Allergies in Phlebology: A National Survey and Review of Literature

Abstract

Background Type I and type IV hypersensitivity can play an important role in phlebology with potential severe consequences for patients and treatment results.

Methods A review of literature was performed for allergic reactions in patients treated for venous insufficiency and venous leg ulcers (VLU), together with a study in the Dutch and European centre for adverse drug reactions. Besides, we performed a survey among 37 Dutch medical hospitals to investigate the incidence of treatment allergies.

Results Hypersensitivity reaction is seen in 46–76% of patient with VLU; about 20% of these reactions are caused by wound dressings products.
In 11 centres urticarial and respiratory complaints were seen and 3 systemic allergic reactions in phlebological treatments. In Europe 25 cases of systemic reactions were reported.

Conclusion Patients with VLU with slow healing tendency should undergo allergy tests. Type I hypersensitivity with anaphylactic reaction, also to sclerosing fluid or tumescent, is very rare.

Zusammenfassung

Hintergrund Typ-I- und Typ-IV-Überempfindlichkeitsreaktionen können in der Phlebologie eine wichtige Rolle spielen, möglicherweise mit schwerwiegenden Folgen für die Patient*innen. Sie können einen negativen Einfluss auf die Behandlungsergebnisse haben.

Methode Es wurde eine Literatursuche nach Suchtermen für allergische Reaktionen bei Patient*innen, die wegen venöser Insuffizienz und venösem Ulcus cruris (VLU) behandelt wurden, in Zusammenarbeit mit dem niederländischen und europäischen Zentrum für unerwünschte Arzneimittelwirkungen durchgeführt. Außerdem führten wir eine Umfrage unter 37 niederländischen Krankenhäusern durch, um die Inzidenz der Behandlung von Allergien zu bestimmen.

Ergebnisse Eine Überempfindlichkeitsreaktion wird bei 46–76% der Patient*innen mit VLU beobachtet, ca. 20% dieser Reaktionen werden durch Wundauflagen verursacht. In 11 Zentren wurden urtikarielle und respiratorische Beschwerden und 3 systemische allergische Reaktionen bei phlebologischen Behandlungen beobachtet. In Europa wurden 25 Fälle von systemischen Reaktionen gemeldet.

Schlussfolgerung Patient*innen mit VLU mit langsamer Heilungstendenz sollten sich Allergietests unterziehen. Eine Typ-I-Überempfindlichkeit mit anaphylaktischer Reaktion, auch auf sklerosierende Flüssigkeit oder Tumeszenz, ist sehr selten.

Schlüsselwörter

Allergie - Überempfindlichkeit - Varikosis - Ulcus cruris venosum - Polidocanol

Keywords

allergy - hypersensitivity - varicose veins - venous leg ulcers - polidocanol

Introduction

There is a great variety in incidence of allergic reactions during phlebological treatments. At one side of the treatment spectrum there is a high percentage (up to 75%) of contact hypersensitivity to components of wound dressings for venous leg ulcers (VLU) [1] [2]. At the other side of this spectrum allergies when treating varicose veins seem virtually non-existent. However, when they occasionally occur, they may cause serious adverse events and even fatalities have been reported [3] [4]. Both systemic reactions, including anaphylaxis, and local reactions such as allergic contact dermatitis (ACD) and urticarial reactions are often mentioned as risk factors in phlebological procedures and treatments. But how often do they really occur and how worried should we be? Phlebological procedures such as sclerotherapy and endovenous laser ablation involve injecting sclerosing liquids or anaesthetics that can cause an anaphylactic shock (type I hypersensitivity), but also other phlebological treatments can cause allergic reactions. For instance, in chronic venous disease (CVD) a leg ulcer may have a chronic course in which the patient is exposed to numerous wound dressings and topical medicaments [5]. The occlusive contact with barrier damaged skin has an increased risk of contact sensitization. The resulting hypersensitivity reaction is said to have a negative impact on wound healing and following future treatments or procedures for patients (type IV hypersensitivity) [1] [6].

Both type I and type IV hypersensitivity can play an important role in phlebological treatments. Type I hypersensitivity (immediate type) is an IgE mediated reaction, resulting in release of histamine and other mediators from mast cells and basophils, which might result in an anaphylactic reaction [7]. Type IV hypersensitivity (delayed type) is a cell-mediated immune reaction that is dependent on the presence of antigen-specific T cells, without the presence of specific antibodies. It results in a T-cell mediated inflammatory reaction, expressing as dermatitis of the skin [7].

There seems to be a knowledge gap concerning the safety issues of allergy-related events in phlebology. Adverse events as deep venous thrombosis and pulmonary embolism are reported, these are important but are no sign of a hypersensitivity/allergic reaction [8] [9]. This article aims to review the incidence and clinical relevance of hypersensitivity and/or allergic reactions in phlebological treatment. Medical online databases were used to identify articles on contact dermatitis and allergic reactions in VLU patients, allergic adverse events in sclerotherapy ([Fig. 1]) and in use of tumescent anaesthesia during endovenous laser ablation. A short survey was performed in medical centres in the Netherlands performing sclerotherapy and endovascular treatment. Also, the national database of adverse events was reviewed on the incidence of reported adverse events in use of sclerotherapy and tumescent anaesthesia.

Fig. 1 Flow diagram of studies.

Methods

Review

A literature search was conducted across Pubmed, MedLine and Embase, using the following terms: ‘leg ulcers’, ‘sensitization’, ‘contact dermatitis’ and ‘allergy’. Articles conform to the following requirements were included: 1) patients with venous leg ulcers, 2) a minimal of hundred patients with VLU were tested, and 3) a minimal of 24 allergens were tested. Articles were excluded if: 1) published before 1985, or 2) not written in English, or 3) case reports or congress abstracts ([Fig. 1]).

Survey

We invited dermatologists working in 37 Dutch hospitals, all eight university and 26 general hospitals (all Dutch “STZ” hospitals with additional specialized care) and three large independent sector treatment centers to take part in our survey. The goal of our survey was to investigate how often dermatologists had encountered allergic reactions to sclerotherapy and tumescent anaesthesia over the previous 10 years. Dermatologist in these centres performing phlebological treatments were invited personally. This approach led to a response rate of 100%. Three university hospitals had stopped performing venous treatments, leading to 34 eligible responses.

Type IV Allergy and Venous Leg Ulcers

The incidence of contact sensitization in VLU patients is significant and its importance seems to be underestimated. With testing, a type IV contact sensitization is seen in 4,2 up to 27% of the general population [10] [11]. It is often assumed that modern wound dressings, because of their hypoallergenic or anti-allergic properties and their comfort to patients, seldom cause allergic reactions. Since allergic reactions are reported in about 3–5% of patients, we only included studies in which at least 100 patients were tested in order to obtain proper information about prevalence of allergic reactions to wound dressings. This leads to the exclusion of 90 of the 98 studies, which might influence results. Seven of the 8 studies were performed in the last 20 years.
We think that sensitization to topical treatment for VLU is still frequent and, moreover, continues to increase, also for new products. In patients with VLU, the prevalence of sensitization seems to be higher than in general population, stressing the importance of potent allergens. One of the first studies describing this problem was published in 1973 by Malten showing sensitization in 76% of 100 patients with VLU [12]. More recent large studies showed a sensitization of 68% in 200 Scottish VLU patients in 2003 and 54% in 354 French VLU patients in 2015. These studies showed positive patch test results to at least one allergen [1] [13]. Prospective analyses were based on European Standard series and common antiseptic and medicament series were developed and used on VLU patients. These results correspond with other percentages in the literature ranging from 46% to 76% of contact sensitization in patients with a chronic leg ulcer [1] [2] [13] [14] [15] [16] [17] [18]. The increased risk at sensitization is probably the result of impaired barrier function and the use of (potential) contact allergens [16]. Dermatitis around an ulcer can be an irritant contact dermatitis (ICD) or an allergic contact dermatitis (ACD). A hypersensitivity for a wound dressing does not always cause ACD around the ulcer, so the absence of a dermatitis does not rule out a hypersensitivity. A type IV hypersensitivity is said to negatively impact the morbidity and the wound healing process [1] [6]. The rather high incidence in this population raises the question of the relevance of the sensitization. Some studies show a positive relation between type IV hypersensitivity and the frequency of ulceration or duration of the ulcerative disease or dermatitis around the ulcer. Two interesting cases that emphasize the importance to prove a hypersensitivity reaction, were reported in the above-mentioned study of Scottish patients. One woman with one-year duration of VLU and dermatitis was found to have a positive patch test to thiuram which is a rubber accelerator. Afterwards a rubber free treatment was started, and the ulcer was healed after six weeks [13]. In the other patient with a 4-month history of 3 leg ulcers a positive patch test for her wound dressing gel and corticosteroids was found. After removing these from her management the ulcers and dermatitis healed after 9 weeks. We summarized studies published in the English language with 100 or more patient with a leg ulcer diagnosed with venous insufficiency. Hypersensitivity for Balsam of Peru, Fragrance, Lanoline and antiseptics are seen most frequent in general and hypersensitivity to modern wound dressings such as hydrocolloids and Ialuset in more recent European studies ([Table 1]).

Table 1 Contact allergies in patients with venous leg ulcers (VLU) and arterial venous leg ulcers (AVLU), > 100 pat.

Auteur	Origin leg ulcer	Type study	N patients	N allergens tested	N (%) patients with sensitization to at least 1 allergen (%)	Top 3 allergens n (%)		Top 3 allergens Wound dressings allergens	Correlation and/or remarks
*Hydrocellular = mepilex, Biatain; + = correlation with leg ulcer
Malten KE, Kuiper JP [14] 1985 VASA	VLU	Retrospective	100	92	69 (69%) 57 (57%) 2 or more	Lanolin Fragrance PPD Wood tar	17 (17%) 14 (14%) 9 (9%) 9 (9%)
Tavadia et all [13] 2003 contact dermatitis	VLU	Observation	200	90	136 (68%) 102 (51%) 2 or more 36 (18%) 5 or more	Fragrance Lanolin alcohol Balsam of Peru Aminoglycosides	47 (23,5%) 33 (16,5%) 29 (14,5%) 29 (14,5%)	Intrasiter gel 19 (9,5%) Hioxylr cream 17 (8,5%) Trimovater cream 13 (6,5%)	Remark: control group was tested, no % are stated
Machet et al [2] 2006 BJD	leg ulcer + Meta-analysis data 1973–2003	Retrospective	106	36	80 (75%) 60 (57%) 2 or more	Balsam of Peru Lanolin Fragrance	42 (39,6%) 22 (20,8%) 19 (17,9%)	Triclocarban 14 (13,2%) Cetavlonr cream 10 (9,4% ) Betadine cream 8 (7,5%)	Remark: control group eczema sensitization 54%
Smart [15] 2008	VLU and AV leg ulcer	Prospective	100	38	46 (46%) 39 (39%) 2 or more	Wood tar Lanolin alcohol Balsam of Peru	21 (21%) 11 (11%) 10 (10%)
Barbaud et al [16] contact dermatitis 2009	Chronic: 55% VLU	Prospective multi-centre	423	62	308 (73%) 85 (20%) antiseptics	Balsam of Peru Fragrance Antiseptics	172 (40%) 112 (26,5%) 85 (20,1%)	Biafiner 36 (8,5%) Duoderm Er 17 (4%) Comfeel transparentr 6 (1,4%)	+ duration ulcer, + eczema (even if 57% + reaction without eczema) No relation with cause
Valois et al[1] 2015 Contact dermatitis	Chronic: 54% VLU 20% AV	Prospective multi-centre	354	64	211 (59,6%) 90 (25,4%) 2 or more	Balsam of Peru Fragrance Benzalkonium- chloride	84 (23,7%) 47 (13,3%) 25 (7%)	Ialusetr cream 45 (12,7%) Hydrocellular *28 (7,9%) Duoderm Er 18 (5,1%)	+ duration leg ulcer history No relation with cause, eczema or duration present ulcer
Rai et al [17] 2018 Int Wound J	VLU India	Prospective multi-centre	172	27	83 (48,2%) 59 (34,3%) 2 or more	Wood tar Framycetin Thiomersal Eosin	19 (10,4%) 16 (8,7%) 13 (7,1%) 13 (7,1%)		Not studied
Raudonis T [18] 2019	Chronic: 65% VLU	Retrospective	145	68	91 (62,8%)	Benzalkonium chl Balsam of Peru Povidone-iodine	27 (18,6%) 26 (17,9%) 25 (17,2%)		+ with pruritus/ eczema

The general top 3 is likely to be relevant for VLU patients, since Fragrance, Lanoline and Balsam of Peru are still used in both wound dressing and all kind of skin care products. Especially an allergy for Balsam of Peru is seen in all studies, while the prevalence of Lanoline seems to decrease, suggesting that Lanoline might be used less in modern wound dressings. In one study Balsam of Peru and Lanoline were not tested [17]. More studies are necessary to indicate hypersensitivity to modern wound dressings. A pitchfall for testing modern wound dressings is that there are so many different products of one “type” that it is difficult to calculate the prevalence of hydrocolloids. Because all these analogue products are slightly different manufacturers claim that their specific product, for instance a hydrocolloid, is not causing allergies. Allergy for Hioxyl cream ([Table 1]) is probably based on an allergy for (ceto) stearyl or cetyl alcohol, an ingredient of Hioxyl. Knowledge about the ingredients and the difference between contact allergies and eczema (hypodermitis) as a result of venous insufficiency is essential in treatment VLU and the underlying cause.
Up to now, even in recent European studies wood tar and eosin are part of the “standard ulcer test series”. Therefor this might not represent relevant allergens in Europe. These allergies were seen in one of the eight studies, this study was performed in India and only 27 allergens were tested. In the other studies, which were performed in Europe, these allergies were not found. This might suggest that these products are not used anymore, and in most cases not even approved in European countries.
In general, several studies show a relevant allergy to wound dressing in up to 20% of patients with VLU. Patch testing patients with VLU which do not show a healing tendency is there for strongly advised. We suggest that patients with VLU without a healing tendency within 3 months after starting therapy or VLU which have not healed within 6 months or with dermatitis around the ulcer should be tested to rule out hypersensitivity. In our opinion the standard ulcer test series should be modernized, since eosin, wood tar and thimerosal are not used anymore in Europe. Hypersensitivity to a certain product must be “translated” to clinical relevance. In VLU hypersensitivity is often underestimated, but knowledge of allergens, and use of these allergens in several wound dressings, requires both knowledge and experience.

Type I Allergy and Sclerotherapy

In Europe Lauromacrogol 400 (polidocanol) is predominantly used for sclerotherapy of varicose veins [19]. In the Netherlands in 1990 three cases were published with an “allergic reaction after sclerotherapy with lauromacrogol” [20]. Studying this article, it appeared that the first patient developed a cardiac arrest, the second patient showed signs of an adult respiratory distress syndrome, while the third patient developed cardiac ischemia complaints, all within 15 minutes after administration with polidocanol, so contrary to the articles title, these patients did not show any signs of hypersensitivity or allergic reaction. These case reports however, caused both an increased awareness but also apprehension amongst phlebologists. Although awareness increased, the number of hypersensitivity reactions still seem to be limited. At the Dutch registration centre for adverse drug reactions (Lareb) over the last 25 years only 17 drug reactions were registered: one male, fourteen female and two unknowns [21]. A drug reaction was registered in two persons under 20 years ([Fig. 2]). In these two patients lauromacrogol, was used probably for congenital venous malformations. Five registrations were immune related anaphylactic reactions: two “anaphylactic reactions”, two “hypersensitivity reactions” and one “anaphylactic shock”. It is not always clear whether these drug reactions are really the result of hypersensitivity or that a pseudoallergy is the cause of complaints. Since 1990 the number of allergic and/or adverse reactions that were reported national and international did not increase. The original article of 3 allergic reactions did not prove an allergic reaction, no intracutaneous test with lauromacrogol were performed, and two patients received polidocanol for the first time, which makes an allergic reaction very unlikely [20]. Knowledge about allergies and testing is importance to prove the cause of the drug reaction.

Fig. 2 Number of total adverse events in Lareb, including possible type 1 reaction (total of 17).

Our study showed that in 34 dermatology departments (5 university and 26 general hospitals and 3 large independent sector treatment centers) there were 3 patients with hypersensitivity reaction ([Table 2]). Urticaria and respiratory complaints after treatment were seen in 11 (32%) hospitals, once a TIA was described.

Table 2 Number of Dutch hospitals with adverse events to sclerotherapy and venous ablation/laser therapy with the use of tumescent in the period 2009–2019 (total 34 hospitals).

	University hospital (5)	Non-academic (26)	Independent sector treatment centers (3)
*not tested for type I or IV allergy **urticaria and pulmonary complaints
Anaphylactic reaction sclerotherapy	0	1	0
Other reaction to sclerotherapy	3*	7	2
Allergic reactions to tumescent	1*	0	0
Other reactions**	0	0	0

Urticaria is characterized by the development of wheals, angioedema or both. Wheals are sharply circumscribed superficial central swelling of variable size and shape with an itching and sometimes burning sensation, with the skin returning to its normal appearance, usually within 30 min to 24 h. Local reaction on injection site is seen when compression therapy is not directly started. This is mainly considered as irritative reaction and occasionally as mild urticarial reaction. The patients with a presumed hypersensitivity reaction were not additionally tested, so also in these patients an allergy is not proven.

In the European registration centre EudraVigilance (general website for Europe, but registrate patients worldwide) a total of 466 adverse events were registered: 336 female, 118 male, 12 unknowns ([Table 3]) [4]. Contact with EudraVigilance informed us about 30 patients with immune reaction, of which 25 in Europe ([Table 4]). One patient died, in combination with pulmonary embolism and the use of olanzapine, suggesting that there was not a type I allergy. Most adverse events of the last 5 years were not specific reactions, skin reactions and hyperpigmentation, phlebitis and DVT [4].

Table 3 EudroVigilance – Adverse events: the four largest groups and the group with possible anaphylactic reactions (immune system disorders) from 1995–2020.

	Age Group			Type Adverse Event
	< 18 yrs	18–64 yrs	65–85 yrs	Serious	Non Serious	Unknown	Total
*8 persons (26%) age unknown
General disorders, administration site	25 (15%)	105 (64%)	34 (21%)	105 (64%)	51 (31%)	8 (5%)	164
Skin and subcutaneous tissue disorder	27 (21%)	67 (53%)	33 (26%)	73 (57%)	39 (31%)	15 (12%)	127
Vascular disorders	11 (10%)	78 (68%)	25 (22%)	99 (87%)	12 (10%)	3 (3%)	114
Nervous system disorder	15 (14%)	73 (70%)	16 (16%)	78 (75%)	19 (18%)	7 (7%)	104
Immune system disorders*		15* (48%)	8* (26%)	4 (13%)	19 (61%)	8 (26%)	31

Table 4 EudroVigilance – Patients with type 1 reaction on lauromacrogol 400.

Type adverse event	Number of patients	Number of patients in Europe
Anaphylactic reaction	5 (17%)	5 (20%)
Anaphylactic shock	7 (23%)	6 (24%)
Anaphylactoid reaction	1 (3%)	1 (4%)
Anaphylactoid shock	2 (7%)	1 (4%)
Drug hypersensitivity	1 (3%)	0 (0%)
Eosinophilic granulomatosis with polyangiitis	1 (3%)	1 (4%)
Hypersensitivity	11 (37%)	9 (36%)
Type I hypersensitivity	2 (7%)	2 (8%)
Total	30	25

Tumescent anaesthesia (TLA)

With the introduction of laser therapy/venous ablation, the use of tumescent anaesthesia has increased tremendously in phlebological treatments. In tumescent anaesthesia a large volume of diluted concentration of lidocaine is infiltrated into a target fat compartment, originally used in liposuction and considered to be a safe procedure [22] [23]. TLA consist of prilocaine (or lidocaine) with Ringer solution (0,9% saline) and 8,4% bicarbonate. The total volume used depends on patient related factors, the volume of the treated area, and the use of epinephrine (1:1000). Now a days most phlebological procedures are performed with this type of anaesthetic and the use of tumescent in phlebological procedures is well known [24].

Hypersensitivity to local anaesthetics in general is often suggested, but seldom proved, although recently a type IV reaction on prilocaine was described [25] [26] [27]. Hypersensitivity to TLA can be caused both by the anaesthesia itself, as by the preservatives (paraaminobenzoic acid or PABA). Preservatives are more used in vials. Patch test can differentiate in the real cause of hypersensitivity. In international literature only a few articles can be found of adverse events and showed complaints like nausea [28]. Tumescent adverse reaction in plastic surgical procedures showed 1 death because of unknown cause (anaphylactic reaction was unlikely) [29]. Lidocaine toxicity is described using doses of 35 mg/kg [30]. The 15 mg/kg dose did not result in any symptoms of lidocaine toxicity. Lidocaine up to 28mg/kg seems safe [28]. Using TLA knowledge about both hypersensitivity and doses toxicity is essential.
In our study we also asked for adverse events when using tumescent anaesthesia. One hospital reported an adverse event the last 10 years with urticaria and respiratory complaints ([Table 2]).

NonThermal nontumescent (NTNT) intervention

Mechanochemical, proprietary endovenous microfoam and cyanoacrylatic adhesive closure are non-thermal treatments requiring no tumescent anaesthesia.

The use of cyanoacrylate intravenously (VenaSeal) seems to cause a ‘phlebitis like abnormal reaction’ (PLAR) in 5% –25% of the patients [31] [32]. In a study with 286 patients, reactions were described as mild (4,2%), moderate (1,3%) and severe (0,3%) [31]. An Asian study with 160 patients showed a PLAR reactions with erythema, swelling and serious complaints of pain in 25,4%. Since the phlebitis reaction was very extensive the authors suggest that a type IV reaction might be considered, and patients were treated with oral antihistamines and corticosteroids[32]. Type IV allergy for cyanoacrylate was seen in a 30 year-old patient, he was tested positive for VenaSeal and negative for other acrylates [33].
The high percentage of PLAR caused by cyanoacrylates may however suggest that this is the direct result of the vasoactive substance causing an immunological reaction (activating the transient receptor potential melastin 8 (TRPM8) rather than a hypersensitivity reaction. Future study on the relation of PLAR and hypersensitivity reactions type I and IV might give more insight into a possible relationship between the two. Until that time, it may be advisable to ask if there is a history of sensitivity or skin reactions to tissue glues, or adhesives, and test further only if there is a strong history.

Conclusion

Type I hypersensitivity reaction with anaphylactic reaction to sclerosing fluid or foam is very rare and has to our knowledge never been confirmed with intracutaneous tests. Most serious but very rare adverse advents are cardiac and vascular events (DVT with PE). Other adverse events such as urticaria, respiratory complaints are seldom mentioned or described.

Type I hypersensitivity to TLA in phlebological treatment have not been reported officially and only one (urticaria and respiratory complaints) in our study. The chance to develop a hypersensitivity reaction to anaesthetics is therefore negligible. A type IV hypersensitivity might be possible and is more likely be caused by preservatives than by anaesthetics itself. Using TLA, this knowledge about both hypersensitivity and dosage is necessary. Acrylates seem to cause a severe phlebitis reaction (PLAR) in the treatment of varicose veins. More studies should be performed to shed some light on this reaction.

A type IV hypersensitivity in VLU and chronic leg ulcers seems to be an underestimated problem, and causes delay in wound healing treatment, even with the absence of clinical signs of dermatitis. When inflamed skin around a venous ulcer is subjected to a variety of subsequent wound dressings there is an increased risk of developing an ICD or ACD. This will influence the healing tendency negatively. In patients with VLU that show no healing tendency within 3 months after initiation of therapy, or leg ulcers that have not healed within six months or leg ulcers with dermatitis additional patch testing should be considered.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

The authors would like to thank Marlieke Sonnenberg and Jeltje Boer for the help and data collection from both Lareb and EudraVigilance. The datasets analysed during the current study are available from the corresponding author on reasable request.

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Publication History

Article published online:
17 October 2022