The association of chronic, enhanced immunosuppression with outcomes of diabetic foot infections

Abstract We investigated if a chronic, enhanced immunosuppressed condition, beyond the immunodeficiency related to diabetes, is associated with clinical failures after combined surgical and medical treatment for diabetic foot infection (DFI). This is a case‐control cohort study in a tertiary centre for diabetic foot problems, using case‐mix adjustments with multivariate Cox regression models. Among 1013 DFI episodes in 586 patients (median age 67 years; 882 with osteomyelitis), we identified a chronic, enhanced immune‐suppression condition in 388 (38%) cases: dialysis (85), solid organ transplantation (25), immune‐suppressive medication (70), cirrhosis (9), cancer chemotherapy (15) and alcohol abuse (243). Overall, 255 treatment episodes failed (25%). By multivariate analysis, the presence (as compared with absence) of chronic, enhanced immune‐suppression was associated with a higher rate of clinical failures in DFI cases (hazard ratio 1.5, 95% confidence interval 1.1–2.0). We conclude that a chronic, enhanced immune‐suppressed state might be an independent risk factor for treatment failure in DFI. Validation of this hypothesis could be useful information for both affected patients and their treating clinicians.


| INTRODUC TI ON
In the past few decades, the number of scientific publications concerning diabetic foot infections (DFI) has increased exponentially. 1,2 These have uncovered several clinical variables that are associated with failure of treatment for DFI, especially severe peripheral arterial disease, presence of osteomyelitis, insufficient surgical debridement and inadequate weight off-loading. 1,2 It is known that diabetes mellitus is associated with defects in immune responses of both innate (including dysfunction of neutrophils and macrophages) and adaptive (including T cells) types. 3 Patients with diabetes can also suffer from a chronic, 'enhanced' immunosuppressed state when they also are afflicted with various serious co-morbidities. To our knowledge, there are no data assessing the influence of this type of immune suppression on the outcome of treatment for DFI. In our tertiary referral medical centre, we have been seeing an increasing number of patients with DFI who are afflicted with complex comorbidities and immune-compromised states. Thus, we investigated the potential effects of these complications on the likelihood of successful treatment for their DFI. adjustments with multivariate Cox regression models. Among 1013 DFI episodes in 586 patients (median age 67 years; 882 with osteomyelitis), we identified a chronic, enhanced immune-suppression condition in 388 (38%) cases: dialysis (85), solid organ transplantation (25), immune-suppressive medication (70), cirrhosis (9), cancer chemotherapy (15) and alcohol abuse (243). Overall, 255 treatment episodes failed (25%). By multivariate analysis, the presence (as compared with absence) of chronic, enhanced immune-suppression was associated with a higher rate of clinical failures in DFI cases (hazard ratio 1.5, 95% confidence interval 1.1-2.0). We conclude that a chronic, enhanced immune-suppressed state might be an independent risk factor for treatment failure in DFI. Validation of this hypothesis could be useful information for both affected patients and their treating clinicians.

K E Y W O R D S
clinical failures, diabetic foot infection, enhanced immunosuppression, epidemiology, risk factors We performed a single-centre, case-control study targeting the primary outcome of 'clinical failure' after treatment for DFI in adult patients. We identified potential cases to include in our study using a DFI registry that listed all episodes we saw since the year 2000. We defined DFI and related osteomyelitis (DFO) based on the criteria in the diabetic foot infection guidelines published by the International Working Group on the Diabetic Foot (IWGDF) criteria. 1 We defined the chronic, enhanced immunosuppressed state as being present in patients who required renal dialysis, had undergone organ transplantation requiring medical immune-suppression, had advanced cirrhosis (CHILD B and C), were undergoing current chemotherapy for cancer, suffered from alcohol abuse (according to the patient, his/her family or the general practitioner) or were being treated with immune-suppressing drugs. We did not include patients in this category who had an acute or transient cause of immunosuppression, such as polytrauma. We defined 'clinical failure' of DFI treatment as either a persistent, recurrent or new infectious problem at the original site. We defined 'microbiological recurrence' as a clinically persistent or recurrent DFI at the same localization from which the same pathogen(s) were isolated as before treatment was begun. This investigation is one of a retrospective group of studies (DF-MANAG) approved by our medical centre's Ethical Committee (BASEC 2019-01994).

| Statistical analyses
Our primary outcome of interest was whether clinical failure was related to the presence of chronic, enhanced immunosuppression.
Our secondary outcome of interest was the risk, and any associations related to, microbiological recurrence. We compared groups with and without chronic, enhanced immunosuppression using the Pearson chi-square or the Wilcoxon rank-sum test. To adjust for the substantial case-mix, we performed multivariate Cox regression analyses with both outcomes. We checked for collinearity and effect modification by interaction terms. Since 'alcohol abuse' was the only subjective parameter composing the variable 'chronic, enhanced immunosuppression', we ran all analyses twice-both with and without alcohol abuse embedded in the definition of immunosuppression.

| Treatment and outcomes
The

| DISCUSS ION
We found that in our large population of patients with DFI that the presence of a chronic, enhanced immunosuppressing condition was significantly associated with clinical treatment failure (25% of cases). The incidence of microbiological recurrences was, however, low (5% of all DFI cases or 18% of the failures) and was not statistically associated with chronic, enhanced immunosuppression. Hence, we associate an enhanced immunosuppression rather with wound breakdowns than with insufficient anti-infectious effects of DFI treatment.
It is perhaps not surprising that the outcome of treatment for DFI would be worse in patients with immunosuppressing conditions, as this is in line with finding in many other infections. But the literature on this topic is very limited, and to our knowledge, this is the first study to address the question. We were unable to find any previous published investigations on the role of immunosuppressive conditions beyond those specifically associated with diabetes in DFI patients, except in selected situations, such as those undergoing renal dialysis 4,5 or having a renal transplant, 6 or addressing risk factors for diabetic foot ulcers 5,7 or mortality. 4 Zou and Wukich reported that diabetic patients with solid transplant have no increased risk for nosocomial DFI after foot surgery (odds ratio 0.5, 95%CI 0.1-3.1). 6 We examined definitions of chronic, enhanced immunosuppression both including and excluding alcohol abuse, 5,7 and the findings were the same. We undertook this assessment because of the high prevalence of elevated alcohol consumption among our DFI population (243/1,013; 24%). In a recent Chinese survey, the prevalence of 'current' alcohol consumption among patients with diabetic foot ulcers was 35.3%. 7 Among the participants in the Eurodiale trial targeting diabetic foot ulcers, prevalence of alcohol consumption was 45%. 5

ACK N OWLED G EM ENTS
We thank all of the teams of our medical centre involved in the care of DFI patients, and especially the UCAR (Unit for Clinical and Applied Research) study nurses, Kati Sairanen and Nathalie Kühne.

CO N FLI C T O F I NTE R E S T S
None of the authors have any financial or other conflicts of interest with this work.

DATA AVA I L A B I L I T Y S TAT E M E N T
The corresponding author can provide anonymized key data upon reasonable scientific request.