cysts, non-vital pulps and ulcerations [ 4 , 5 ]. A distinction is made between acute and chronic oral foci of infection. If the focus is related to pain, ulceration, purulent discharge or swelling, the focus is considered acute, while if the focus is asymptomatic and has been so during 3 months before the onset of cancer therapy, it is considered chronic [ 6 ]. Acute oral foci of infection should be eliminated, unless there is insufficient time to heal before the onset of chemotherapy [ 6 ]. Invasive dental treatment directly before the initiation of intensive chemotherapy carries a risk of infection, bleeding and delayed wound healing [ 7 ].

Once haemoglobin levels, white blood cell counts and platelet counts have recovered sufficiently and there are no further complications after HCT, a patient can be discharged from the hospital. Hospital length of stay (LOS) varies and is associated with factors such as type of HCT, conditioning intensity, cell source and occurrence of complications [ 8 ]. HCT is a resource-intensive and costly medical procedure, and hospital LOS is the major driver of total costs within the first hundred days after transplant [ 9 ].

Previous studies showed that chronic oral foci of infection may be left untreated in HCT patients, as they do not increase the risk of infectious complications during chemotherapy and in the post-HCT phase [ 10 , 11 ]. Additionally, research showed that exacerbation of a chronic focus to an acute state during chemotherapy is infrequent [ 10 , 12 ]. Previous studies on the impact of oral foci of infection had relatively small populations. Larger studies are needed to explore the impact of oral foci of infection on complications early post-HCT. This retrospective study aimed to assess the association between the number of oral foci of infection and both hospital LOS and mortality rate in the first hundred days after transplant.

Materials and methods

Ethical approval was waived by the ethical committee of the Radboudumc because this research was not subjected to the law governing research involving human subjects (2022–13453). STROBE guidelines were followed in the reporting [ 13 ].

Study population

Patients who received a pre-HCT oral focus screening at Radboudumc (Nijmegen, the Netherlands) between April 2013 and May 2023 for allogeneic HCT and between April 2013 and December 2018 for autologous HCT were considered for inclusion. Exclusion criteria were patients without a haematological malignancy or autoimmune disorder, patients who did not consent to sharing medical data for research at their first admission to the Department of Hematology, patients whose scheduled HCT was cancelled and patients who were transplanted in another hospital. Patients involved in the prospective Orastem study [ 14 ] were excluded. For patients who underwent a double transplantation, HCT closest in time to the oral focus screening was included.

Oral focus screening

Oral focus screenings were performed by one experienced dentist (MCH). An intraoral inspection of mucosae, dentition and periodontium was performed, supplemented with a panoramic radiograph (if already present, used if no more than 6 months old) and occasionally periapical radiographs. Dental care was provided if deemed necessary and possible. Treatment usually consisted of extraction of teeth with acute infections (pain in preceding 3 months, ulceration, purulent discharge, swelling), endodontic treatment in case of necrotic pulps generally with apical periodontitis, (temporary) restoration of large cavitated caries lesions, supra- and/or subgingival cleaning and oral hygiene instructions. Patients were referred to the oral and maxillofacial surgeon for extractions. Endodontic treatments were carried out at patients’ dental practice upon request. Temporary restorations and cleaning almost exclusively took place during the screening session, without the use of local anaesthetics. During the follow-up visit after HCT, the completion of the pre-HCT treatments was verified.

Oral foci of infection

A tooth was considered a focus of infection when at least one of the following clinical or radiographic signs was present: pocket probing depth ≥ 6 mm around natural tooth (periodontal pocket), pocket probing depth ≥ 7 mm around dental implant (peri-implant pocket), furcation radiolucency, periapical radiolucency with or without endodontic treatment present, deep caries lesion, partial eruption (usually third molars) and retained root. An oral ulcer was also considered a focus of infection. A deep caries lesion was defined as a clinically extensive distinct cavity with visible dentine (ICDAS 6 [ 15 ]) or radiographically visible lesion extending to the inner third of dentine. Foci with pain in the preceding 3 months, ulceration, purulent discharge or swelling were considered acute, including pockets with purulent discharge. A distinction was made between treated and untreated oral foci of infection. Pocket probing depths of ≥ 6 mm (natural teeth) or ≥ 7 mm (implants) were considered treated after subgingival cleaning or extraction. Furcation radiolucencies were considered treated only after extraction. Periapical radiolucencies were considered treated after endodontic treatment or extraction. Deep caries lesions were considered treated after restoration (with or without endodontic treatment) or extraction. Partially erupted teeth and retained roots were considered treated after extraction. Ulcers caused by dentures were considered treated after adjustment of the dental prosthesis. The number of oral foci of infection per patient before and after pre-HCT dental treatment was calculated. Patients were categorized in three groups based on their number of oral foci locations: no oral focus, one or two oral foci and at least three oral foci. A tooth with multiple foci was considered as a single oral focus location.

Early post-HCT mortality and morbidity

All outcomes were collected for the first hundred days after HCT. Hospital LOS was the primary study outcome. Secondary study outcomes were mortality and oral exacerbations. LOS was assessed by counting the days of hospital admission. If a patient was discharged from the hospital and readmitted, days of readmission were also included in the total count. An oral exacerbation was defined as a serious exacerbation requiring intervention from an oral and maxillofacial surgeon or dentist.

Confounders

Potential confounders were identified based on existing literature and included conditioning intensity, age, socioeconomic status and number of teeth [ 8 , 16 ]. Conditioning regimens were categorized based on intensity: myeloablative, reduced-intensity or non-myeloablative [ 2 ]. The number of teeth was counted including third molars. House value determined by the tax assessment system provided by the Dutch Central Office for Statistics based on zip code (PC6), measured in euros, was used as a proxy measure for socioeconomic status [ 17 ].

Statistical analysis

Complete-case analysis was performed due to the low percentage of missing data. Socioeconomic status was the only variable with missing values (< 10%). To assess the association between the number of oral foci of infection and hospital LOS, linear regression analysis was performed. Patients who were admitted to the hospital for a second HCT or deceased before HCT day + 100 were removed from the dataset for this analysis. LOS was log-transformed to normalize its skewed distribution. Analysis was adjusted for conditioning intensity, age, number of teeth and socioeconomic status, and ratios of means with corresponding 95% confidence intervals were reported. Additionally, analyses were stratified for type of transplantation (autologous or allogeneic). Analysis for autologous recipients was not adjusted for conditioning intensity as they almost exclusively received myeloablative conditioning. To assess the association between the number of oral foci of infection and mortality, logistic regression analysis was performed. This analysis was adjusted for conditioning intensity, and risk differences with corresponding 95% confidence intervals were reported. The association between the number of oral foci of infection and oral exacerbations was not analysed due to the low incidence of oral exacerbations. Statistical analyses were performed using R (version 4.1.3; R Foundation for Statistical Computing, Vienna, Austria).

Results

In total, 520 patients were subjected to an oral focus screening within the inclusion period and actually received their planned autologous or allogeneic HCT. Eighteen patients did not consent in sharing medical data; one patient was excluded due to a disease other than a haematological malignancy or autoimmune disorder, and one patient was transplanted in another hospital. Table 1 shows the characteristics of the total study population by type of HCT ( N = 500). Among allogeneic HCT recipients, 26 patients received a transplant from bone marrow, 4 from cord blood, and 226 from peripheral blood, while the cell source was unknown for 24 patients. Table 1 Baseline characteristics Total ( N = 500) Autologous HCT ( N = 220) Allogeneic HCT ( N = 280) Age at HCT (years), median [IQR] 58 [48–64] 58 [49–64] 59 [47–64] Sex Male 315 (63%) 139 (63%) 176 (63%) Female 185 (37%) 81 (37%) 104 (37%) Diagnosis AML 108 (22%) 17 (8%) 91 (33%) MM 106 (21%) 100 (45%) 6 (2%) NHL 88 (18%) 61 (28%) 27 (10%) MDS 50 (10%) 1 (0%) 49 (18%) ALL 24 (5%) 0 (0%) 24 (9%) MPN 23 (5%) 0 (0%) 23 (8%) SS 19 (4%) 19 (9%) 0 (0%) HL 19 (4%) 15 (7%) 4 (1%) Other 63 (13%) 7 (3%) 56 (20%) Conditioning intensity NMA 104 (21%) 0 (0%) 104 (37%) RIC 121 (24%) 22 (10%) 99 (35%) MA 275 (55%) 198 (90%) 77 (28%) First transplant 495 (99%) 218 (99%) 277 (99%) Second transplant After autologous HCT 4 (1%) 2 (1%) 2 (1%) After allogeneic HCT 1 (0%) 0 (0%) 1 (0%) Screening to HCT (days), median [IQR] 44 [26–84] 40 [23–66] 49 [28–90] Number of teeth, median [IQR] 26 [22–28] 27 [21–28] 26 [22–28] Percentage bleeding on probing, median [IQR] 17 [7–30] 14 [5–29] 18 [8–31] Number of endodontic treated teeth, median [IQR] 1 [0–2] 0.5 [0–2] 1 [0–2] Number of dental implants, median [IQR] 0 [0–0] 0 [0–0] 0 [0–0] Periodontal disease 162 (32%) 69 (31%) 93 (33%) Values are N (%) unless otherwise stated. Periodontal disease was defined as the presence of at least one periodontal pocket ≥ 6 mm or one peri-implant pocket ≥ 7 mm Abbreviations: HCT haematopoietic cell transplantation; IQR interquartile range; AML acute myeloid leukaemia; MM multiple myeloma; NHL non-Hodgkin lymphoma; MDS myelodysplastic syndrome; ALL acute lymphocytic leukaemia; MPN myeloproliferative neoplasm; SS systemic sclerosis; HL Hodgkin lymphoma; NMA non-myeloablative; RIC reduced-intensity; MA myeloablative

Oral foci of infection

Table 2 shows oral foci of infection identified during focus screening and the subsequent situation after dental treatment. Treatment entailed extraction in 85 patients, restoration in 18 patients, endodontic treatment in 24 patients and subgingival cleaning in 152 patients. In four patients, the dental prosthesis was adjusted. At focus screening, 64% had one or more oral foci of infection ( N = 321). In these 321 patients, 995 foci were present of which 502 persisted after treatment. After dental treatment, 48% had one or more oral foci ( N = 242). At focus screening, 35 patients presented with acute oral infections (pain, ulceration, purulent discharge or swelling). Following dental treatment, four locations with acute oral infections persisted in two patients. One patient had three teeth with pockets exhibiting purulent discharge, and another patient had a painful third molar. Table 2 Oral foci of infection at focus screening and after pre-HCT dental treatment. Patients were categorized based on the number of oral foci into three groups: no oral focus, one or two oral foci and at least three oral foci. A tooth with multiple foci was considered as a single oral focus location Tooth level (number of locations with oral foci) Patient level (number of patients with oral foci ( N = 500)) Before DT DT After DT Before DT After DT Extraction Restoration Endo Subg. cleaning Prosth. correction 0 foci 1–2 foci ≥ 3 foci 0 foci 1–2 foci ≥ 3 foci Total 995* 1 184 20 25 479 4 502 179 (36%) 184 (37%) 137 (27%) 258 (52%) 183 (37%) 59 (12%) Acute Pain/ulcereration/purulent discharge/swelling 40 26 1 4 N/A 4 4 *2 465 (93%) 33 (7%) 2 (0%) 498 (100%) 1 (0%) 1 (0%) Periodontal Pocket and/or furcation 709 *3 107 N/A N/A 412 N/A 319 280 (56%) 126 (25%) 94 (19%) 354 (71%) 107 (21%) 39 (8%) Pocket 532 95 N/A N/A 325 N/A 112 338 (68%) 97 (19%) 65 (13%) 457 (91%) 29 (6%) 14 (3%) Furcation 273 49 N/A N/A N/A N/A 224 361 (72%) 107 (21%) 32 (6%) 376 (75%) 100 (20%) 24 (5%) Peri-apical Primary and/or secondary 260 70 N/A 23 N/A N/A 167 334 (67%) 150 (30%) 16 (3%) 382 (76%) 110 (22%) 8 (2%) Primary 113 47 N/A 22 N/A N/A 44 419 (84%) 75 (15%) 6 (1%) 465 (93%) 33 (7%) 2 (0%) Secondary 147 23 N/A 1 N/A N/A 123 395 (79%) 98 (20%) 7 (1%) 410 (82%) 84 (17%) 6 (1%) Caries Extensive caries and/or retained root 97 54 18 2 N/A N/A 23 442 (88%) 49 (10%) 9 (2%) 484 (97%) 14 (3%) 2 (0%) Extensive caries 68 31 18 2 N/A N/A 17 459 (92%) 34 (7%) 7 (1%) 489 (98%) 9 (2%) 2 (0%) Retained root 29 23 N/A N/A N/A N/A 6 476 (95%) 24 (5%) 0 (0%) 495 (99%) 5 (1%) 0 (0%) Partial eruption 34 4 N/A N/A N/A N/A 30 476 (95%) 23 (5%) 1 (0%) 479 (96%) 20 (4%) 1 (0%) Values are N (%) *1 Number of oral locations with any oral focus is not equal to the sum of teeth with distinct oral foci, as multiple foci can exist within a single tooth *2 One patient experienced ulcers in the floor of the mouth, which healed without dental intervention *3 Number of oral locations with periodontal focus is not equal to the sum of teeth with pockets and furcation, as both foci can exist within a single tooth Abbreviation: DT dental treatment

Early post-HCT morbidity and mortality

Table 3 shows hospital LOS, mortality rate and oral exacerbation rate before HCT day + 100 according to the number of oral foci of infection.

Hospital LOS was assessed in 470 patients as 20 patients died before HCT day + 100 and 10 patients were admitted to the hospital for a second HCT before day + 100. HCT recipients had a mean LOS of 22 (SD ± 13) days. Hospital LOS according to various baseline characteristics is shown in the supplemental material (Table S1 ). Mean LOS for NMA, RIC and MA patients was 15 (SD ± 15), 26 (SD ± 13) and 23 (SD ± 12) days, respectively . Mean LOS was 20 (SD ± 10) days for autologous HCT recipients and 24 (SD ± 15) days for allogeneic HCT recipients. Mean LOS was 22 (SD ± 15) days in recipients without oral foci of infection, 21 (SD ± 11) days in recipients with one or two oral foci of infection and 24 (SD ± 12) days in recipients with at least three oral foci of infection.

Twenty patients (4%) died before HCT day + 100. Of these, eight were prepared with NMA conditioning, eight with RIC and four with MA conditioning. Eighteen patients died after allogeneic HCT, and two patients died after autologous HCT. Among the 20 deceased HCT recipients, 12 had no oral foci of infection. Of the remaining deceased recipients, three had one oral focus, one had two oral foci, three had three oral foci and one had seven oral foci.

In four patients (1%), intervention by an oral and maxillofacial surgeon was required due to an oral exacerbation. Of these, one was prepared with NMA conditioning, two with RIC and one with MA conditioning. Three patients had an oral exacerbation after allogeneic HCT and one patient after autologous HCT. One patient experienced both mucormycosis and osteonecrosis of the mandible; another patient presented with sinusitis; a third patient presented with pericoronitis of a third molar, and the fourth consulted the surgeon because of a sinus tract. The patient who developed mucormycosis and osteonecrosis of the mandible had no oral focus of infection and did not undergo dental extractions pre-HCT. The patient with sinusitis already suffered from the condition 1 month before HCT. An oral and maxillofacial surgeon concluded no oral focus contributing to the sinusitis. The patient who presented with pericoronitis of the lower right third molar had two partially erupted teeth (both lower third molars) after pre-HCT dental treatment. Treatment involved application of hydrogen peroxide using gauze. The fourth patient with an oral exacerbation, experiencing a sinus tract, had a secondary periapical radiolucency where the sinus tract was originating from. The patient was scheduled for dental extraction of the lower left first premolar after HCT day + 100. Table 3 Hospital length of stay, mortality rate and oral exacerbation rate before HCT day + 100 according to the number of oral foci after pre-HCT dental treatment No oral focus ( N = 258) One or two oral foci ( N = 183) At least three oral foci ( N = 59) Hospital LOS (days), mean ± SD ( N = 470) 22.4 ± 14.7 21.4 ± 11.0 23.9 ± 11.7 Mortality ( N = 500) 12 (5%) 4 (2%) 4 (7%) Oral exacerbation ( N = 500) 1 (0%) 3 (2%) 0 (0%) Values are N (%) unless otherwise stated Abbreviations: LOS length of stay, SD standard deviation

Association between oral foci of infection and early post-HCT morbidity and mortality

Figure 1 illustrates the association between the number of oral foci of infection after pre-HCT dental treatment and both hospital LOS and mortality rate within the first hundred days after HCT. The association between the number of oral foci of infection and oral exacerbation rate was not analysed, as there were only four oral exacerbations in total. After adjustment for confounders, HCT recipients with one or two oral foci had an equal LOS compared to those without oral foci (ratio of means 1.00; 95% CI 0.89 – 1.13). HCT recipients with at least three oral foci had a statistically significantly longer LOS compared to those without oral foci (ratio of means 1.21; 95% CI 1.00 – 1.46). Mean LOS in HCT recipients without oral foci was 22.4 days, and therefore, a ratio of means of 1.21 translates to a clinically relevant extended LOS of approximately five additional days. The number of oral foci was not associated with mortality risk before HCT day + 100. After adjustment for conditioning intensity, HCT recipients with one or two oral foci had a non-significantly lower risk of death in comparison to those without oral foci (risk difference − 2.65%; 95% CI − 6.00 to 0.58%). HCT recipients with at least three oral foci had a non-significantly higher risk of death compared to those without oral foci (risk difference 1.54%; 95% CI − 3.61 to 10.60%). Fig. 1 Association between the number of oral foci after pre-HCT dental treatment (reference category is no oral focus) and both hospital length of stay and mortality in the first hundred days after transplant. Models were adjusted for conditioning intensity, age, socioeconomic status and number of teeth for the outcome hospital length of stay and for conditioning intensity for the outcome mortality

Additionally, analyses were stratified for the type of transplantation (Fig. 2 ). After adjustment for confounders, autologous HCT recipients with one or two oral foci of infection had a non-significantly shorter hospital LOS compared to autologous HCT recipients without oral foci (ratio of means 0.90; 95% CI 0.78 – 1.04). Autologous HCT recipients with at least three oral foci had an equal LOS compared to those without oral foci (ratio of means 1.00; 95% CI 0.80 – 1.24). There was a different trend in allogeneic HCT recipients. After adjustment for confounders, allogeneic HCT recipients with one or two oral foci had a non-significant increase in LOS compared to allogeneic recipients without oral foci (ratio of means 1.09; 95% CI 0.92 – 1.30). Allogeneic HCT recipients with at least three oral foci had a statistically significantly longer LOS compared to those without oral foci (ratio of means 1.50; 95% CI 1.15 – 1.96). Mean LOS among allogeneic HCT recipients without oral foci was 24.4 days, and therefore, a ratio of means of 1.50 translates to a clinically relevant LOS extension of approximately 12 additional days. Fig. 2 Association between number of oral foci after pre-HCT dental treatment (reference category is no oral focus) and hospital length of stay in the first hundred days after transplant for autologous and allogeneic HCT recipients. Models were adjusted for age, socioeconomic status and number of teeth for autologous HCT recipients and for conditioning intensity, age, socioeconomic status and number of teeth for allogeneic HCT recipients

Discussion

This retrospective study aimed to assess the association between oral foci of infection and early post-HCT morbidity and mortality. Among 500 autologous and allogeneic HCT recipients, few acute oral foci of infection were present prior to HCT, whereas nearly half of HCT recipients had at least one chronic focus of infection left after pre-HCT dental treatment. HCT recipients with at least three oral foci had a statistically significant and clinically relevant extended hospital LOS compared to those without oral foci. After stratification, this association was reinforced in allogeneic HCT recipients, while this association was not found in autologous HCT recipients. The number of oral foci was not associated with early post-HCT mortality.

Prior research concluded that oral foci of infection should be eliminated pre-HCT, as dental treatment could potentially prevent additional deaths and reduce systemic infections [ 18 ]. Various treatment approaches have been adopted in clinical research to prepare patients for autologous and allogeneic HCT. Some studies solely addressed acute oral pathology [ 10 , 12 ], while both in our study and previous studies chronic oral pathology was also (partially) treated among patients with sufficient time before HCT [ 7 , 11 , 19 ]. Literature suggested that chronic foci of infection may be left untreated in HCT patients as they do not result in more odontogenic complications, infections, mucositis and deaths [ 10 – 12 , 19 , 20 ]. This is in line with the present study as there was no association between oral foci and all-cause mortality in the first hundred days post-HCT. It is important to note that the most common cause of death after allogeneic HCT is disease relapse, and death due to infection is relatively infrequent [ 21 ]. Schuurhuis et al. [ 10 ] investigated the effect of chronic oral foci on neutropenia and fever duration among 63 leukaemia and autologous HCT patients and showed a strong trend for a longer duration of neutropenia and fever in patients with chronic oral foci of infection [ 10 ]. They suggested that larger populations are needed to see if leaving chronic oral foci untreated may lead to a significantly longer duration of fever and neutropenia. In the present study, hospital LOS was the primary study outcome to assess peri-HCT morbidity. Interestingly, our results showed that allogeneic HCT recipients with at least three oral foci after pre-HCT dental treatment had clinically relevant longer LOS compared to those without oral foci.

There can be various mechanisms through which oral foci of infection may contribute to prolonged hospital LOS. Firstly, oral foci may result in oral exacerbations. This could not be confirmed in this study, as the incidence of oral exacerbations was very low and two out of four oral exacerbations could not be linked to an oral focus. Secondly, oral infections can act as site of origin for dissemination of pathogenic organisms to distant body sites triggering systemic infections [ 22 ]. Bloodstream infections are frequent in neutropenic patients, and inadequacy of the inflammatory response makes sepsis a significant cause of morbidity in this setting [ 23 ]. However, prior research did not find an association between pre-HCT oral health status and increased risk of bacteraemia [ 24 ]. Thirdly, oral foci may directly induce an inflammatory response in mucosal tissues, potentially increasing the incidence and severity of oral mucositis and thereby increasing LOS [ 25 ]. However, prior research did not find a relationship between oral foci and the development of oral mucositis during chemotherapy in patients with solid tumours or lymphoma [ 26 ]. Lastly, there might be a shared risk profile for both oral foci occurrence and extended LOS, with unmeasured variables possibly distorting this association. Multivariate analyses were adjusted for all known and measured confounders. Nevertheless, other factors such as the impact of underlying disease and antineoplastic therapy in the past and remission status could have influenced the results.

Data for this study were collected in a clinical setting where patients received treatment based on clinical indication. Severity of chronic oral foci of infection likely played a role in the treatment decision. For instance, larger periapical radiolucencies and deeper periodontal pockets may have been treated more frequently than smaller periapical radiolucencies or less severe periodontal pockets. As a consequence, the association between oral foci and hospital LOS could be even more substantial than our current findings suggest.

In conclusion, our study showed that the presence of at least three oral foci of infection after pre-HCT dental treatment was associated with a statistically significantly longer hospital LOS in the early post-HCT phase. Allogeneic HCT recipients with at least three oral foci had an additional 12 days in the hospital compared to those without oral foci. These findings suggest that minimal intervention before transplantation, especially in allogeneic HCT recipients, may not always be adequate. However, this association does not imply causation, and there is insufficient evidence to state that pre-HCT dental treatment reduces LOS. Further research should clarify the association between oral foci of infection and bacteraemia, neutropenia, fever and oral mucositis.

Supplementary information

Below is the link to the electronic supplementary material. ESM 1 (DOCX 15KB)

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Nicole M. A. Blijlevens and Stephanie J. M. van Leeuwen contributed equally to this work.

Author contribution

LvG: conceptualization, methodology, formal analysis, investigation, data curation, writing – original draft, visualization. RT: conceptualization, methodology, data curation, writing—review & editing, supervision. MB: conceptualization, methodology, writing—review & editing. GH: formal analysis, writing – review & editing. EB: validation, formal analysis, writing—review & editing. NB: conceptualization, methodology, writing—review & editing, supervision. SvL: conceptualization, methodology, writing—review & editing, supervision. MCH: conceptualization, methodology, investigation, data curation, writing—review & editing, supervision.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval

Ethical approval was waived by the ethical committee of the Radboudumc because this research was not subjected to the law governing research involving human subjects.

Competing interests

The authors declare no competing interests.

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