Toenail alterations in chronic venous disease patients are not always of mycotic origin

Abstract

Objective

The prevalence of toenail alterations in chronic venous disease has only rarely been studied. We aimed to establish the frequency and clinical characteristics of toenail onychomycosis in chronic venous disease.

Methods

We included 80 adult patients, in all stages of chronic venous disease. Onychomycosis was confirmed by mycological examination. The clinical type of onychomycosis and the onychomycosis severity index were determined. Clinical characteristics of non-fungal nail changes were also analyzed.

Results

We included 58 women and 22 men, with a mean age of 67.0 years. Pathological toenail changes were observed in 83.8% of patients. Onychomycosis was confirmed in 33.8% of all patients and was more frequent in higher clinical stages of chronic venous disease (p = 0.009). Trichophyton rubrum was the leading causative pathogen. Disto-lateral onychomycosis was most commonly present. Average onychomycosis severity index was 23.1.

Conclusion

Onychomycosis accounted for 40% of all toenail alterations. Patients with chronic venous disease often have severe and difficult to treat toenail onychomycosis.

Keywords

Chronic venous disease onychomycosis tinea pedis

Introduction

Toenail onychomycosis and chronic venous disease (CVD) are significant health problems. The incidence of both diseases increases with advancing age and can significantly reduce the patient’s quality of life.

CVD of the legs occurs commonly in the general population in the Western world. Estimates of the prevalence of varicose veins vary widely, from 2 to 56% in men and from 1 to 60% in women.^1,2 These variations reflect the variability of study populations, including age, race and gender, methods of measurement and disease definition. Venous ulcer is present in approximately 1% of the general population, but the prevalence can be three times higher in individuals older than 65 years.^3,4

Onychomycosis is a fungal nail infection of multifactorial etiology. It can also affect the nail matrix and periungual skin and may lead to severe complications.^5,6 It is more common in toenails than in fingernails.⁷ Its prevalence in the general population is estimated to be between 2% and 10%.⁸ Heikkilä et al. discovered onychomycosis in 13.0% of men and 4.3% of women, with a total prevalence of 8.4%.⁹ In recent Canadian research, the prevalence of onychomycosis in the general population was estimated to be 3.2%, while it was 10.3% in the elderly.¹⁰ The frequency can reach 20% in individuals older than 60 years of age.¹¹ The prevalence of toenail onychomycosis is increasing due to population aging, life-style changes and an increasing prevalence of various predisposing factors.⁷ Patients with diabetes mellitus have 2.77 times higher risk of toenail onychomycosis.^12–14

The etiopathogenesis of skin and toenail abnormalities in CVD is complex. Venous hypertension causes a decrease in the blood flow through the capillaries and decreases their number, leading to pathological changes in their walls.^15–17 Ischemia and nutrient deficiency are the most likely reasons for increased cell death and decreased tissue regeneration. Nail regrowth is slower, the skin becomes dry and nail plate more brittle, and immune response decreases.^15–18

Our study aimed to evaluate the frequency and clinical characteristics of toenail onychomycosis in CVD. Previous studies have shown that onychomycosis is more common in patients with CVD.^4,19–22 Only a few studies on this topic have been published, and they included a smaller number of patients. To the best of our knowledge, none of the studies have included all stages of CVD and the majority of these studies did not define the clinical characteristics and severity of toenail onychomycosis.

Methods

Patients

In the prospective clinical study we included 80 consecutive patients with clinical signs and symptoms of CVD. The exclusion criteria were coexistence of lymphedema, peripheral arterial disease, diabetes and previous topical or systemic treatment with antifungal agents.

Patient history included personal data and relevant medical history, including comorbid diseases. Patients were asked about the duration of signs and symptoms of CVD and toenail changes. Meticulous dermatologic examination of the lower extremities was performed in all patients. The clinical stage of CVD was determined in accordance with the CEAP classification: C₁: presence of telangiectasia, C₂: presence of varicose veins, C₃: edema due to varicose veins, C₄: skin damage due to varicose veins (hyperpigmentation, athrophie blanche, stasis dermatitis, lipodermatosclerosis), C₅: changes as in C₄ with healed venous leg ulcer, C₆: changes as in C₄ with venous leg ulcer.²³ We divided patients into six groups in relation to the clinical stage of CVD.

In the case of onychomycosis, the clinical type of onychomycosis was defined, such as disto-lateral subungual onychomycosis (DLSO) or total dystrophic onychomycosis (TDO) and the number of affected nails was assessed. The severity of toenail onychomycosis was evaluated using the onychomycosis severity index (OSI).²⁴ Mild onychomycosis corresponds to OSI values of ≤5, moderate to values from 6 to 15 and severe to values from 16 to 35.

Mycological examination

In the case of toenail abnormalities, mycological examination was performed in the Mycological laboratory of the Department of Dermatovenereology. Nail scrapings were collected. In DLSO and TDO the specimen was obtained from the distal and lateral part of the nail bed by curettage. A part of each sample was prepared with a 20% KOH solution for microscopic examination. Another part of the sample was inoculated onto Sabouraud glucose agar with added chloramphenicol and cycloheximide (bioMérieux, Marcy l’Étoile, France) and incubated at 27°C. Identification of the dermatophyte was based on macroscopic and microscopic colony characteristics.

Data analysis

Statistical analysis was performed using Statistica (StatSoft, version 12). Numerical data are presented as average ± standard deviation. Analysis of categorical data was performed with Pearson’s chi square test.

Results

The 80 patients with CVD included 58 women and 22 men. The average age of patients was 67.0 ± 15.3 years. Women were 66.7 ± 15.4 years old, while men were 67.8 ± 15.3 years old.

The duration of CVD signs and symptoms, based on patients’ histories, was 12.4 ± 11.4 years on average. The number and age of patients in different stages of CVD, with the anamnestic data on the duration of CVD, are presented in Table 1.

Table 1.

Number of patients, their age and duration of clinical symptoms of CVD in relation to the clinical stage of CVD.

Clinical stage of CVD	1	2	3	4	5	6
Number of patients	12	18	14	8	7	21
Age (years)	55.8 ± 13.9	65.5 ± 13.0	62.9 ± 18.3	72.8 ± 7.6	73.9 ± 12.2	72.8 ± 13.6
Duration of symptoms (years)	11.0 ± 8.7	9.5 ± 7.0	17.0 ± 20.0	9.0± 7.6	17.1 ± 11.6	13.4 ± 5.0

CVD: chronic venous disease.

Toenail abnormalities were found in 67 patients (83.8%). Detailed data on the frequency of onychomycosis and non-fungal onychopathy with respect to the clinical stage of CVD are presented in Figure 1.

Figure 1.

Percentage of patients with onychomycosis, non-fungal onychopathy and healthy toenails, divided by the clinical stage of CVD. Numbers above diagrams are the number of patients in each subgroup.

Onychomycosis was confirmed by mycological examination in 27 patients (33.8%): 11 men and 16 women. In two of them (7.4%), cultures were negative, and onychomycosis was therefore confirmed only by KOH examination. Onychomycosis represented 40.3% of all nail deformations. The results of mycological examination, with the findings of the KOH test and cultivation on Sabouraud glucose agar, are presented in Table 2.

Table 2.

Results of microscopic examination (KOH test) and cultivation on Sabouraud glucose agar.

Mycological examination	Cultivation positive	Cultivation negative	Total
KOH test positive	20	2	22
KOH test negative	5	53	58
Total	25	55	80

Among the causative pathogens, Trichophyton rubrum was isolated in 17 patients (63.0%), Trichophyton mentagrophytes in 4 patients (14.8%), Candida spp. in 3 patients (11.1%) and Scopulariopsis brevicaulis in 1 patient (3.7%).

DLSO was found in 19 patients (70.4%) and TDO in 8 patients (29.6%). Patients estimated the duration of toenail changes to be 7.6 ± 7.5 years. On average, 6.4 ± 3.0 toenails were affected. Onychomycosis was more common in men (50.0%) than in women (27.6%). However, this difference did not reach the level of statistical significance (p = 0.058).

The average OSI score was 23.1 ± 11.0, with a median value of 26. In the majority of patients (N = 20, 74.1%), OSI was severe. The numbers of patients with respect to their OSI status and clinical stage of CVD are presented in Figure 2.

Figure 2.

OSI in relation to the clinical stage of CVD. Numbers above diagrams are the number of patients in each subgroup. OSI: onychomycosis severity index.

Onychomycosis was more frequent in patients with higher clinical stages of CVD. The frequency of onychomycosis in the 5th and 6th stages was 60.7% and was significantly higher compared to the 3rd and 4th stages (at 9.1%) and compared to the 1st and 2nd stages (at 26.7%) (p < 0.001 and p = 0.009, respectively).

Various non-fungal toenail alterations were observed in 40 patients. Nail discoloration was the most common finding, followed by onycholysis, thickening of the nail plate, lines, subungual hyperkeratosis, nail desquamation and nail plate splitting. Clinical signs of non-fungal onychopathy are presented in Table 3. In some of the patients, multiple non-fungal toenail abnormalities were observed concomitantly. Tinea pedis was diagnosed clinically in 37 patients and was more common in men (p = 0.003) with co-occurring onychomycosis (p = 0.009). It was present in 66.7% of patients with onychomycosis.

Table 3.

Clinical findings of toenail examination in patients with non-fungal onychopathy.

Non-fungal onychopathy	Number and percentage of changes (%)
Nail discoloration	25 (62.5)
Onycholysis	18 (45.0)
Thickening of nail plate	10 (25.0)
Lines	7 (17.5)
Subungual hyperkeratosis	7 (17.5)
Nail desquamation	6 (15.0)
Nail plate splitting	4 (10.0)
Subungual hematoma	2 (5.0)
Onychogryphosis	1 (2.5)
Onychodystrophy	1 (2.5)
Leukonychia	1 (2.5)
Nail atrophy	1 (2.5)
Pincer nail	1 (2.5)

The sum of all changes is higher than the number of patients with non-fungal onychopathy, since multiple toenail abnormalities were occasionally observed in the same patient.

Discussion

Our study confirmed a high frequency of toenail alterations in patients with CVD, observed in 83.8% of all patients. A comparable high frequency (84%) was reported by Schemer.¹⁹ However, our findings are difficult to compare with other reports. Some of the previous studies included only patients with chronic leg ulcer,²² or were designed in the opposite way, to analyze the prevalence of chronic venous insufficiency (CVI) in patients with toenail onychomycosis.^4,21

Cabete et al. included 81 patients with chronic leg ulcer (mean age of 76.0 years), which was of venous etiology in 63%. Onychomycosis was proven in 27.2% of patients and tinea pedis was observed in 7.4% of patients.²² Kulac et al. studied 42 patients with onychomycosis (mean age of 51 years) and 39 patients with healthy toenails. Using Valsalva maneuver and Doppler ultrasound, they diagnosed CVI in 35.7% of patients with onychomycosis and in 15.4% in the control group; the difference was statistically significant.⁴ Ozkan et al. compared 33 patients with bilateral toenail onychomycosis (mean age of 52.6 years) and 37 patients with healthy nails. Doppler ultrasound confirmed CVI in 42.4% of patients with onychomycosis and in only 10.8% of patients in the control group. The difference between the two groups was statistically significant.²¹

The only two studies with a similar design as in our study were performed by Shemer et al.¹⁹ and Sáez de Ocariz et al.²⁰ Shemer et al. included 44 relatively young patients, between 39 and 63 years old (mean age of 51.7 years), with moderate to severe CVI. Toenail alterations were observed in 84% of patients and onychomycosis was confirmed in 75% of them (in 64% of all patients).¹⁹ Sáez de Ocariz et al. evaluated onychomycosis and non-fungal onychopathy in 36 patients between 18 and 59 years of age (mean age of 46.4 years) with venous leg ulcer. Non-fungal onychopathy was found in 9 patients (25%), while onychomycosis was confirmed in 13 patients (36%).²⁰ In none of the previous studies was the severity of onychomycosis assessed.

We included a considerably higher number of patients, with all stages of CVD. In addition, the mean age of our patients was higher than in the majority of previous studies (67.0 years). The overall frequency of toenail onychomycosis was 33.8%, which is a much higher proportion than the estimated prevalence in the general population. A higher percentage of onychomycosis than in our study was only reported by Schemer (overall frequency was 64%),¹⁹ while it was 36% in the study by Sáez de Ocariz.²⁰ In both of these studies, onychomycosis was confirmed by mycological examination, and histopathological examination of nail fragment was additionally performed in the study by Sáez de Ocariz. The percentage of onychomycosis in our patients might have been higher if histopathological examination of nail fragments had been performed in order to improve the detection of fungi. In advanced stages of toenail onychomycosis with thickened nails, mycological examination of nail scrapings is less reliable and can yield a false negative result.

Trichophyton rubrum was the most common isolated pathogen in our study, similar to the studies by Schemer and Sáez de Ocariz.^19,20 Most of the patients referred to our department had severe toenail onychomycosis, with OSI above 16 (74.1%), meaning that they presented with an advanced stage of onychomycosis, with a high number of nails affected (6.4 nails on average). Older age may be one of the reasons for the high proportion of severe onychomycosis found in our patients.

DLSO was the most common type of toenail onychomycosis, found in 70.4% of patients. A high proportion of our patients had TDO (29.6%), a finding that is consistent with severe OSI and long duration of nail infection.

Non-fungal toenail alterations are common in patients with CVD and may mimic onychomycosis. In majority of our patients with toenail alterations (in 59.7%) mycological examination was negative and onychomycosis was therefore not diagnosed. Clinical features in these patients were similar to those in onychomycosis. Non-fungal toenail deformations can be contributed to microcirculatory dysfunction in CVD,¹⁷ which may also lead to dry skin and hair loss. The clinical characteristics of non-fungal onychopathy in CVD were described in only one of the previous studies, which most commonly presented as color changes, nail plate thickening, opacity, subungual hyperkeratosis and onycholysis,²⁰ similar as in our patients. Mycological examination of toenails is therefore important, in order to avoid misdiagnosis of onychomycosis and overtreatment with systemic antifungal drugs. On the other hand, underestimation of toenail onychomycosis can lead to delay or omitting antifungal treatment.

Moreover, non-fungal nail deformations and onychomycosis can occur concomitantly in CVD. Both nail pathologies may also have been present in some of our patients. Previously damaged nails due to CVD are more predisposed to onychomycosis. This dual nail pathology is difficult to recognize clinically and to treat. Schemer found only a 25% cure rate after treatment of onychomycosis with itraconazole in older patients with CVD. The reason for the low cure rate was attributed to nail deformities caused by venous insufficiency, which remained unimproved after antifungal treatment.¹⁹

Tinea pedis was often present concomitantly in our patients with onychomycosis, which is a common observation in clinical practice. Clinical examination of the skin on the feet is thus very helpful because it can reveal a higher possibility of toenail onychomycosis.

In conclusion, toenail alterations were present in a very high proportion of patients with CVD in our study. Onychomycosis was the etiological reason for toenail changes in less than half of those patients (in 40.3%). Nevertheless, onychomycosis was at least two times more frequent than the reported prevalence in the general population. Older patients with CVD often have severe toenail onychomycosis. Onychomycosis can significantly decrease the quality of life and expose patients to a higher risk of secondary bacterial infection.^5,6,25 In addition, comorbidities in older patients significantly influence the choice, safety and efficacy of antifungal treatment of toenail onychomycosis. Diagnosis and treatment of severe toenail onychomycosis in CVD is difficult, but important for preventing the spread of the infection, permanent damage to the nail plate and secondary complications.

Footnotes

Acknowledgement

None declared.

Contributorship

VB and MDV researched literature. MDV was involved in protocol development and gaining ethical approval. VB, NKL, TPR and ABS were involved in patient recruitment. MDV performed mycological part of the study. VB analyzed the data and wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

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.

Ethical approval

National Medical Ethics Committee of Slovenia approved this study (Number: 30/01/15).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

MDV.

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