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.
