All-cause and cancer-specific overall survival in kidney transplant recipients with pre-transplant malignancies in a German cohort

Abstract

Kidney insufficiency and immunosuppression are well established contributors of tumor development, both before and after kidney transplantation. Patients with pre-transplant malignancies (PTM) are at risk of tumor recurrence and of the development of an unrelated tumor after transplantation. In this retrospective study of a German patient cohort, we analyzed 1089 patients that underwent kidney transplantation to determine the frequency, recurrence rate and overall survival of patients with pre-existing tumors across a 10-year period. PTM were found in 5.79% of the patients and appeared at a mean time of 7.39 (SD 6.8) years before transplantation. The tumors were most frequently of urologic (41.43%) origin, followed by malignancies of the skin (25.71%) and gynecologic tumors (10%). Tumor recurrence was observed in one case (1.6%) where the patient died of metastatic spinocellular carcinoma. Patients with pre-existing malignancies had a statistically significantly worse overall survival compared to transplant recipients without tumors (HR = 2.71, 95% CI 1.49–4.969). However, these differences could be entirely ascribed to the age (HR = 1.06, 95% CI 1.04–1.08) and gender (HR = 1.67, 95% CI 1.11–2.52) of the patients. We found that there was no difference in cancer-specific mortality or posttransplant cancer rate between patients with and without pre-existing malignancies (HR = 0.94, 95% CI 0.21–4.26).

Keywords

Kidney transplantation pre-transplant malignancies retrospective cohort study overall survival recurrence rate

Introduction

It is widely accepted that chronic (CKD) and end stage renal disease (ESRD) increase the risk of tumor development, the second most frequent cause of death in ESRD patients.^1,2 Tumors of the urinary tract, in particular renal cell carcinomas (RCC), have an up to ten times higher incidence rate, relative to healthy individuals and their incidence rises by 0.1% annually.^3,4 The incidence of RCC depends on the duration of dialysis and often develops from an acquired cystic disease. Thus, pre-existing malignancies are found in 0.4% to 4% of patients with ESRD awaiting kidney transplantation and represent a relative contraindication.^4
–7 Several studies have reported that patients with pre-transplant malignancies (PTM) are at risk of tumor recurrence, although this risk depends on the tumor type and on the tumor-free waiting period before transplantation.^8,9 Moreover, a history of PTM seems to be a risk factor for the development of an unrelated tumor after transplantation.¹⁰ A recent metanalysis that included the limited number of studies available found that patients with PTM and any solid organ transplantation have an inferior overall survival.¹¹ However, it is unknown whether this assertion applies to the restricted group of renal transplant recipients with PTM that often display particular cancer types.¹²

Here we report the frequency, recurrence rate and overall survival of patients with pre-existing tumors who received a kidney transplant during the last decade at the Kidney Center in Heidelberg, Germany. We found that among the 1089 transplant recipients, PTMs were frequent (5.9%). We observed one tumor recurrence with a lethal outcome. Patients with PTM had a statistically significantly worse overall survival compared to transplant recipients without tumors. However, these differences could be ascribed to the age and gender of the patients. Additionally, we did not find any significant differences in terms of cancer-specific mortality or development of posttransplant tumors in patients with or without pre-existing malignancies and conclude that the outcome of patients with PTM mainly depends on their age at transplantation and gender.

Methods

Study design

For this retrospective study, data were collected from 1089 patients that underwent a kidney or combined kidney-pancreas transplantation at the Kidney Center Heidelberg, University of Heidelberg, during the years 2003 to 2013. The data were screened for malignancies that arose either before (referred to as pre-transplant or pre-existing malignancies) or after transplantation (referred to as post-transplant tumors). For patients with pre-transplant tumors, transplant eligibility was determined as suggested by the American Society of Transplantation (AST), by Caring for Australians with Renal Impairment (CARI) and by the European Best Practice Guidelines (EBPG).^5
–7 Transplantation was prohibited in patients with active tumor disease or ongoing cancer treatment. The study was approved by the Ethics Committee of the University of Heidelberg (S-610/2017).

Outcome assessment

Some of the patients that were included into our analysis were transplanted before the year 2003 and received a second, third or fourth transplant during the years 2003 to 2013. Both pre- and post-transplant tumor development was reported relative to the patients’ first transplantation. Follow-up is reported from the time of the last transplantation. Duration of dialysis is reported as cumulative time on dialysis if there were multiple transplantations and dialysis was intermittently resumed. Tumor recurrence was defined as a tumor that came back after a period of time during which it could not be detected. Furthermore, recurrence of skin cancers was defined as the recurrence of the same tumor at the same anatomical location as the initial tumor or by the detection of distant metastases thereof. Diagnosis of any tumor recurrence was made by a specialist for the particular tumor entity. During the pre-transplant period, patients were screened yearly for the detection of abdominal tumors, including renal cancer. Posttransplant tumor screenings were performed as suggested by the Kidney Disease Improving Global Outcome (KDIGO) and included yearly skin screenings and abdominal ultrasound.¹³

Statistics

Data were summarized using descriptive statistics and reported as either arithmetic means with standard deviation (SD), Hazard ratios (HR), Odds Ratios (OR) or percentages. Differences for categorical variables were analyzed using Chi square tests, multivariate testing for survival data was performed using Cox regression analysis and the results presented as HRs with 95% confidence intervals (CIs). The Cox model included patients’ age at transplantation, gender and the time of dialysis. Time of dialysis was chosen as a covariate because end-stage renal disease is a known risk factor for tumor development. All statistical analyses were performed using the Graphpad prism 8 and Sigmaplot 13.0 software packages.

Results

Patients’ characteristics

We evaluated 1089 patients who received a kidney or pancreas-kidney transplant during the years 2003 to 2013. At the time of transplantation, the mean age of the cohort was 50.76 years (range 16.6–81.85), 71.44% were younger and 28.55% were older than 60 years. 663/1089 (60.88%) patients were male and 426/1089 (39.12%) were female (Table 1). During this time period, 1110 transplantations were performed, 953/1089 patients (87.51%) were transplanted for the first time, whereas 132 of the 1089 (12.49%) patients received a second, third or fourth transplant. 19/1089 patients received two and one patient three organs during the observation period, respectively. In 124 patients, additional 150 transplantations were performed prior to our observation time of which one patient had a heart transplantation (Table 1).

Table 1.

Patients characteristics.

	All patients (n = 1089)	Percentage
Age median in years (range)	50.76 (16.6–81.85)
<60 years	778	71.44
>60 years	311	28.55
Sex
Male	663	60.88
Female	426	39.12
Mean time of dialysis (in years (range))	4.56 (0–27.27)
Number transplanted patients (n = 1089)
First transplantation	953	87.51
Second transplantation	104	9.55
Third transplantation	29	2.66
Fourth transplantation	3	0.28
Number of transplantations (n = 1260)
2003–2013	1110	88.10
Before 2003	150*	11.90
Number of transplantations per person before 2003 (n = 150)
One	100	66.67
Two	22	14.67
Three	2	1.33
Four	0	0
Number of transplantations per person 2003–2013 (n = 1110)
One	1069	96.31
Two	19	1.71
Three	1	0.09
Four	0	0
Follow up
Time from Tx to last FU (median (95%CI))	6.27 (5.97–6.6)
Patients alive	118	10.84
Patients dead	971	89.16

FU: follow up; CI: confidence interval.

Characteristics of 1089 patients that received a kidney transplant.

Including one patient with heart transplantation.

The median follow-up time for all patients included in our analysis (patients with and without PTM) was 6.27 (95% CI 5.97–6.6), during which 118 patients died (10.84%). Glomerulonephritis (35.72%), Cystic kidney diseases (14.78%), and diabetes (12.40%) were the most common underlying diseases that caused ESRD. In rare cases, acute kidney injury, kidney stones or kidney necrosis were the reasons for chronic kidney insufficiency, in 8.3% of the cases the underlying disease was unknown (Supplemental Table 1). Posttransplant immunosuppression consisted of calcineurin inhibitors in combination with steroids and/or mycophenolate mofetil in 96.7% of the patients (98.8% in patients without pre-existing tumor and 94.6% in patients with pre-existing tumor).

Frequency and spectrum of pre-transplant malignancies

Of 1089 patients that underwent transplantation 5.79% had a history of PTM, that arose at a mean time of 7.39 (SD 6.8) years prior to transplantation. Patients with PTM were predominantly of male gender (71%) and 58.59 years old on average (range 26.87–76.89). The vast majority of these patients had one tumor (96.83%), two patients had two and one patient three tumors prior to transplantation (Table 2).

Table 2.

Tumor characteristics.

	All patients (n = 1089)	Percentage
Patients without tumor	1026	94.21
Patients with pre-exisiting tumor	63	5.79
Age (median in years (range))	58.59 (26.87–76.89)
Sex
Male	45	71.43
Female	18	28.57
Development of pre-existing tumor relative to Tx
Mean in years (SD)	−7.39 (6.8)
<1 year	3	4.76
1–10 years	48	76.19
>10 years	12	19.04
Number of pre-existing tumors	68
Tumors per patient
One tumor	61	96.83
Two tumors	2	3.17
Three tumors	1	1.59

SD: standard deviation; Tx: transplantation.

Tumor characteristics of patients that were transplanted between the years 2003 and 2013.

In almost half of all cases with pre-existing malignancies, patients suffered from urological malignancies (29/68, 47.65%), followed by malignancies of the skin (18/69, 25%), gynecological (8/69, 11.76%), endocrine and gastrointestinal (4/68, 5.88%) and hematological (2/68, 2.94%) malignancies (Table 3). Among the urologic malignancies, cancers of the prostate (13/29) and the kidney (11/29) were most frequently observed. Transplantation was performed between 1 and 10 years after tumor diagnosis and treatment in 76.19% of the patients. However, the time at which the tumor appeared before transplantation differed within and between the entities and was longest for one case of retinoblastoma (27.16 years) and urothelial carcinoma (26.65 years) and shortest for basal cell carcinoma (2.02 years), squamous cell carcinoma (3.51 years) and prostate cancers (4.81 years) (Tables 2 and 3).

Table 3.

Pre-existing tumors onset.

	Number of pre-existing tumors (n = 68)	Percentage of all pre-transplant tumors (n = 68)	Mean time of tumor appearance prior to Tx in years (min/max)	SD
Malignancies of the skin	17	25.00
Basal cell carcinoma	9	13.24	−2.02 (−0.66/−2.79)	0.62
MM	4	5.88	−14.07 (−4.14/−22.03)	9.33
Spinocellular carcinoma	4	5.88	−3.59 (−0.83/8.37)	3.29
Endocrine malignancies	4	5.88
Thyroid carcinoma	4	5.88	−5.88 (−4.33/−7.61)
				1.47
Gastrointestinal tract malignancies	4	5.88
Colorectal cancer	3	4.41	−11.19 (−3.18/24.21)
HCC	1	1.47	−0.60
				11.37
Gynecological malignancies	8	11.76
Breast cancer	3	4.41	−4.30 (−1.12/−6.99)
Endometrial cancer	3	4.41	−9.80 (−3.18/−24.21)
Cervical cancer	1	1.47	−7.94
Non-germinomatous cancer	1	1.47	−9.21
Hematological malignancies	2	2.94		2.97
Malignant lymphoma	2	2.94	−8.69 (−7.15/−10.23)	0.72
Head and neck malignancies	1	1.47
Tongue cancer	1	1.47	−6.59
Urologic malignancies	29	42.65
Renal cell carcinoma	11	16.18	−7.15 (−2.64/−21.59)
Prostate cancer	13	19.12	−4.81 (−1.81/−8.44)
Urothelial carcinoma	1	1.47	−26.65
Testicular cancer	4	5.88	−15.95 (−2.25/−26.03)	2.18
Others	3	4.41
Ewing-Sarcoma	1	1.47	−5.65
Retinoblastoma	1	1.47	−27.16
PNET	1	1.47	−5.65

MM: malignant melanoma; PNET: Primitive neuroectodermal tumor; SD: standard deviation; min: minimum; max: maximum.

Onset of 68 pre-existing malignancies given as mean time in years prior to first transplantation.

Recurrence of pre-transplant malignancies

One (1.6%) of all patients with PTM suffered from a tumor recurrence. This patient had a pre-existing squamous cell carcinoma, experienced tumor recurrence and presented with a distant metastasis of the parotid gland 5.33 years after tumor onset, 2.67 years after renal transplantation. He died of metastatic tumor disease half a year after tumor recurrence was detected (Supplemental Table 2).

Posttransplant malignancies in patients with pre-transplant tumors

Some reports suggest that patients with pre-existing malignancies also harbor a greater risk to develop posttransplant tumors.¹⁰ Of the 63 patients with pre-existing tumors, 14 (22.22%) developed posttransplant malignancies during a median follow-up time of 12.05 (11.00–14.88) years, two of these patients developed two tumors (Table 4 and Supplemental Table 3). We found no statistically significant difference when we compared the frequency of posttransplant malignancies to patients with no pre-existing tumor disease (22.22% vs 14.42%, OR 1.695, 95% CI 0.9328–3.124). Despite the relative low number of patients with pre- and posttransplant tumor, malignancies of the skin were the dominating tumor entities (65.75%). There was no difference between the two groups of patients with respect to the frequency of any tumor type (Table 4). Of note, the median follow-up time from transplantation was almost twice as long for patients without pre-existing malignancy (4.79 years (95% CI 4.02–6.10) vs 8.65 years (95% CI 6.92–9.72)) (Table 4).

Table 4.

Posttransplant tumors in patients with pre-existing tumors and in patients without.

	Posttransplant tumors in patients with pre-existing tumors (n = 16)	Posttransplant tumors in patients without pre-existing tumors (n = 205)	Odds ratio	95% CI
Number of patients	14/63 (22.22%)	148/1026 (14.42%)	1.695	0.9328–3.124
Malignancies of the skin	11 (65.75%)	114 (55.6%)	1.692	0.8676–3.268
Basal cell carcinoma	4 (25.0%)	59 (28.78%)
MM	1 (6.25%)	2 (0.97%)
Spinocellular carcinoma	5 (31.25%)	49 (23.9%)
Urologic malignancies	3 (18.75%)	35 (17.07%)	1.416	0.4451–4.352
Renal cell carcinoma	2 (12.5%)	25 (12.1%)
Urothelial carcinoma	1(6.25%)	4 (1.95%)
Lung tumors	1 (6.25%)	9 (4.39%)	1.823	0.1635–11.34
NSCLC	1 (6.25%)	4 (1.95%)
Gynecological malignancies	1 (6.25%)	11 (5.36%)	1.488	0.1358–8.519
Vulvar cancer	1 (6.25%)	2 (0.75%)
Head and neck malignancies	1 (6.25%)	4 (1.95%)	4.121	0.3318–25.33
Squamous cell carcinoma	1 (6.25%)	1 (0.48%)
FU time post Tx (median in years (95%CI))	4.79 (4.02–6.10)	8.65 (6.92–9.72)

NSCLC: non-small cell lung cancer; MM: malignant melanoma; RCC: renal cell carcinoma; FU: follow up; Tx: transplantation; CI: confidence interval.

Overall survival, cancer specific and all-cause mortality

At the median follow-up time of 12.05 (95% CI 11.00–14.88) years, 79.73% of the patients with pre-existing malignancies were alive, 20.63% were dead. The majority of the patients died of systemic infection (n = 6), cardiac arrest (n = 2) or unknown reasons (n = 3). Two patients died because of tumor disease, one of a recurrent spinocellular carcinoma (see above) and one of a posttransplant non-small cell lung cancer (NSCLC) (Table 5). When compared to patients with no PTM, we found that the overall survival of patients with PTM was significantly lower (Figure 1(a)). However, after consideration of known variables that have an impact on death, such as age and gender and dialysis time, we found that there was no more difference in overall survival between the two groups (Table 6) (HR = 1.354, 95% CI 0.728–2.517, p = 0.338). Patients of male gender and older age were at increased risk (HR = of 1.67 95% CI 1.113–2.525 and 1.063, 95% CI 1.045–1.081, respectively). The cumulative time of dialysis however, did not have an influence on the overall survival (HR = 1.001 95% CI 0.960–1.043, p = 0.973) (Table 6, Figure 1(b)–(d)).

Table 5.

Follow-up.

	Patients with pre-existing tumors (n = 63)
Time from tumor diagnosis to last follow-up in years (median (95%CI))	12.05 (11.00–14.88)
Status (percentage)
Alive	50 (79.37)
Dead	13 (20.63)
Death (percentage)	13 (20.63)
Tumor	2 (15.38)
Sepsis	6 (46.15)
Cardiac arrest	2 (15.38)
Other causes	3 (23.08)

CI: confidence interval.

Follow-up of patients with pre-existing tumors.

Figure 1.

(a) All-cause overall survival of patients with or without pre-existing tumor. The percentage of patients alive with (PTM) or without pre-existing (no-PTM) tumors is plotted as unadjusted all-cause overall survival and differences are given as the result of a log-rank test. The number of patients at risk is given as table. (b) Same as in (a) but stratified for male or female gender. (c) Survival is given stratified for patients’ age (<60 years and >60 years). (d) Same as in (a) but stratified for cumulative dialysis time. (e) The cancer-specific percentage of patients alive with or without pre-existing tumors was censored for non-cancer death and is plotted as unadjusted survival and differences are given as result of a log-rank test.

Table 6.

All-cause and cancer specific mortality.

	HR	95% CI	p value
All-cause mortality, not adjusted
Pre-existing malignancy	2.71	(1.49–4.969)	0.001
All-cause mortality, adjusted
Pre-existing malignancy	1.354	(0.728–2.517)	0.338
Gender	1.676	(1.113–2.525)	0.014
Age at transplantation	1.063	(1.045–1.081)	<0.001
Time on dialysis	1.001	(0.960–1.043)	0.973
Cancer specific mortality, adjusted
Pre-existing malignancy	0.949	(0.211–4.267)	0.946
Gender	2.303	(0.764–6.941)	0.138
Age at transplantation	1.095	(1.046–1.146)	<0.001
Time on dialysis	0.953	(0.843–1.077)	0.44

Estimation of hazard risk (HR) and confidence interval (CI) for all-cause mortality of patients with pre-existing malignancies in comparison to patients with no pre-existing malignancy.

We then asked whether patients with pre-transplant malignancies would have a higher risk of cancer-specific mortality. We again considered age and gender and cumulative dialysis time as variables and found that there is no increased risk in these patients compared to patients with no pre-existing malignancies (HR = 0.949, 95% CI 0.211–4.267, p = 0.946). Patients at older age at transplantation had a significant higher risk to die of cancer (HR = 1.095, 95% CI 1.046–1.146, p = <0.001), whereas gender (HR = 2.303, 95% CI 0.764–6.941, p = 0.138) and dialysis time (HR = 0.953, 95% CI 0.843–1.077, p = 0.44) were of no significant impact (Table 6, Figure 1(e)).

Discussion

The link between chronic kidney disease and an increased risk of tumor development is well established.^1,2 Therefore, a number of potential transplant recipients will suffer from PTM and this has potential consequences both for the decision to transplant and for the survival of the recipient. Indeed, studies reporting follow-up of transplant recipients over the past decades have concluded that transplant recipients with PTM have an inferior overall survival and carry an increased risk of tumor recurrence.^8,11,14 We studied 1089 patients who received a kidney transplant at the Heidelberg kidney center in Germany and found that 5.79% of them had a cancer history prior to transplantation. Reports from the United Kingdom (UK), the United States (US) or from Taiwan suggest that the number of kidney transplant recipients with PTM are much lower in these countries, ranging from 0.4% to 2.4%.^14
–16 This discrepancy could be explained by longer waiting period before transplantation in Germany (4.4 years on average in our cohort), as compared to the US (3.6 years on average) or the UK (2.5–3.0 years on average).^17,18 Indeed, the risk of tumor development in patients with ESRD increases with time and this could account for the higher rate of PTM that we observed.^1
–3 The majority of pre-transplant tumors we observed were of urologic origin, in line with the literature that reports an up to 10 times higher risk in the ESRD population for these malignancies.^1
–3

Of our 63 Patients with PTM, only one with spinocellular carcinoma experienced a lethal tumor recurrence. Both patients were 2 to 2.6 years free of tumor disease before transplantation. There are unfortunately no guidelines available to define the optimal tumor-free interval before transplantation for spinocellular carcinomas, although a two-year interval is suggested for basal cell carcinomas.^5
–7 The recurrence rate for non-melanoma skin cancer was studied by Penn and reported to be as high as 50% if transplantation was performed less than 2 years after diagnosis.⁸ We observed only one recurrence out of four patients with a spinocellular carcinoma prior to transplantation. However, our patients with PTM had a long mean tumor-free waiting time of 7.3 years before transplantation was performed which could explain the lower rate of tumor recurrences (Table 2). This would suggest that the immunosuppression that follows transplantation inhibited the anti-tumor immune response that is necessary to prevent relapses, even multiple years after diagnosis.

PTMs are associated with an increased risk of posttransplant malignancies that are not relapses of the initial tumor.¹⁰ We can indeed confirm a higher rate of posttransplant tumors in PTM patients (22.22%) as compared to patients without PTM (14.42%). However, this result did not reach statistical significance, probably because of the different median follow-up periods (patients with vs without PTM 4.79 years vs 8.65 years).

Several studies have suggested that patients with PTM have a worse overall survival compared to patients without PTM.^11,12,14 We could confirm this finding for all-cause mortality. However, after multivariate analysis we found that this effect could be ascribed to the patients’ gender and age, two well-described mortality risk factors. Whether or not these risk factors also influenced the outcome in previous studies is unknown as they did not consider covariates.^14,19 Interestingly, one of these studies included renal transplant recipients within a larger transplant cohort.¹² However, a restriction of the analysis to the kidney recipients showed that there was no inferior overall survival in this particular population, a result in line with our own findings.¹² In a study that reported inferior overall survival, the PTM included a high frequency of tumors of the urinary tract (25%) (excluding kidneys) and of the liver (12.5%). These malignancies are recognized as high risk cancers relative to the asymptomatic renal cell carcinomas that were frequently found in our cohort.^8,15 Furthermore, the post-transplant secondary cancers developed in this cohort included urothelial carcinomas and breast cancer that usually require invasive and/or systemic therapy that has probably influenced the overall survival of these patients. Unfortunately, the authors did not report on cancer-specific survival in the studied population.¹⁵

We could not find any statistical difference in the cancer-specific mortality between patients with or without PTM, here again age was the main risk for cancer death. These results differ from some previous reports.^11,16 These discrepancies between our results and these studies can be explained by several differences. As mentioned previously, the long waiting period after diagnosis of PTM may positively influence the outcome. In studies that identified inferior all-cause and cancer-specific mortality because of a high rate of recurrences of the tumor pre-transplantation, patients were either transplanted earlier, or no information was given on the time interval between transplantation and tumor development.^12,15 Furthermore, the spectrum of posttransplant tumors that we observed differed from those reported in other studies. In particular, we observed a low frequency of urinary tract tumors and of liver cancers relative to the studied Asian populations.¹⁵ Furthermore, we cannot exclude that differences in the follow-up time of patients, which was nearly twice as long as for patients without PTM, positively affected our results. Further follow-up should be able to clarify this issue.

The prognosis of posttransplant tumors in patients with PTM also influences overall survival and cancer-specific mortality. While in the study reported by Farrugia et al., patients with PTM who developed posttransplant cancer died in 53% of the cases of renal tumors, none of our patients with PTM who developed a posttransplant renal tumor died.¹⁶ Another difference between the present study and the study reported by Farrugia and colleagues lies in the PTM tumor incidence. While Faruggia et al. found 74 PTM cases in a 19,100-patient cohort, we identified 63 cases in a 1089 patient cohort. This difference could be potentially explained by a yearly systematic sonographic screen of all kidney patients in our center that allow detection of infra-clinical tumors and early treatment. This strategy probably both increases the rate of discovered and treated infra-clinical tumors and reduces both the incidence of post-transplantation renal tumors and the risk of cancer-related mortality.

In summary, our study provides evidence that the outcome of patients with PTM after kidney transplantation does not show any statistically significant difference to non-PTM patients and mainly depends on the patients age and gender. A long tumor-free interval before transplantation and systematic yearly sonographic screening of all patients with ESDR and of transplant recipients might lower tumor recurrence rates and the risk of post-transplant tumor, thereby positively influencing the outcome of PTM patients.

Supplemental Material

sTab_all_revised – Supplemental material for All-cause and cancer-specific overall survival in kidney transplant recipients with pre-transplant malignancies in a German cohort

Supplemental material, sTab_all_revised for All-cause and cancer-specific overall survival in kidney transplant recipients with pre-transplant malignancies in a German cohort by Fabian Jacoby, Holland-Letz Tim, Martin Zeier and Susanne Delecluse in Journal of Onco-Nephrology

Footnotes

Authors’ contributions

F.J. collected data, T.H.L. performed statistical analyses, M.Z. designed the study, S.D. designed the study, analyzed data, and wrote the paper.

Declaration of conflicting interests

The author(s) declared no potential conﬂicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the German research community (DFG) and the German Center for Infection Research (DZIF).

ORCID iD

Susanne Delecluse

Supplemental material

Supplemental material for this article is available online.

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