Association between onychomycosis and ulcerative complications in patients with diabetes: a longitudinal cohort study in Dutch general practice

Abstract

Introduction

Diabetic foot ulcers are feared complications of diabetes mellitus (DM), requiring extensive treatment and hospital admissions, ultimately leading to amputation and increased mortality. Different factors contribute to the development of foot ulcers and related complications. Onychomycosis, being more prevalent in patients with diabetes, could be an important risk factor for developing ulcers and related infections. However, the association between onychomycosis and diabetic complications has not been well studied in primary care.

Research design and methods

To determine the impact of onychomycosis on ulcer development and related complications in patients with diabetes in primary care, a longitudinal cohort study was carried out using routine care data from the Extramural Leiden University Medical Center Academic Network. Survival analyses were performed through Cox proportional hazards models with time-dependent covariates.

Results

Data from 48 212 patients with a mean age of 58 at diagnosis of DM, predominantly type 2 (87.8%), were analysed over a median follow-up of 10.3 years. 5.7% of patients developed an ulcer. Onychomycosis significantly increased the risk of ulcer development (HR 1.37, 95% CI 1.13 to 1.66), not affected by antimycotic treatment, nor after adjusting for confounders (HR 1.23, 95% CI 1.01 to 1.49). The same was found for surgical interventions (HR 1.54, 95% CI 1.35 to 1.75) and skin infections (HR 1.48, CI 95% 1.28 to 1.72), again not affected by treatment and significant after adjusting for confounders (HR 1.32, 95% CI 1.16 to 1.51 and HR 1.27, 95% CI 1.10 to 1.48, respectively).

Conclusions

Onychomycosis significantly increased the risk of ulcer development in patients with DM in primary care, independently of other risk factors. In addition, onychomycosis increased the risk of surgeries and infectious complications. These results underscore the importance of giving sufficient attention to onychomycosis in primary care and corresponding guidelines. Early identification of onychomycosis during screening and routine care provides a good opportunity for timely recognition of increased ulcer risk.

Correspondence to Mr Roeland M Watjer; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• This is the first large retrospective cohort study investigating the association between onychomycosis and diabetic complications using primary care data.

• This study establishes the significant and independent association between onychomycosis and ulcerative complications in primary care.

• Inherent to the use of routine-care data, results may have been influenced by potential over-reporting and under-reporting.

• Due to the use of observational data, no causal relationship between onychomycosis and ulcerative complications could be established.

Introduction

According to the International Diabetes Federation, an estimated 537 million people worldwide suffer from diabetes mellitus (DM).¹ In 2019, 1.1 million patients with diabetes were registered in Dutch primary care, about 7% of the adult population.² Complications of DM are the cause of significant morbidity and medical costs.³ With the prevalence of DM projected to continue to rise, prevention and management of diabetic complications are becoming increasingly important.²

One of the most feared complications of DM is the diabetic foot, which includes diabetic foot ulcers.⁴ Ulcers often require extensive treatment and hospitalisation and can ultimately lead to lower extremity amputation.⁵ To prevent ulcer development and its consequences, early recognition of patients at risk is essential.⁶

Various risk factors for ulcer development have been identified. The most prominent are prior ulcer or amputation, neuropathy, foot deformity, focal pressure points and peripheral arterial disease.⁷ Furthermore, male gender, signs of microangiopathy, including visual impairment, poor glycaemic control (ie, elevated glycated haemoglobin A1c levels), insulin therapy and onychomycosis were identified as additional significant risk factors.^{8 9}

Regarding the latter, patients with diabetes are more prone to fungal infections in general and onychomycosis in particular: up to one-third of patients with diabetes are estimated to have onychomycosis compared with 4.3% in the general population.^{10 11} Although onychomycosis is often considered a nuisance and unaesthetic at most, numerous studies have shown onychomycosis to have a substantial negative effect on the quality of life and predispose patients to complications such as bacterial infections, especially in patients with diabetes.^12–14 However, the underlying pathophysiological mechanism that explains the relationship between onychomycosis and diabetic complications remains unclear.^{15 16} Although previous studies suggest that onychomycosis may be an important risk factor for ulcer development, this relationship has not been well studied in primary care.^{7 17}

The aim of this study was to assess if onychomycosis, treated or not, is a risk factor for diabetic foot ulcers, and second, for related complications in primary care. Therefore, we conducted a longitudinal cohort study using routine-care data of patients with diabetes from primary care.

Methods

Study design

This study was designed as a longitudinal, retrospective cohort using routine-care data from primary care patients with DM. The date of diagnosis of DM was considered the start of follow-up; the end of follow-up was either development of an outcome, date of death, deregistration or data extraction. Using predefined risk factors, primarily onychomycosis and secondarily antimycotic treatment and related, often underlying conditions, both exposed and unexposed individuals were identified. Following patients forward in time, the incidences of the outcomes of interest were compared between the two groups.¹⁸ Ulcer development was considered the primary outcome; hospital referrals, surgical interventions (performed within primary care) and the bacterial skin infections, cellulitis and erysipelas, were secondary outcomes.

Data and setting

Routine-care data from primary care practices affiliated with the Extramural Leiden University Medical Center (LUMC) Academic Network (ELAN) were used. ELAN is a collaboration between Dutch general practitioners (GPs) and the Department of Public Health and Primary Care from the LUMC, in the western part of the Netherlands. ELAN periodically extracts and stores these data in its database in compliance with local and European privacy legislation.^{19 20} The investigators had no access to the ELAN database used to create the dataset for analysis. The data used to create the dataset provided to the investigators were extracted on 11 May 2022.

Participants

The records of all patients with diabetes, regardless of subtype, were extracted. Based on the intended analyses, patient records meeting the following criteria were selected:

• Date of diagnosis of DM recorded.

• Age between 0 and 100.

• Date of exposure (risk factor) and event (complication) recorded, that is, time between diagnosis of DM and exposure or outcome of interest known.

• Exposure or event occurred after diagnosis of DM and before deregistration, death or data extraction, that is, during follow-up.

Regarding the latter, since the start of follow-up was defined as the date on which the diagnosis of DM was established, only exposures and events occurring after baseline were used for analyses.

Patient and public involvement

It was not appropriate to involve patients or the public in the design, conduct, reporting or dissemination plans of our research.

Measurements and outcomes

Regarding exposures and outcome measures, the diagnoses and comorbidities extracted were coded using the International Classification of Primary Care coding system and their corresponding dates of registration. Similarly, data on medication, referrals and interventions were extracted using their corresponding coding systems.

Besides onychomycosis, the available risk factors of interest were tinea pedis, peripheral artery disease, venous insufficiency, ankle oedema, psoriasis, lichen planus, eczema, neuropathy, smoking and antimycotic treatment. In addition, age and sex were also considered potential confounders and used for analyses.

Our primary outcome measure was ulcer development. Secondary outcome measures were hospital referrals, surgical interventions performed within primary care, that is, minor procedures such as debridement, and infectious complications (cellulitis and erysipelas). Only hospital referrals related to DM referring to surgery, internal medicine or dermatology, were used for analyses.

Cellulitis and erysipelas, although coded differently, were combined since both entities are used interchangeably. The same was done for ulcus cruris and diabetic foot ulcers, combining them into a single variable for ulcers. In case two variables were combined and a patient was diagnosed with having both, the diagnosis that occurred first, that is, with the shortest time to diagnosis of DM, was used for analysis.

Statistical analyses

Descriptive statistics were used to analyse patient characteristics at baseline and to describe the occurrence of both exposures and outcomes during follow-up.

Since exposures and outcomes of interest were not constant over time, that is, occurring at different moments during follow-up, these were considered to be time-dependent covariates. Therefore, to answer our research questions, Cox-proportional hazards (PHs) models with time-dependent covariates were used, thus taking into account the time between baseline and diagnosis of an exposure or event. The PH assumption was checked by testing whether the covariates interacted significantly with time. In case of violation, the corresponding HR was modelled as a time-dependent effect by including an interaction term between the logarithm of time and the covariate.

To answer our research questions, three models were constructed. First, the association between onychomycosis and ulcer development was evaluated as single predictor (univariate model), then adjusted for antimycotic treatment (first multivariate model), and finally for all potential confounders mentioned above (second multivariate model). The PHs assumption (PH) was violated for age and neuropathy in the last model, hence corrected for by including the interaction terms with the logarithm of time in the corresponding model.

Regarding secondary outcomes, the associations between onychomycosis and hospital referrals, surgeries and bacterial skin infections were evaluated. The same set of models, that is, a univariate model, a multivariate model to adjust for antimycotic treatment and a final multivariate model to adjust for all confounders combined, were used for each of the secondary outcomes, respectively. Again, the interaction terms with the logarithm of time were used for the covariates for which the PH assumption was violated. These were neuropathy and smoking in the final multivariate model for hospital referrals, age and ankle oedema in the final model for surgical interventions, and age in the final model for bacterial skin infections.

P values of <0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics (V.28).

Results

Patient characteristics

The initial data extraction consisted of 50 292 patient records. After applying the criteria as described, 48 212 records were selected for analysis. Patient characteristics are shown in table 1. Our sample included 22 877 women (47.5%) and 25 335 men (52.5%). The mean age at baseline was 58.3 years (SD 15.7). The vast majority of patients (87.8%) were diagnosed with type 2 DM; only 6.5% had type 1 DM and the remaining cases (5.7%) were unspecified.

Table 1

Patient characteristics at baseline, that is, start of follow-up

Patients, total (N)	48 212
Mean age at onset of DM in years (SD)	58.3 (15.7)
Gender, N (%)
Male	25 335 (52.5)
Female	22 877 (47.5)
Type of diabetes mellitus, N (%)
Type 1	3131 (6.5)
Type 2	42 312 (87.8)
Unspecified	2769 (5.7)

DM, diabetes mellitus.

The median follow-up time was 10.3 years (IQR 10.8). Exposures and events recorded during follow-up are presented in table 2.

Table 2

Exposures and events during follow-up

	N (cumulative incidence, %)
Total cohort	48 212
Exposures
Onychomycosis	1959 (4.1)
Tinea pedis	2006 (4.2)
Peripheral arterial disease	2381 (4.9)
Venous insufficiency	275 (0.6)
Ankle oedema	6494 (13.5)
Psoriasis	1193 (2.5)
Lichen ruber planus	166 (0.3)
Eczema	5870 (12.2)
Neuropathy	3287 (6.8)
Smoking	2930 (6.1)
Antimycotic treatment
Any type	3005 (6.2)
Local	2777 (5.8)
Systemic	228 (0.5)
Events
Ulcer	2771 (5.7)
Cellulitis/erysipelas	4889 (10.1)
Hospital referral	3060 (6.3)
Surgical intervention	6149 (12.8)

The cumulative incidence of onychomycosis in our sample was 4.1%. Regarding the other exposures, ankle oedema (13.5%) and eczema (12.2%) were most frequently recorded. During follow-up, 6.2% of patients received any form of antimycotic treatment. In total, 2771 patients (5.7%) developed an ulcer after a median of 8.8 years (IQR 9.6). Regarding the secondary outcomes, surgical interventions occurred most frequently (12.8%) after a median of 7.8 years (IQR 8.9), followed by infections (10.1%) after a median 7.7 years (IQR 9.4). 6.3% needed a hospital referral after a median of 7.4 years (IQR 9.2).

Primary outcome: ulcer development

The results for the association between onychomycosis and ulcer development are shown in table 3. In univariate analysis, onychomycosis was significantly associated with ulcer development (HR 1.37, 95% CI 1.13 to 1.66). After adjusting for antimycotic treatment and all confounders combined, onychomycosis remained significantly associated with ulcer development (HR 1.37, 95% CI 1.13 to 1.66 and HR 1.23, 95% CI 1.01 to 1.49, respectively).

Table 3

Cox proportional hazards models for effect of onychomycosis on primary and secondary outcome measures

Outcome	Onychomycosis		Univariate model		Adjusted for antimycotic treatment		Multivariate model*
	Yes (%)	No (%)	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Primary
Ulcer	140 (5.1)	2631 (94.9)	1.37 (1.13 to 1.66)	0.001	1.37 (1.13 to 1.66)	0.001	1.23 (1.01 to 1.49)	0.036
Secondary
Hospital referral	186 (6.1)	2874 (93.6)	1.24 (1.02 to 1.52)	0.035	1.27 (1.04 to 1.55)	0.021	1.17 (0.96 to 1.43)	0.128
Surgical intervention	427 (6.9)	5722 (93.1)	1.54 (1.35 to 1.75)	<0.001	1.46 (1.29 to 1.66)	<0.001	1.32 (1.16 to 1.51)	<0.001
Cellulitis/erysipelas	317 (6.5)	4572 (93.5)	1.48 (1.28 to 1.72)	<0.001	1.45 (1.25 to 1.68)	<0.001	1.27 (1.10 to 1.48)	0.001

*Adjusted for: age, sex, peripheral arterial disease, venous insufficiency, ankle oedema, tinea pedis, psoriasis, lichen planus, eczema, neuropathy, smoking, antimycotic treatment (any).

Secondary outcomes

The results, describing the association between onychomycosis and our secondary outcome measures, are also shown in table 3.

Onychomycosis was significantly associated with hospital referrals in univariate analysis (HR 1.24, 95% CI 1.02 to 1.52). Adjusting for treatment did not significantly alter this association (HR 1.27, 95% CI 1.04 to 1.55). However, when adjusted for all confounders, onychomycosis was not significantly associated with hospital referrals (HR 1.17, 95% CI 0.96 to 1.43).

Onychomycosis was also significantly associated with surgical interventions in primary care (HR 1.54, 95% CI 1.35 to 1.75). Antimycotic treatment did not significantly influence this association (HR 1.46, 95% CI 1.29 to 1.66), nor did adjustment for all confounders combined (HR 1.32, 95% CI 1.16 to 1.51).

Finally, onychomycosis was significantly associated with the bacterial infections cellulitis/erysipelas (HR 1.48, 95% CI 1.28 to 1.72), again not significantly affected by treatment (HR 1.45, 95% CI 1.25 to 1.68), nor after adjusting for all confounders (HR 1.27, 95% CI 1.10 to 1.48).

Conclusions

Summary

Our study demonstrated that onychomycosis in primary care patients with diabetes was significantly associated with the development of an ulcer compared with patients without onychomycosis. Even when adjusted for antimycotic treatment and additional confounders, onychomycosis remained independently associated with ulcer development. The same association was found for bacterial skin infections and surgical procedures in primary care.

Comparison with existing literature

Our results confirm the association between onychomycosis and ulcer development previously found in other populations, establishing its important role in patients with diabetes, independently from already well-established risk factors like vascular disease, neuropathy and pre-existing skin disease.^{7 8 21}

Boyko et al found an adjusted HR of 1.58 (95% CI 1.16 to 2.16) in their final multivariate model but used prospective data from veterans, predominantly male (98%) and of higher average age (62.4) attending internal medicine clinics, that is, a different setting.⁸ Monteiro-Soares et al, in their endeavour to optimise the prediction model as proposed by Boyko, also found a significant association between onychomycosis and ulcer development using data from patients attending a tertiary podiatry clinic. However, they did not include the effect of time, thus limited to logistical regression analyses and unable to produce HR’s to compare our results with.²²

Furthermore, we were able to confirm the association between onychomycosis and surgical interventions as well as bacterial skin infections in primary care, previously suspected but not sufficiently supported by clinical evidence.^{16 23}

Strengths and limitations

The major strength of this study was the ability to analyse data from a large cohort of primary care patients, our results therefore being representative for primary care settings in general. Although the association between onychomycosis and ulcer development has been described as mentioned above, this is the first study that establishes this association in primary care.⁸

In addition, we specifically evaluated the effect of antimycotic treatment on the association between onychomycosis and diabetic complications, which was addressed in the systematic review of Monteiro et al, but not previously done.^{7 8 24} Since onychomycosis increased the hazard for developing an ulcer, one might speculate that antimycotic treatment would decrease this hazard. However, it did not, suggesting that antimycotic treatment was not effective in preventing ulcers or that antimycotic treatment merely represents a selection of patients with more severe disease burden, already more prone to ulcer development due to other contributing factors.

An important limitation due to the use of observational, routine-care data, was our inability to proof a causal relationship between onychomycosis and ulcer development. The finding that antimycotic treatment did not significantly affect the association between onychomycosis and ulcers also suggests that onychomycosis is probably a marker rather than a direct cause of ulcer development.

Another limitation is the inherent level of uncertainty that comes with routine-care data. For example, coding is not always accurate and registration has improved over the last decades; effects based on data registered by GPs in the past might differ from data more recently registered. This could lead to over-reporting or under-reporting. Also, looking at the cumulative incidence of onychomycosis in our study sample, a lower number was found than reported by population-based studies likely due to the fact not all patients consulted their GP.¹⁰ However, it is unlikely that these data-registration limitations would be different for those with or without onychomycosis within our study population, therefore probably not affecting our results.

In parallel, specific groups of patients were likely to be checked more often by their GP, for example, those having more severe disease. Their chance of being diagnosed with onychomycosis would be higher compared with healthier individuals, which potentially could have introduced confounding by indication and an overestimation of the association found. However, when correcting for all confounders, the independent and significant contribution of onychomycosis remained intact, pleading against a substantial effect from this form of confounding.

Finally, we only analysed a prespecified, available set of variables, not including important predictors of previous ulcers or amputations. Our results therefore only represent ulcer risk in those without prior ulcers or amputation.

Implications for practice and future perspectives

In conclusion, our study demonstrates that onychomycosis is independently associated with ulcer development in patients with diabetes in primary care. As ulcers may precede lower extremity amputations and ultimately increase mortality, our findings support the clinical relevance of onychomycosis in patients with diabetes, emphasising the importance of recognising fungal toenail infections in diabetes care.^25–27 Therefore, we would recommend all healthcare professionals involved in the care of patients with diabetes within primary care, to systematically check for the presence of onychomycosis during routine care.

Investigating if treatment of onychomycosis could reduce the risk of diabetic ulcer development and related complications by a prospective study design could be an important next scientific step.

Adjusted for: age, sex, peripheral arterial disease, venous insufficiency, ankle oedema, tinea pedis, psoriasis, lichen planus, eczema, neuropathy, smoking, antimycotic treatment (any).

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Medical Ethics Committee Leiden Den-Haag Delft (METC-LDD), reference number G21.206. The METC-LDD decided that, in accordance with national regulations, further approval by an institutional review board was not necessary, that is, a waiver was granted and the study was exempted since the study was not subject to the Medical Research Involving Human Subjects Act, according to the guidelines of the Central Committee on Research Involving Human Subjects (CCMO). For additional information in English, refer to: https://english.ccmo.nl/investigators/legal-framework-for-medical-scientific-research/yourresearch-is-it-subject-to-the-wmo-or-not or in Dutch: https://wetten.overheid.nl/jci1.3:c:BWBR0009408&z=2022-03-15&g=2022-03-15 https://wetten.overheid.nl/jci1.3:c:BWBR0009408&z=2022-03-15&g=2022-03-15

Footnote

X @tbonten

Contributors All authors read and approved the final manuscript. RW: guarantor. RW, JE and TB: conceptualisation. RW, KH, LG and TB: methodology and formal analysis. RW, KH and LG: investigation, data curation, writing. RW, JE, KQ, MN and TB: review. TB and JE: supervision.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

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