The analysis for time of referral to a medical center among patients with diabetic foot infection

This study investigated the referral time among patients with limb-threatening DFI and still found barriers on early referral to a diabetic foot center for most patients, even under such serious conditions. More than 25% of patients took more than two months to admit themselves to the hospital from disease onset. The study also revealed poor prognosis among patients with longer referral time. Major LEA and in-hospital death were defined as poor treatment outcomes and it was found that the latest referral group (> 59 days) had more patients (21.21%) with poor outcomes (15.15% major LEA and 6.06% in-hospital mortality) and the earliest referral group had 10.47% (8.14% major LEA and 2.33% in-hospital mortality) of such outcomes (Fig. 2a). The referral barrier was also noted in Europe because of various causes including inconsistent or vague guidelines on management of DFUs, and possible unawareness of the risk among patients and general practitioners [4, 5]. In the Eurodiale study, duration of ulcer < 1 week was noted in 17% of patients; 1 week to 3 months in 58%; and > 3 months in 24.9% [4]. Manu et al. investigated the referral times of patients with diabetic foot ulcers across Europe, and reported 13–24% of patients had ≥ one month between the onset of the wound and the diagnosis of DFU, while 11–22% were not referred until one or more months after diagnosis. The other two single-center cohort studies revealed patients with a diabetic foot ulcer had a median time between ulcer onset and diagnosis of 4 (0–247) days (diagnosis delay), and the median time between first review and first referral to the specialist clinic was 15 (0–608) days (referral delay) by Macfarlane and Jeffcoate [17], and 3 days of diagnosis delay with 7 days of referral delay in the study by Antal et al. [18]. In these studies, only Antal et al. investigated the correlation between referral time and clinical outcome and their study suggested healing time was postively correlated to referral time.

This study further disclosed that each increased referral day contributed to the increased poor outcome probability and the tendency was still noted when stratifying the DFI patients according to their comorbidities (Fig. 3). People like these patients with comorbidities are supposed to seek medical help proactively because of their poor health, although surprisingly, in this study, the population coexisting with ESRD, cardiovascular diseases or PAD had a less active attitude to manage their DFI and tended to postpone medical consultations (Fig. 1). Although lacking causal evidence, the reason for the late referral in these patients was supposedly due to the obscureness of the infection symptom by poor perfusion. Both cardiovascular diseases [19, 20] and ESRD [21, 22] are associated with PAD and hence such patients would have poor peripheral perfusion. In theory, poor perfusion is supposed to hinder the symptoms and signs of foot infection by regionalizing the infection only in the foot area, therefore presenting limited inflammation response because of less immune cell reaction [23]. The wound margin tissue necrosis might also develop a barrier to prevent inflammation cytokine dissemination into systemic circulation; consequently, obscure symptoms or signs might lead to unawareness of severity of DFI, particularly in patients with cardiovascular comorbidities. Of note, poorer prognosis was also noted in later referral DFI patients with PAD as well as ESRD or MACE (Fig. 2b). It is known that poor perfusion causes poor tissue oxygen tension and hinders delivery of antibiotics to the infected tissue, thereby influencing poor response to treatment [23]; nevertheless, if the poor perfusion is prolonged in the limb, collateral vessel blood supply would no longer be sufficient to compensate for tissue hypoperfusion, which would then result in increased cell loss and ultimately a local inflammatory reaction [24]. Furthermore, inflammation causes injury in tissue and the damaged cells are broken down and replaced by fibrosis, which presents an additional barrier to oxygen diffusion in the tissue thereby further exacerbating ischemia, resulting in a vicious cycle of poorer perfusion, let alone poor limb outcome.

Unlike the comorbidities, the proportions of SIRS presentation were subtly higher in early referral groups but with limited diversity between the different range of referral days (Fig. 1). The presentation of SIRS in patients with DFI always results from more damaged and inflammatory tissue like necrotizing fasciitis, osteomyelitis or abscess formation [9]. SIRS indicates inflammation beyond the infected site traversing throughout the entire body. Such severe infection suggests higher risks to limb loss or mortality, and will almost certainly turn aggressive for DFI treatment once patients experience obvious symptoms such as SIRS. In our study, the similar proportions of SIRS presentation in four groups meant not all DFI patients developed SIRS as soon as disease onset and those with underlying cardiovascular diseases or ESRD might only develop SIRS when infection is advanced. Given previous research, DFI patients would have poor prognosis once they developed SIRS [9]. Our study further documented that despite the same SIRS presentation on arrival, later referral patients still suffered from poorer treatment outcomes. Accordingly, patients and clinicians should recognize the severity of DFI in a timelier manner and patients should be referred to the hospital with a diabetic foot team, even under obscure symptoms.

To grasp time for treatment is important for some diseases to rescue damaged organs. For example, a concept of “time is muscle” was deliberated over by cardiologists regarding the treatment of primary percutaneous coronary intervention for acute ischemic heart disease, aiming to limit the extent of myocardial damage [25, 26], meaning that severity and extent of myocardial ischemic injury resulting from coronary occlusion could be radically altered by timely intervention [26]. A similar thought of “time is limb” was also mentioned in acute limb ischemia needing early recognition of poor perfusion thereby requiring revascularization to prevent limb loss and life-threatening morbidity [27, 28]. Beyond limb ischemia, in this study, early referral for early treatment is also supposedly as important for diabetic patients having foot infection, and the analysis revealed the probability of poor outcome (major LEA or death) vis-à-vis each increased referral day. The time impact was more obvious when the patient presented with SIRS or PAD on arrival; therefore, delayed referral to the hospital until severe inflammation or critical limb ischemia has set in should be avoided to prevent limb loss or mortality.

This study was limited by a single center and retrospective design, so it is uncertain whether the correlation between comorbidities and referral time could be applied to the causal factors of delayed referral. The prognosis analysis was according to in-hospital outcomes, and long-term limb preservation and survival require further prospective study designs to be validated.