The spectrum of cutaneous infection in diabetic patients with hepatitis C virus infection: a single-center study from egypt.

CONTEXT: Hepatitis-C virus (HCV) infection and diabetes mellitus (DM) have a significant association with skin disorders. AIMS: The aim of this study was to assess the impact of HCV infection on the pattern of cutaneous infections among diabetic patients. METHODS AND MATERIAL: A prospective study included diabetic patients who attended Al-Hussein University hospital, Cairo during the period from 2008 to 2010. Patients were examined for skin infections, and investigated for HCV infection. STATISTICAL ANALYSIS USED: SPSS (version 11.5).
RESULTS: The study included 163 patients (102 males and 61 females) with a mean age of 46.2 ± 4.83 years. Ninety five patients (58.3%) were HCV+ve (group A) while 68 patients (41.8%) were HCV-ve (group B). Skin infections in group A included fungal (48.4%), viral (26.3%), bacterial (22.1%) and parasitic (3.2%) while in group B, the spectrum included bacterial (41.2%), fungal (39.7%), viral (11.7%) and parasitic (7.4%). Onychomycosis was the commonest infection in group A (25.2%) compared with folliculitis in group B (19.1%). Cutaneous infections in HCV+ patients were more characterized by increased severity, aggressive course, resistance to treatment and rapid relapse.
CONCLUSIONS: HCV infection has a significant impact in increasing and changing the spectrum of skin infections in diabetic patients. Severe and resistant infections in diabetics could be an important sign of HCV infection.

What was known?

Cutaneous infections are the most common skin disorders in diabetic patients and could be the earliest sign of diabetes mellitus.

Introduction

Hepatitis C virus (HCV) infection and Diabetes mellitus (DM) are major health problems in many countries including Egypt. The prevalence rate of HCV in Egypt is relatively high (up to 15%) with an incidence rate of 2.4 per 1000 person/year.[1] The prevalence rate of DM in Egypt varied from 4.1 to 9.3% with common risk factors including family history of the disease, obesity, premature atherosclerosis and hypertension.[2]

Skin manifestations may be the first clinical sign of HCV infection leading to early detection of the disease. Dermatological disorders which were proved to have a strong correlation with HCV included cutaneous necrotizing vasculitis with mixed essential cryoglobulinaemia, porphyria cutanea tarda and lichen planus. All patients with these disorders are recommended to be investigated for HCV.[3]

DM is the most common disease which is associated with cutaneous disorders. Type-1 DM may be associated with periungual telangiectasia, necrobiosis lipoidica diabeticorum, skin depigmentation and oral lichen planus while type-2 DM could be associated with yellow nails, diabetic thick skin, diabetic dermopathy, acquired perforating dermatosis, calciphylaxis and acanthosis nigricans.[4]

Cutaneous infections specially fungal and bacterial infections commonly complicate DM and it was suggested that poor microcirculation, peripheral vascular disease, peripheral neuropathy, and decreased immune response are implicated in the increased susceptibility to infection in diabetic patients.[5] The spectrum of skin diseases in Egyptian population with both DM and HCV infection was not studied before. In this study, we assessed the impact of HCV infection on the spectrum of cutaneous infections in diabetic patients and monitored the therapeutic response of those patients in comparison with diabetic patients without HCV infection.

Materials and Methods

The study was conducted at Al-Hussein University hospital, Cairo including all known diabetic patients who attended the diabetic, internal medicine or dermatology clinics in addition to admitted patients during the period from January 2008 to December 2010. Exclusion criteria included children, pregnant or lactating women, patients who had any other systemic diseases or internal malignancy and HCV infected patients under treatment with interferon.

Patients were fully examined for any cutaneous infection. The diagnosis was based on the clinical background with typical site and distribution of the disease in addition to common diagnostic tools such as Wood's light, direct skin smear, tissue culture and skin biopsy. Laboratory investigations included blood glucose levels, anti HCV-antibodies, liver function tests, kidney function tests, lipid profile, thyroid profile, and abdominal ultrasonography.

Quantitative viral load test (measurement of the amount of virus in one milliliter of blood) measured by copies/mL was done for each patient showing positive HCV-Ab. The range was considered low if below 1 million, medium between 2-5 millions, high above 5 millions and very high above 25 millions.

The study was approved from the local ethical committee. Medical photography was performed for some patients after obtaining a written consent. After treatment, monitoring of therapeutic response was recorded and all patients were followed up for a minimum of 6 months duration.

Statistical analysis

Data was analyzed using SPSS for Windows 11.5 software package and compared by a Chi-square test with a significant P < 0.05.

Results

Throughout 3 years duration, a total of 682 diabetic patients were examined. Infectious skin diseases were observed in 163 patients (23.9%) who constituted the total number of patients in this study. Male patients constituted 68.3% while female patients constituted 31.7% with male to female ratio 1.7:1. The age of patients ranged from 34 to 76 years with a mean age of 46.2 ± 4.83 years. The duration of DM ranged from 2 to 17 years with a mean duration of 7.49 ± 3.61 years. There were no significant differences between both groups in relation to the duration of DM.

According to the result of HCV test, patients were classified into 2 groups; group A (95 patients) included HCV diabetic patients while group B (68 patients) included only diabetic patients. The incidence of HCV patients among diabetic patients was estimated as 13.9%. The incidence of skin infections was higher in group A (58.3%) compared with group B (41.7%). There was a predominance of male patients in group A (74.7%) while female patients were more in group B (54.4%). The spectrum of skin infections in both groups are shown in Table 1. There was a significant difference between both groups in both bacterial (P = 0.01) and viral infections (P = 0.04) while fungal and parasitic infestation showed no significant differences.

Table 1

The spectrum of cutaneous infections in diabetic patients with and without HCV infection

Onychomycosis was the most common recorded infection (25.2% in group A compared with 7.4% in group B). In group A, Distal lateral subungual onychomycosis (DLSO) was observed in 18 patients (18.9%) while candidal onychomycosis (CO) was diagnosed in 7 patients (7.3%). Toe nails were affected in 13 patients [Figure 1a], fingernails in 4 patients and both were affected in 7 patients. The diagnosis was confirmed by demonstration of hyphae in direct KOH smear or in Periodic Acid Schiff (PAS) stained section [Figure 1b] after nail clipping. In group B, 4 patients (5.9%) had CO while DLSO was diagnosed in one patient (1.5%). All patients showed fingernails affection [Figure 1c] and the diagnosis was confirmed by the demonstration of pseudo-hyphae, spores and budding cells in PAS stained sections [Figure 1d] Fungal culture was required to confirm the diagnosis in 8 patients (6 in group A and 2 in group B).

Figure 1

HCV+ diabetic patient showing DLSO affecting toenail (a) (b, ×100) with demonstration of hyphae in PAS stained section (c) Another patient with CO affecting fingernail (d, ×100) with demonstration of spores in PAS stained sections

Itraconazole was the treatment of choice for all patients of onychomycosis. The average dose was 200 mg/day for 6 weeks in fingernails onychomycosis and 12 weeks in toenails onychomycosis (with or without fingernails affection). At the end of treatment period, 5 patients (20.8%) in group A showed significant improvement while poor or mild improvement was observed in 19 patients (79.2%). In group B, 4 patients (80%) showed significant improvement while one patient (20%) showed mild improvement.

Tinea corporis formed the second common fungal infection in group A (11.6%). In 4 patients, the lesions were solitary but more inflammatory and usually showed many pustules on the surface [Figure 2a]. There was marked resistance and very poor response of these lesions to topical antifungal medications that indicated the use of systemic therapy (Terbinafine 250 mg/day or itraconazole 100 mg bid for 1-2 weeks) which showed moderate to marked response in the majority of patients [Figure 2b].

Figure 2

(a) HCV+ diabetic patient with inflammatory tinea corporis on the forearm (b) that showed significant improvement after treatment with terbinafine for one week

Viral infections constituted the second common infectious skin diseases in group A (26.3%) compared with 11.7% in group B. Warts (verrucae) were the commonest viral infections in both groups (13.7% and 8.8%) followed by herpes zoster (8.4% and 2.9% respectively). In group A, a gangrenous form was observed in 2 patients [Figure 3a] who did not respond to acyclovir but they significantly improved after shifting to famciclovir (500 mg twice daily for 7 days) [Figure 3b].

Figure 3

(a) HCV+ diabetic patient with a gangrenous form of herpes zoster (b) that showed significant improvement after treatment with famciclovir for one week

Bacterial infections were the third common skin infections in group A (22.1%) while in group B they constituted the most common infectious diseases (41.2%). It was observed that the common bacterial micro-organisms in group B were staphylococci and streptococci (75%) while in group A they were corynebacteria or micrococci (71.4%). Parasitic infestations were the least common in both groups (3.2% in group A versus 7.4% in group B) with predominance of scabies (7 patients).

Laboratory investigations showed a significant correlation (P < 0.005) between hyperglycemia and increased incidence of skin infections in group B, while other investigations showed no significant correlations as shown in Table 2. Viral load test of HCV+ patients showed low count in 52 patients (54.7%), medium in 8 patients (8.4%), high in 22 patients (23.2%) and very high in 13 patients (13.7%). High viral load was more recorded with viral skin infections (19 patients) in comparison with fungal infections (8 patients) and bacterial infections (7 patients) denoting the significant correlation between HC viremia and increased incidence of viral skin infections.

Table 2

Correlation between the results of laboratory investigations in group A (+DM/+HCV) and group B (+DM/-HCV)

Discussion

The association between DM and HCV infection was firstly reported in 1994. In a recent meta-analysis study, it was found that HCV infected patients had a higher risk of developing type 2 DM compared with uninfected controls. It was also found that among HCV infected patients, male patients with age over 40 years had an increased frequency of type 2 DM.[6] It was suggested that an expression of the HCV core protein induces hepatic insulin resistance through alterations in signaling in the insulin receptor substrate-1 pathway. This, along with other factors such as diet and obesity, can result in expression of the diabetic phenotype.[7]

Although the complex interaction of chronic HCV infection with the host hepatic glucose and lipid metabolism has not been fully understood, it was conceivable that patients with an earlier stage of chronic HCV infection have β-cell dysfunction but that diabetes does not become established until cirrhosis has supervened. Thus, a combination of β-cell dysfunction and insulin resistance is required for overt expression of DM.[8] It was also reported that HC viremia is associated with diabetes related complications and comorbidity of chronic HCV infection and DM is associated with a higher mortality rate.[9]

Although bacterial and fungal infections were commonly described in diabetic patients, cutaneous infections are not common manifestations of HCV infection which is more associated with non-infectious dermatologic diseases.[10] In this study we compared the spectrum of infectious skin diseases in diabetic patients alone and in combination with HCV infection.

Our results demonstrated a significant increase in cutaneous infections among HCV diabetics (58.3%) more than those with diabetes alone (41.7%). The spectrum of infections in both groups was different with predominance of fungal infections in group A (47.4%) compared with bacterial infections (41.2%) in group B. The increased incidence of fungal and bacterial infections among diabetic patients was also reported among Indian patients in whom cutaneous infections were seen in 31% of diabetic patients; 16% were fungal while 15% were bacterial. The spectrum of bacterial infections in this study included impetigo contagiosa (4%), boils (6%), erythrasma (2%) and folliculitis (3%) while the spectrum of fungal infections included candidal infection (9%) and dermatophytosis (7%).[11]

In Pakistani population, skin infections were reported in one study as the commonest cutaneous manifestations in diabetics (30.9%) which included 19% bacterial infections, 8.9% fungal infections and 2.9% viral infections.[12] However, the incidence of skin infections in diabetics was higher in other studies as reported by Mahajan et al., who found skin infections in 54.7% of diabetic patients. They reported fungal infections as the predominant infection (32.8%) followed by bacterial infections (18.8%) and lastly viral infections (3.1%). The spectrum of fungal infections included 17.2% dermatophytosis (onychomycosis 7.8%, tinea corporis 6.3%, tinea pedis 1.6% and tinea incognito 1.5%) and 15.6% candidal infections (vulvovaginitis 7.8%, balanoposthitis 3.1%, intertrigo 3.1% and paronychia 1.6%). Folliculitis (10.9%) formed the most common bacterial infections in this study in addition to one patient of impetigo, carbuncle, Ecthyma, infected eczema and erythrasma while only 2 patients of herpes zoster were recorded.[13]

In Kuwait, Al-Mutairi et al. also reported skin infections as the major cutaneous manifestations in diabetic patients (68%) with predominance of fungal infections (38.7%) followed by bacterial infections (25.5%) while viral infections (herpes simplex) were only observed in 3%. They found tinea pedis as the most common fungal infection while folliculitis was the most common bacterial infection.[14] The results of these studies confirmed the predominance of fungal and bacterial infections in diabetic patients.

A significant finding in our HCV diabetic patients was the predominance of viral infections with significant increase compared to diabetics without HCV infection. To our knowledge, this observation has not been reported before and it could be a unique association in HCV diabetics. The significant correlation between high HC viral load and viral skin infections was the only positive finding that could explain the higher incidence of viral skin infections among HCV diabetics but this observation needs more documented evidences to support it.

The spectrum of fungal infections in diabetic patients usually ranged from dermatophytosis to candidal infections, while in HCV diabetics we observed the changing of spectrum from dermatophytosis to pityrosporum infections. It was reported that pityriasis versicolor is one of the dermatologic manifestations of HCV infection in Egyptian patients.[15] This may support our finding and suggest the role of HCV infection in changing the spectrum of fungal infections among diabetic patients.

We found that the majority of bacterial infections in HCV diabetics were non-staphylococcal, non-streptococcal but were mostly due to Corynebacteria, which was an unusual finding. This may be contributed to the alteration of cellular immunity in diabetic and HCV patients, which leads to modulation of the skin cellular immunity to be more susceptible to uncommon pathogenic organisms.[1617]

The co-existence of both diseases showed a significant alteration in the course and prognosis of skin infections; some were characterized by rapid progressive course such as tinea corporis, others were resistance to treatment as onychomycosis, some showed severe clinical form as herpes zoster, and others showed high relapse rate as warts. One theory that could explain the increased comorbidity is the alteration of the immune system in HCV diabetics either through higher production of pro-inflammatory cytokines (tumor necrosis factor [TNF]-alpha, soluble TNF receptor [sTNFR]1, sTNFR2, and interleukin (IL)-6),[18] or increased insulin resistance associated with higher production of anti-inflammatory cytokines (adiponectin and IL-10).[19] One of the limitations of our study was to investigate the changes of immune system and studying the cytokine profile in both groups that may help in greater understanding and clarifying the mechanisms which lead to the changes in the spectrum of cutaneous infections in HCV diabetics.

Our results also suggested an increased incidence of HCV infection in diabetic patients with severe or resistant cutaneous infections. This may also support the previous suggestion of screening of HCV in diabetic patients and screening of type II DM in HCV patients,[20] which confirm the rising of correlation between DM and HCV infection in addition to the increasing prevalence of both conditions worldwide.

Conclusion

HCV infection and DM are common worldwide diseases and their co-existence has a significant comorbidity. We found that HCV infection has a significant impact in increasing and changing the spectrum of skin infections in diabetic patients. Screening for HCV in diabetic patients with severe or resistant infections should be a routine investigation. This will help in identifying hidden patients of HCV and decreasing the infectivity rate of the disease especially in endemic areas.

What is new?

Hepatitis C virus infection influence and change the spectrum of cutaneous infections among diabetic patients.