Frequency of allergen sensitivity in patients with leg ulcers in the present study compared with the 1998 to 2000 North American Contact Dermatitis Group (NACDG) database.
Saap L, Fahim S, Arsenault E, Pratt M, Pierscianowski T, Falanga V, Pedvis-Leftick A. Contact Sensitivity in Patients With Leg UlcerationsA North American Study. Arch Dermatol. 2004;140(10):1241-1246. doi:10.1001/archderm.140.10.1241
(1) To determine the prevalence of allergen sensitivity in patients with past or present leg ulcers in 2 North American study centers vs European study findings and the North American Contact Dermatitis Group (NACDG) database and (2) to delineate a standard battery of allergens for patch testing in North American patients that is representative of the newer dressings and wound care products.
Fifty-four patients, with or without dermatitis, were prospectively entered in the study. The patients were patch tested to the NACDG standard series and a comprehensive supplemental series of 52 allergens.
Wound healing clinics at Boston University Roger Williams Medical Center and University of Ottawa.
Sixty-three percent (n = 34) of patients had 1 or multiple positive patch test results, and 37% (n = 20) had no positive patch test result. The most common allergens were Myroxylon pereirae (balsam of Peru) (30% [16/54]), bacitracin (24% [13/54]), fragrance mix (20% [11/54]), wood tar mix (20% [11/54]), propylene glycol (14% [7/52]), neomycin sulfate (13% [7/54]), benzalkonium chloride (13% [7/54]), carba mix (11% [6/54]), nickel sulfate (11% [6/54]), and control gel hydrocolloid (11% [6/54]).
Comparable to European study findings, there is a high incidence of positive patch test results in patients with past or present leg ulcerations. The incidences of the most common allergens in our patient population were higher than those seen in the NACDG, except for nickel. Using a modified leg ulcer series along with the standard NACDG series is important in evaluating patients with leg ulcers.
During the past 2 decades, European studies have investigated contact sensitivity in patients with chronic leg ulcerations. The frequency of positive patch test results found in this patient population has ranged from 40% to 82.5%, and sensitivities have involved 1 or multiple allergens.1- 10 One study4 found a direct relationship between the duration of leg ulcers and the number of multiple positive allergen sensitivities. These authors' findings suggest that an ulcer of long duration has greater opportunity for contact with different allergens and leads to increased sensitivity to these allergens.
Patients with leg ulcers frequently become sensitized to topical allergens. Examples of these allergens include neomycin sulfate, lanolin alcohols, Myroxylon pereirae (balsam of Peru), Amerchol L101, colophony, fragrance mix, propylene glycol, paraben mix, budesonide, tixocortol-21-pivalate, thiuram mix, and nickel sulfate, among others.1- 10
It is suspected that the high incidence of sensitization in the leg ulcer patient population is due to (1) the intrinsic allergenic properties of different ointments and wound products used to heal the ulcer, (2) the excessive duration of use of these products, and (3) the disrupted skin barrier (increased permeability and inflammation) to which these products are applied.11 These conditions can lead to contact dermatitis of the leg, ultimately impairing healing and prolonging morbidity associated with leg ulcerations. Recurrence of leg ulcers may be due to persistent or recurrent dermatitis.
Although several groups have studied contact sensitization in leg ulcer patients in Europe, the incidence of sensitization has not been studied in North America, to our knowledge. In addition, many new wound care products have not been recently tested for contact sensitization. This is particularly important considering that wound care clinics in North America may have different sensitization patterns compared with those in Europe because of differences in the wound care products used.
The goals of this study were the following: (1) to determine the incidence of allergen sensitivity in patients with past or present leg ulcers in 2 North American study centers, (2) to compare the incidence and frequency of these sensitivities with those in patients studied in Europe, (3) to compare the frequencies of the common allergens in the study with those in the North American Contact Dermatitis Group (NACDG) database, and (4) to establish a standard battery of allergens for patch testing in North American patients.
We prospectively recruited 54 patients (19 men and 35 women; mean ± SD age, 65.24 ± 13.96 years) with past or present leg ulcerations, regardless of etiology or presence or absence of dermatitis. Twenty-two patients were recruited at the Advanced Wound Healing Center of Boston University Roger Williams Medical Center, and 32 patients were recruited at the Wound Care Center of Ottawa Civic Hospital, Ottawa. Patients were excluded from participation in the study if they were receiving an oral prednisone dosage of 20 mg/d or higher, or if they were receiving any oral immunosuppressive therapy (ie, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, or cyclophosphamide). Informed consent was obtained from all patients in accord with each study center's human research committee, and the study protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
A comprehensive questionnaire was filled out by all the patients and included a detailed history of ulcer duration, healing times, frequencies of ulcer recurrence, past and present ulcer treatment, any associated dermatitis, and allergic reactions. A physical examination was performed at the initial evaluation and consisted of the following: general appearance, evaluation of skin disease and presence and severity of any dermatitis, description of lower extremity ulcerations, and evaluation of the vascular state, including dorsalis pedis pulses, ankle-brachial index by Doppler testing (if the patient did not have diabetes mellitus), and results of Doppler testing of the arteries and veins, if previously performed.
Patch tests consisting of 110 allergens affixed to 8-mm-diameter Finn Chambers were applied and taped in a standardized order to hairless skin on the backs of the patients. The patch test allergens consisted of the 2001 standard series from the NACDG (Dr Pratt, written communication, July 10, 2001) and a leg ulcer series designed at our study centers consisting of 52 allergens (Table 1). The leg ulcer series included a battery of cosmetic allergens, topical medicaments, and wound care products typically used in patients with leg ulcers at our 2 study centers and other North American wound healing centers. This leg ulcer series incorporated representative samples of the major types of dressings and products used in wound healing, such as transparent films, foams, hydrogels, hydrocolloids, alginates, hydrofibers, and composite dressings, as well as topical antibiotics, antiseptics, debriding agents, and topical corticosteroids.
Patch test results were read 48 hours and 96 or 120 hours after application and were interpreted following the NACDG protocol.12 Reactions that were evaluated as 1+ to 3+ (1+, weak positive; 2+, strong positive; and 3+, extremely strong positive) were included in the results, while equivocal reactions were excluded. Clinical relevance was determined for each positive result based on previously published criteria.12 Spearman rank correlation coefficient was used to determine any association between ulcer duration and number of positive allergen sensitivities.
The results of our study showed that 63% (n = 34) of the patients had 1 or more allergen sensitizations. Fifty-two percent (n = 28) of the patients had more than 1 allergen sensitization, and 11% (n = 6) had only 1 positive allergen sensitization. Thirty-seven percent (n = 20) of the patients had no positive allergen sensitization. The following data further subdivide the 34 patients who had positive allergen test results: 1 positive allergen test result, 11% (n = 6); 2 positive results, 4% (n = 2); 3 positive results, 17% (n = 9); 4 positive results, 9% (n = 5); 5 positive results, 2% (n = 1); and more than 5 positive results, 20% (n = 11).
The most common allergens found in our patients from the NACDG standard series and the rates of sensitization to these allergens were balsam of Peru (30% [16/54]), bacitracin (24% [13/54]), fragrance mix (20% [11/54]), propylene glycol (14% [7/52]), neomycin (13% [7/54]), benzalkonium chloride (13% [7/54]), carba mix (11% [6/54]), nickel (11% [6/54]), lanolin (9% [5/54]), formaldehyde (9% [5/54]), 2-bromo-2-nitropropane-1,3-diol (bronopol) (9% [5/54]), methyldibromo glutaronitrile phenoxyethanol (Euxyl K400) (9% [5/54]), and quaternium-15 (9% [5/54]) (Table 2). The most common allergens found from the leg ulcer series were wood tar mix (20% [11/54]), control gel hydrocolloid (11% [6/54]), hydrogel with propylene glycol (9% [5/54]), cadexomer iodine gel (7% [4/54]), framycetin sulfate (7% [4/54]), and thin polyurethane hydrocolloid (6% [3/54]). Table 3 lists the rare positive allergens found in our patient population.
Of the 54 patients, 15 denied having dermatitis on the lower extremity with present or past ulceration. However, 11 (73%) of these patients had positive contact sensitivity to at least 1 allergen. Of the 54 patients, 39 admitted to having dermatitis on the affected leg, and 22 (56%) of these patients had positive contact sensitivity to at least 1 allergen.
A prior study4 showed that longer ulcer duration is associated with a higher number of allergen contact sensitivities. However, in our study we did not find an association between ulcer duration and number of positive allergen sensitivities (Spearman rank correlation coefficient, −0.013; P = .93).
There were 189 positive allergens among the 54 patients. Twenty (11%) of these had a definite relevance, 19 (10%) had a probable relevance, 106 (56%) had a possible relevance, 22 (12%) had a past relevance, and 21 (11%) had an unknown relevance. Relevance for allergens is given in Table 2.
A high cross-reactivity was found between positive allergic reactions to balsam of Peru and wood tar mix. In 55% (6/11) of patients allergic to wood tar mix, allergy was also present to balsam of Peru, and 38% (6/16) of patients allergic to balsam of Peru were also allergic to wood tar mix. In addition, and not surprisingly, 60% (3/5) of patients allergic to hydrogel with propylene glycol were also allergic to propylene glycol, while 43% (3/7) of patients allergic to propylene glycol were also allergic to hydrogel with propylene glycol. Another interesting finding was that 75% of patients allergic to framycetin sulfate dressing were also allergic to neomycin (3 of 4 patients) and bacitracin (3 of 4 patients).
Control gel hydrocolloid and thin polyurethane hydrocolloid are known to contain pentaerythritol tetranitrate ester of hydrogenated rosin. This is a tackifying agent that commonly cross-reacts with colophony.13 However, only 17% (1/6) of patients with a positive patch test result to control gel hydrocolloid and 25% (1/4) of patients with a positive patch test result to thin polyurethane hydrocolloid were also allergic to colophony. The sole patient allergic to colophony was allergic to control gel hydrocolloid and thin polyurethane hydrocolloid.
We compared the allergens with the highest frequencies in our study population with the 1998 to 2000 NACDG data14 and found that patients with leg ulcerations had higher frequencies of positive contact sensitization to balsam of Peru (30% vs 12%), bacitracin (24% vs 9%), fragrance mix (20% vs 11%), propylene glycol (14% vs 4%), and carba mix (11% vs 5%). The frequency of contact sensitization to nickel was higher in the NACDG database (16% vs 11%) (Table 2 and Figure).
We also compared the most frequent allergens in our study group with those in several European studies (Table 4). We found the following differences in allergen sensitization: balsam of Peru (30% vs 3.4%-40%), bacitracin (24% vs 13.1%), fragrance mix (20% vs 7.4%-28%), wood tar mix (20% vs 1.8%-15.0%), propylene glycol (14% vs 0%-8.3%), neomycin (13% vs 2%-34.0%), benzalkonium chloride (13% vs 2.8%-15.32%), carba mix (11% vs 1.7%-8.6%), nickel (11% vs 0%-16.7%), formaldehyde (9% vs 0.67%-8.0%), Quaternium-15 (9% vs 0%-4.9%), lanolin (9% vs 8.5%-33.3%), Euxyl K400 (9% vs 0%), and hydrogel with propylene glycol (9% vs 8.3%)2- 11 (Table 2 and Table 4).
The frequency of contact allergen sensitivity has been shown to be high in the leg ulcer population in multiple studies performed in Europe. Studies1- 11 showed that the frequency of positive patch test results ranges from 40% to 82.5%. However, many of these studies are older, and until the present study, the frequency of allergen sensitivity had not been studied in the North American leg ulcer population, to our knowledge. In addition, the studies performed in Europe did not necessarily incorporate many of the allergens, wound dressings, medicaments, and ointments that are being used in the management of leg ulcers in North America.
In this investigation, we determined the frequency of allergen sensitivity in leg ulcer patients at 2 North American wound healing centers. In agreement with the prior European studies, our results showed a high frequency of allergen sensitivity in our population of leg ulcer patients. Sixty-three percent (n = 34) of all patients were sensitized to 1 or more allergens, and 37% (n = 20) of patients were not sensitized to any allergen.
Of the 16 most common allergens, 13 were from the standard NACDG series, while 3 were from the leg ulcer series developed at our study centers (Table 2). In addition, cadexomer iodine gel, framycetin sulfate, thin polyurethane hydrocolloid, Amerchol L101, fuscidic acid, and hydroactive gel are allergens from the leg ulcer series that showed allergen sensitivity and should be considered in leg ulcer patients who have contact dermatitis and a history of exposure to these products.
In designing this investigation, we tried to be representative of the main categories of wound dressings and wound care products. We included alginate and composite dressings, compression bandages, debriding agents, foams, topical antibiotics, hydrocolloids, hydrogels, hydrofibers, topical antiseptics, and topical corticosteroids, among others. Our goal was not to single out a particular product but to see what categories tend to produce a higher frequency of contact sensitivity. In this endeavor, products commonly used for fragrance were the most allergenic (ie, balsam of Peru, fragrance mix), followed by nonprescription topical antibiotics and products found in commonly used cosmetic and personal care products (ie, wood tar, propylene glycol, benzalkonium chloride, lanolin, Amerchol L101, and formaldehyde-releasing agents).15Of the wound dressings, control gel hydrocolloid had the highest frequency of sensitization. This is thought to be due to pentaerythritol ester of hydrogenated rosin, a tackifying agent that commonly cross-reacts with colophony.13 In addition, there have been case reports of other hydrocolloids causing contact dermatitis thought to be due to this component.16- 18 However, only 1 of 6 patients allergic to control gel hydrocolloid in our study was also allergic to colophony, indicating that there may be other allergens in control gel hydrocolloid that we have not yet identified. The essential point is that hydrocolloids, although important in wound care, can cause contact dermatitis. This should not necessarily restrict use of these dressings but should make us aware that, in a wound that is not healing, a contact dermatitis to the dressing may be an exacerbating factor.
Another wound care product found to cause a high frequency of contact sensitivity was hydrogel with propylene glycol. We believe that the most likely allergen in this product is propylene glycol, as 60% (3/5) of patients allergic to this hydrogel were also allergic to propylene glycol. This emphasizes the importance of knowing all the ingredients in a wound care product before using it.
The frequency of allergen sensitivity was high in patients with no history of leg dermatitis (73% [11/15]), suggesting that these patients are at higher risk of developing contact sensitivity. We also found a high cross-reactivity between patients sensitized to balsam of Peru and wood tar mix, which has been shown in prior investigations.19
In our study population, we were not able to find a correlation between ulcer duration and number of allergen sensitivities, as had been shown in a prior study.4 However, ulcer duration was determined through a patient questionnaire, which may have introduced recall bias. Recall bias may also be an important factor in determining relevance to the allergens tested, as many patients had difficulty remembering products used on their legs. In addition, many patients with past contact dermatitis may have been inappropriately diagnosed as having stasis dermatitis or cellulitis, making relevance more difficult to interpret in this setting.
Compared with the NACDG database, patients with leg ulcers had a higher frequency of contact sensitization to balsam of Peru, bacitracin, fragrance mix, propylene glycol, and carba mix. This higher frequency of allergen sensitization makes sense because many wound care regimens incorporate products with all of these allergens. Furthermore, the disturbed skin barrier in patients with leg ulcers is thought to be a major mechanism for increased allergen sensitivity in this patient population.
The European contact allergen studies of patients with leg ulcers showed variability in results of the allergens tested. Some of the European studies showed similar high frequencies of sensitization to the following allergens compared with our study: balsam of Peru,3,7- 9,11 fragrance mix,4,7,9,11 benzalkonium chloride,9,11 nickel,4,6,8 and hydrogel with propylene glycol.8 Allergen sensitivities to neomycin2- 6,8- 11 and lanolin3- 11 were higher in the European studies. However, sensitivities to the following allergens were lower in the European studies compared with our study: bacitracin,3 wood tar mix,2- 5,8,10 propylene glycol,3,5,7- 10 carba mix,4- 6 formaldehyde,2- 4,6- 10 quaternium-15,4- 6,9,10 Euxyl K400.8 Control gel hydrocolloid and 2-bromo-2-nitropropane-1,3-diol (bronopol) were not tested in any of the European studies. Bacitracin was tested in a European study3 and showed a frequency of 13.1% vs 24% in our study (25/192 vs 13/54)3 (Table 2 and Table 4). This increase of contact allergen sensitivity to bacitracin may be secondary to increased use of this allergen during the past 10 years, as has been speculated in other recent studies.20,21
In conclusion, we showed that allergen sensitivity is high in the North American leg ulcer population. The frequency of positive allergen sensitivity is increased compared with the NACDG database and has some marked differences to previous studies done in Europe. In a patient whose leg ulcer is not healing, it is important to consider that a contact allergy might be impeding healing. This is particularly important because it can sometimes be difficult to differentiate infection from contact dermatitis in patients with chronic ulcers. Based on our results, it may also be important to avoid products with fragrances, formaldehyde-releasing preservatives, propylene glycol, and nonprescription topical antibiotics in this patient population.
Patch testing patients with leg ulcers to the standard NACDG series and the leg ulcer series is a useful adjunct to standard wound care, as it can aid in tailoring treatment to each patient. Table 5 lists a minimum number of allergens to test in patients with leg ulcers, based on our results. If the patient has been exposed to allergens or wound care products not included in this leg ulcer series or the standard NACDG series, these allergens can be easily added.
Correspondence: Anita Pedvis-Leftick, MD, Department of Dermatology and Skin Surgery, Boston University Roger Williams Medical Center, 50 Maude St, Providence, RI 02908 (firstname.lastname@example.org).
Accepted for publication April 30, 2004.
This study was supported by grants AR42936, AR46557, and DK067836 from the National Institutes of Health, Bethesda, Md (Dr Falanga). Drs Fahim, Saap, and Arsenault received the 2002 Alexander A. Fisher Resident Gold Award from the American Contact Dermatitis Society, Chicago, Ill.
Data from this study were presented at the American Contact Dermatitis Society 14th Annual Meeting; March 20, 2003; San Francisco, Calif; Residents and Fellows Symposium at the 62nd Annual Meeting of the American Academy of Dermatology; February 8, 2004; Washington, DC; 65th Meeting of the Society for Investigative Dermatology; April 28, 2004; Providence, RI; and the 15th Annual Meeting of the Wound Healing Society; May 24, 2004; Atlanta, Ga.