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Insights into hypersensitivity reactions in dentistry

Article  in  Porto Biomedical Journal · November 2020

DOI: 10.1097/j.pbj.0000000000000090

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 Review Article
OPEN

Insights into hypersensitivity reactions in

dentistry
Tiago Azenha Rama, DMD, MDa,b,∗, Josefina Cernadas, MDa,c

Abstract
Hypersensitivity reactions are an important hazard in healthcare. Modern dentistry depends on the use of drugs and materials widely
known to elicit them. Such reactions are either immediate or nonimmediate – the former carries the risk of anaphylaxis, whereas the
latter includes potentially fatal severe cutaneous adverse reactions.
Apart from well-established immunoglobulin E–mediated immediate hypersensitivity reactions (IHRs), recent advances have shed
Downloaded from http://journals.lww.com/pbj by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 12/11/2020

light on the pathophysiology of other IHRs, suggesting a role for MRGPRX2-induced mast cell activation.
Hypersensitivity to both drugs and metals may come as a challenge to dentists, often requiring changing to infrequently used
compounds. Local anesthetics are cause for concern, but are a rare cause for IHRs. The opposite occurs with antimicrobials, as
antibacterials frequently cause hypersensitivity reactions. Nonsteroidal anti-inflammatory drugs are another common cause,
especially in patients suffering from asthma and/or chronic spontaneous urticaria. General anesthetics are a common cause for
immediate hypersensitivity, whereas most drugs used for conscious sedation are rare elicitors. Chlorhexidine is a remarkable cause
for anaphylaxis, nowadays, despite rare reports linked to rinsed formulations.
Preservatives, flavors, and other compounds present in dentifrices cause both irritative and allergic contact dermatitis/mucositis.
Metals, notably nickel and cobalt, are a very common cause for hypersensitivity in dentistry. Acrylates may induce contact mucositis,
due to lack of proper polymerization of residuals, being an important cause for contact stomatitis and a dentistry occupational hazard.
Acute reactions require a prompt treatment, especially in the presence of anaphylaxis, which should be treated using intramuscular
epinephrine. Delayed type reactions with fever should be referred to tertiary urgent care facilities. Suspicion of hypersensitivity in
dentistry requires a thorough allergological study and referral is mandatory in all cases.
Keywords: allergy, contact allergy, dental materials, drug hypersensitivity

Introduction drugs (NSAIDs) and opioids] and antibacterials, which rival

each other for the number 1 spot for drug hypersensitivity
Practice of modern dentistry relies on the use of multiple drugs
culprits.
and different dental materials either with or without prosthetic
Although less frequently than drugs, dental materials are
purposes. Hypersensitivity reactions may arise from the use of
known to elicit hypersensitivity reactions.4 Although drugs can
both drugs and materials, being categorized according to Gell and
induce all 4 types, materials are mostly elicitors for type IV
Coombs hypersensitivity classification.1 Types I and IV are the
hypersensitivity.5 Metals are the most frequent allergen, but
most frequent, but, however rare, types II and III may also occur.2
acrylates, epoxy resins, and others have also been found to elicit
Modern classification distinguishes type I/immediate hypersensi-
hypersensitivity reactions in the oral cavity.4
tivity reactions (IHRs) from the remainder nonimmediate
This review aims to go through the current knowledge on
hypersensitivity reactions (NIHRs), as only the former carries
hypersensitivity to drugs and materials used in dentistry.
risk for anaphylaxis.3 Dentists daily prescribe analgesics
[paracetamol/acetaminophen, nonsteroidal anti-inflammatory
a
Drug hypersensitivity
Serviço de Imunoalergologia, Centro Hospitalar Universitário de São João,
b
Serviço de Imunologia Básica e Clínica, Departamento de Patologia, Faculdade Risk factors
de Medicina da Universidade do Porto, c Unidade de Imunoalergologia, Hospital
Lusíadas, Porto, Portugal. Risk factors for hypersensitivity to drugs are still a matter of
∗
Corresponding author. Serviço de Imunoalergologia – Centro Hospitalar
debate.6 These may be related to the patient or to the drug.
Universitário de São João, 4200-319 Porto, Portugal. E-mail address: Patient-related risk factors include age – adults are more
tarama@med.up.pt (Tiago Azenha Rama). frequently affected, when compared to children2 –, gender –
Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on adult women are more prone to report drug hypersensitivity
behalf of PBJ-Associação Porto Biomedical/Porto Biomedical Society. All rights reactions2, while prevalence may be similar among genders in
reserved. children6 –, prior history of drug hypersensitivity - both
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
structurally-related and -unrelated drugs, namely in patients
ND), where it is permissible to download and share the work provided it is with the so called “multiple drug hypersensitivity syndrome”7 –,
properly cited. The work cannot be changed in any way or used commercially familial history of drug hypersensitivity8 – concurrent infectious
without permission from the journal. disease – e.g. cotrimoxazole hypersensitivity in HIV patients and
Porto Biomed. J. (2020) 5:6(e090) the so called “ampicillin rash” in patients suffering from EBV-
Received: 16 June 2020 / Accepted: 6 September 2020 caused mononucleosis6 –, hereditary traits – e.g. Human
http://dx.doi.org/10.1097/j.pbj.0000000000000090 leukocyte antigen (HLA)-DRA single nucleotide polymorphisms

1
Rama and Cernadas Porto Biomed. J. (2020) 5:6
and hypersensitivity to penicillin9 or polymorphisms involving
enzymes responsible for drug metabolism.6” Despite being quite
often overlooked in the literature, mastocytosis and other mast
cell (MC) diseases seem to be a risk factor for immediate
hypersensitivity or even anaphylaxis to some drugs, such as
NSAIDs, or drugs used in the perioperative period.10 Other
chronic conditions, such as cystic fibrosis, malignancies,
autoimmune diseases, chronic kidney disease, and cardiovascular
disease may also pose as risk factors for drug hypersensitivity.6
Some drug classes seem to be more prone to elicit
hypersensitivity than others, for both immunoglobulin E (IgE)-
and non–IgE-mediated IHR and for NIHR.11 Other factors
include route of administration – transdermal sensitization and
the intravenous administration is more often than per os, the
length of treatment – especially when high doses are used – and
posology – intermittent or repeated administrations seem to
increase risk for reactions.12 Simultaneously intake of multiple
drugs may also pose as a risk factor for drug hypersensitivity,
while also generating diagnostic difficulties.6
Mechanisms and clinical manifestations
IHR result from activation of MCs and, or basophils through
immune (ie, IgE linkage to FceRI), or nonimmune mechanisms
(eg, MRGPRX2 activation). Following activation, these cells
release a myriad of vasoactive and inflammatory mediators which
may induce mucocutaneous – pruritus, urticaria, and angioe-
dema; gastrointestinal – vomiting and diarrhea; respiratory –
rhinitis, laryngospasm, and bronchospasm; and cardiovascular
manifestations – hypotension, syncope, and shock. Depending on
the route of administration and gastric content (if ingested), these
reactions can occur minutes up to 6 hours, following exposure to
the drug.13
Amongst NIHR, type IV reactions are by far the most
common, being characterized by T cell involvement.3 These are
lettered IVa to IVd according to the type of cellular involvement.
Reactions arise hours up to several days after exposure to the
drug. Most common manifestations include mild maculopap-
ular exanthems, but severe, even life-threatening reactions [eg,
Steven-Johnson syndrome (SJS) and drug reaction with
eosinophilia and systemic symptoms (DRESS)] may also occur.3
Differential diagnosis of subtypes is frequently hard to achieve,
as more than 1 can manifest simultaneously.14 The major cells
involved in subtype IVas are macrophage/monocytes, being
Th1-mediated and manifesting as eczema.14 IVbs mainly
involve eosinophils, are T2 driven, and mostly present as
maculopapular exanthems, but occasionally with hepatic,
renal, respiratory, or cardiac involvement; fever; adenomega-
lies; and malaise, with associated peripheral eosinophilia, in
DRESS.15 Like IVa, IVc reactions occur mostly together with
other subtypes of NIHR. Subtype IVcs are mediated by
cytotoxic T cells that may cause isolated hepatitis, nephritis,
or even severe life-threatening bullous exanthems – SJS/toxic
epidermal necrolysis (TEN).14 Subtype IVd reactions result
from neutrophilic inflammation, being mediated by Th17 cells
and presenting as the so called acute generalized exanthematous
pustulosis (AGEP).16
Types II and III reactions usually occur several days after
exposure and manifest as hemolytic anemia, thrombocytopenia,
or neutropenia in the former and serum sickness, Arthus
reactions, or vasculitis in the latter case.3
Although drugs can induce all 4 types of hypersensitivity,
materials are mostly elicitors for type IV hypersensitivity.
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Dental material hypersensitivity
Risk factors
Virtually every xenobiotic compound can sensitize the skin and
generate contact hypersensitivity. Albeit less consensual than
drug hypersensitivity, risk factors for dental material hypersensi-
tivity have also been proposed and include those related to the
patient and to exposure. Similar to type IV drug hypersensitivity,
sensitization may occur due to a long exposure.17 Occupational
exposure is therefore a very important risk factor.18 However, in
dentistry this bears significant importance, since patients carry
the potential allergen either permanently (eg, dental restorations/
fillings, implants, fixed prosthetic elements, and orthodontic
appliances) or during long periods (eg, removable dentures and
orthodontic appliances). Also, there seems to be a direct
correlation between area of exposure and sensitization, and
between dose and sensitization.17 Patient-related risk factors
overlap those described for drug hypersensitivity, namely age and
sex.17 Several genetic factors are important, namely those related
to skin barrier dysfunction (eg, filaggrin mutations).17,19
Mechanisms and clinical manifestations
Although all subtypes of type IV hypersensitivity may be involved
in reactions, involvement of specific subtypes are often difficult to
establish.20 Th2 and Th17 cells seem to be less important in this
case.21 Mainly in the case of nonmetallic materials, one should
keep in mind that many compounds elicit inflammatory, rather
than hypersensitivity reactions, these are irritant contact
dermatitis/mucositis.22 Such is the case of hydrogen peroxide
and carbamide peroxide contained in dental bleaching products.
Also, ill-fitted dentures and irregular dental restorations/
obturations may produce irritative mucositis that is unrelated
to the material in question.
Although metal hypersensitivity (eg, nickel, cobalt) seems to
manifest more often as oral lichenoid reactions, nonspecific
stomatitis, and perioral dermatitis, other manifestations such as
gingivitis or lip angioedema may occur for other materials.20
Moreover, hypersensitivity reactions may also involve distal
regions of the body (eg, palmoplantar pustulosis,23 genital
lichenoid reactions).24 Although scarcely supported by strong
evidence, other oral manifestations such as recurrent aphthous
ulcers, burning mouth syndrome, and benign migratory glossitis
have also been linked to contact allergy to dental materials.22
Hypersensitivity to drugs used in dentistry
Local anesthetics
The molecular structure of local anesthetics (LAs) includes a
lipophilic aromatic ring bound to a hydrophilic amine group, by a
radical chain that may be either ester or amide, hence
classification into ester- and amide-type LA.25
In the past, ester-type LAs (eg, benzocaine, procaine) were
associated with frequent IHR, as they are metabolized into p-
aminobenzoic acid, a substance known for its allergenicity.26
However, since the use of ester-type LA has decreased, immune
and nonimmune IHR caused by LA became extremely rare.27 In
fact, amide-type LAs (eg, lidocaine, mepivacaine, articaine) are
not metabolized into p-aminobenzoic acid, being safe alter-
natives.25 However, anecdotical cases of IHR reactions due to
amide-type LAs have been reported.26,28–33 Nonetheless, the
number of cases with positive skin prick and intradermal tests is
considerably lower than that of overall reported cases.34,35
Rama and Cernadas Porto Biomed. J. (2020) 5:6
Studies have shown that skin tests are often falsely positive, as
shown following a negative subcutaneous drug challenge.36 Most
adverse reactions following the administration of injectable
formulations can be caused by emotional stress.34,37 There may
in fact be an individual susceptibility for such reactions resulting
from a specific hyperexcitability of peripheral nerve.34 True
allergy can be due to preservatives and antioxidants contained on
LA preparations, such as parabens, metabisulfite, or even latex
residues from rubber stoppers and diaphragms in dental
cartridges.26,38–40 As opposed to ester-type LA, cross-reactivity
among amide-type LA is uncommon, usually deriving from
common preservatives.41 In exceptional cases in which allergy to
1 amide-type LA is demonstrated, drug challenges should be
performed using alternative amide-type LA.42 Successful use of
diphenhydramine as alternative local anesthetic for oral
procedures has been reported, making it a potential alternative
for patients with demonstrated LA immediate-type hypersensi-
tivity.43
In contrast to IHR, NIHR to LA are not uncommon.34,44,45
The international standard patch testing series contains a “caine
mixture,” for which patients often test positive.44,45 However,
this mix includes ester-type LAs. Nonetheless, positive lympho-
cyte transformation tests to LAs have been found.46 Studies show
that lidocaine is the most frequent culprit for NIHR reactions,
followed by mepivacaine.34,47,48 Crossreactivity with other
amino acyl derivatives, like prilocaine and bupivacaine, is often
present,49–51 and has not been reported with articaine,31,51–53 so
far. As patch testing with lidocaine often generates false positive
results, intradermal tests, and subcutaneous challenges are
recommended to assess systemic tolerance.45
Nonsteroidal anti-inflammatory drugs and paracetamol
NSAIDs are widely used as analgesics in dental practice,54 being
known to cause IHR in susceptible patients.55
NSAIDs exert their action through the inhibition of prosta-
glandin (PG) synthesis by the cyclooxygenases (COX) 1 and 2.
Underlying restrained expression of PG E2 is thought to allow the
production of leukotrienes,56 as this PG is thought to have a
inhibiting effect on the production of cysteinyl-leukotrienes (Cys-
LTs), through inhibition of the expression of LTC4 synthase.57
The resulting overproduction of Cys-LTs is thought to derive
mostly from COX-1 inhibition and may lead to exacerbation of
existing chronic airway disease – NSAIDs-exacerbated respira-
tory disease or chronic spontaneous urticaria – NSAIDs-
exacerbated cutaneous disease.58,59 Furthermore, hypersensitivi-
ty to NSAID may also manifest as urticaria and/or angioedema,
in patients without chronic cutaneous conditions.58,59 Genetic
polymorphisms have also been associated with such reactions.60
Patients who react to several NSAIDs through this pathway are
called multiple reactors. Although not as common, some patients
– single reactors – display immediate reactions to 1 drug/1 group
of drugs, which are probably IgE mediated.58,59
Paracetamol (acetaminophen) is excluded from the NSAID
group, in the anatomical therapeutic chemical classification
system of the World Health Organization (ATC-WHO), because
it is thought to inhibit central nervous system COX,61 being
known to exert limited effects on peripheral COX-1 and -2.62,63
Few studies showed that up to 34% of NSAIDs-exacerbated
respiratory disease patients may present mild bronchospasm
following the administration of paracetamol dosages above the
therapeutic dosage of 1000 mg.64 This occurrence seems to be
common in patients which are particularly susceptible to aspirin,
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occurring in 2% of cases,65 and may result from a high-dose
paracetamol-provoked inhibition of COX-1.55 IgE-mediated
reactions to paracetamol have also been reported.66
Patients with mastocytosis were classically considered to be
prone to NSAID hypersensitivity. However, preliminary data
from the Spanish Network on mastocytosis has shown that
prevalence of such reactions is around 12% in adults and 5% in
children/adolescents.67
NIHR to NSAIDs have been described, but their prevalence,
although mostly unknown, is thought to be much lower than that
described for IHR.59,68
Antimicrobials
Antibacterials from different classes are used in dentistry for
preoperative prophylaxis and treatment of oral/odontogenic
infections.69
PN and aminopenicillins, such as ampicillin and amoxicillin,
are both the first-line treatment for most indications70 and the
most frequent cause for IHR to antibacterials. Allergy to PN and
other b-lactams has been thoroughly and widely studied, with a
self-reported prevalence of about 10%.71 However, in 90% of
self-reported PN allergy, IHR is excluded following a correct
work up study.72 Nonetheless, PN may be responsible for up to
75% of fatal cases of anaphylaxis, in the United States.41 Major
and minor antigenic determinants arise from the breakdown of
PN: 95% of PN is transformed into the major antigenic
determinant, the penicilloyl moiety, and only 5% is transformed
into penilloate and penicilloate, which alongside PN itself
constitute the minor determinants.73 Less frequently, the side
chain radical may be the allergenic determinant. This may induce
IHR to aminopenicillins without crossreactivity with other
PNs,74 while displaying crossreactivity with first- or even
second-generation cephalosporins, such as cephalexin, cefa-
droxil, cefaclor, or cefprozil.75–77 In fact, crossreactivity among
cephalosporins and PNs is often referred to as an issue to keep in
mind when prescribing, in most cases, due to sensitization to side
chains.77 However, many cephalosporins, such as cefuroxime,
ceftriaxone, cefepime, cefotaxime, ceftazidime, and cefazolin do
not share the aforementioned side chain radical and may be used
as alternatives to aminopenicillins or PN, when a broader-
spectrum antibacterial is required.77
Other antibacterials are often prescribed empirically, or when
there is allergy/ suspected allergy, or even resistance to PNs.70
Allergy to tetracyclines (tetracycline, doxycycline, minocy-
cline) seems quite rare, with minocycline being the most frequent
culprit.78 However, crossreactivity among tetracyclines seems to
be common.78 Several isolated case reports of both IHR (urticaria
and anaphylaxis) and NIHR (SJS/TEN, fixed drug eruptions)
have been described.78 Minocycline has been found to be a
frequent cause of DRESS.16 As such, its use in systemic therapy of
periodontitis should be thoroughly pondered and the use of
doxycycline should be preferred.
The prevalence of allergy to clindamycin has not been well
established, being described as ranging from <1% up to 10%.79
Cutaneous reactions are present in most allergic reactions.80
Prevalence of IHR to fluoroquinolones may round 1:1000
cases.81 Moxifloxacin may be the most frequently implicated,
followed by ciprofloxacin.82 Crossreactivity between different
fluoroquinolones seems to be rare, but has been reported.83 These
drugs are thought to possess the ability to directly activate MCs in a
small number of patients, potentially through MGPRX2 activation,
as some cases of IgE-independent reactions have been reported.84
Rama and Cernadas Porto Biomed. J. (2020) 5:6
Allergic reactions to macrolides are exceedingly rare and
are usually restricted to urticaria.85 Erythromycin has been the
most frequently implicated drug, followed by spiramycin, and
azithromycin.85 Although cross-reactivity is thought to be
inexistent among macrolides, irrespective of their chemical
structure, the only evidence that supports this claim comes from
case reports.86
Like macrolides, allergy to metronidazole seems to be quite
rare.87 Dentists often prescribe topical (nystatin, clotrimazole,
miconazole) and systemic (fluconazole, itraconazole) antifungals
for the treatment of oral candidiasis. Allergic reactions to
antifungal agents are considered to be uncommon. A study
conducted on 1254 German patients showed that <1% suffered
from contact sensitivity following the administration of topical
antifungals.88 No crossreactivity was reported, even between
antifungals from the same group.88
In dentistry, antivirals are mostly used for the treatment of oral
infections caused by the Herpesviridae family – zoster and herpes
simplex. Hypersensitivity reactions are rare. Acyclovir is a rare
elicitor of IHR reactions, being most often responsible for NIHR
reactions.89 However, these effects may become a problem to the
clinician since crossreactivity with famciclovir and valacyclovir
seems to be common.90 Foscarnet and cidofovir may potentially
be used as alternatives, but a stronger evidence on this claim is
necessary.90
Opiates and opioids
Opiates and opioids are widely used in dentistry, for pain
control.91 The administration of some opioids is acknowledged
to carry the risk of nonimmune anaphylactic reactions.92
Codeine, one of the most prescribed opiates in dentistry, seems
to display the strongest MC degranulation potential, followed by
morphine and meperidine.93 These effects may be dose
dependent.94,95 Fentanyl and other piperidine-derived synthetic
opioids seem to be safer, inducing no more than a slight
activation of MC and minor histamine release.93,94 The
mechanism through which opioids activate MC is still unclear
and may be multifactorial, probably resulting from activation of
d-receptors, present on MC membrane.94
Although less frequent, IgE-mediated IHR to opiates and
opioids have been reported.96 Crossreactivity between opiates
and opioids seems to be low.96
Contact dermatitis to opiates has also been described, but may
be infrequent.97
Drugs used on general anesthesia and sedation
Although general anesthesia may be provided by dentists in
North America,98 in Europe dentists only provide conscious
sedation, using nitrous oxide99 and/or hypnotics.100 Currently,
general anesthesia for dental procedures usually requires the use
of several drugs. Some of these drugs have been reported to cause
direct MC activation, whereas others are frequently involved in
IgE IHR.
Neuromuscular blocking agents (NBMAs) are, by far, the most
frequent cause for perioperative anaphylaxis.101,102 Overall,
incidence for NBMA-related anaphylaxis is 1 in 6500.103 These
may induce both IgE-mediated IHR and direct MC activation.104
Succinylcholine, atracurium, and rocuronium display the highest
potential to cause IgE-dependent reactions.101,105 Interestingly,
succinylcholine and isoquinoline-type NBMA, such as cisatracu-
rium display the lowest potency for direct MC activation.104,106,107
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Aminosteroids such as vecuronium, rocuronium, pancuronium,
and rapacuronium are thought to have an intermediate potency for
MC activation.104 Benzylisoquinolinium NBMAs, such as atra-
curium108 and mivacurium, have the highest potency for MC
activation.104 Although crossreactivity among different NBMA
groups is not that frequent, aminosteroids and benzylisoquinoli-
niums display a high crossreactivity with drugs within their
respective groups.109 As such, alternative NBMA should be sought
in distinct groups.
Intravenous induction drugs have been also been related to
both immune and nonimmune anaphylactic reactions. In vitro
studies suggest that propofol, thiopental, and ketamine may
induce differential release of histamine in both cutaneous and
pulmonary MCs.110 Propofol is currently prepared with soybean,
egg lecithin, and glycerol. However, its use seems to be safe in
both soybean- and egg-allergic patients.111 Incidence of anaphy-
lactic reactions to the current formulation is 1 in 60,000.43
Although positive skin tests have been reported for thiopental,102
IgE-dependent IHR are considered rare.41 Anaphylaxis to
ketamine and etomidate is considered rare, and has not been
reported on recent studies.101,102
Midazolam and other benzodiazepines (BZPs) are generally
considered safe drugs in what concerns direct MC activation, and
are even indicated on the premedication of patients with MC
disorders.112 MCs have been shown to possess high affinity
binding sites for BZPs.113,114 Moreover, experimental studies
have suggested that BZPs may inhibit MC proliferation and
activation.115 Exceedingly rare IgE-dependent reactions to these
drugs have been described.116
Currently used inhaled general anesthetics are considered to be
devoid of MC activation potential and IgE-mediated reactions
have not been described.41,117
Chlorhexidine
Chlorhexidine (CHX) is widely used in dentistry due to its broad-
spectrum antiseptic properties, being present on mouthwashes,
sprays, toothpastes, gels, and varnishes.118 Despite its wide-
spread use, CHX hypersensitivity is uncommon, although often
overlooked.119 The whole CHX molecule has been shown to
constitute the allergenic determinant.120
Reports of both anaphylaxis and contact dermatitis have
increased in the past few years,118 with prevalence of CHX-
related perioperative hypersensitivity reactions reaching 8% to
10%.121 Sensitization is believed to occur mostly during
transcutaneous/transmucosal surgery/procedures,119,121 but
may derive from oral use, although less frequently.122
NIHR elicited by CHX are more prevalent than anaphylax-
is.122,123 Cases with concomitant types I and IV hypersensitivity
reactions have also been described.119 Hypersensitivity to CHX
mouthwashes may manifest locally (eg, stomatitis) or distally (eg,
abdominal and facial urticaria).22
Glucocorticoids
Glucocorticoids are widely used in oral medicine for the
treatment of inflammatory oral diseases (eg, recurrent aphthous
stomatitis)124 and oral manifestations of systemic inflammatory
diseases (eg, lichen planus)125 and in oral surgery for prevention
of postoperative inflammation.126
Although infrequent, both IHR and NIHR to glucocorticoids
have been described.127 Although intravenous and intra-articular
routes have been shown to be most implicated in IHR, topical
Rama and Cernadas Porto Biomed. J. (2020) 5:6
cutaneous route is by far the most frequent for NIHR.127
Hydrocortisone and methylprednisolone are the most often
involved drugs for both IHR and NIHR.128
Glucocorticoids may be grouped according to their allergenicity,
into 3 groups – group 1 includes budesonide, hydrocortisone,
prednisolone, and methylprednisolone; group 2 includes triamcin-
olone; group 3 betamethasone, clobetasone, and dexametha-
sone.128 For IHR reactions, crossreactivity is vastly unknown,
whereas group 1 and especially methylprednisolone and hydro-
cortisone, seem to crossreact. For NIHR, 2 distinct patients profiles
have been proposed: those allergic only to group 1 and those
allergic to all glucocorticoid molecules.128 Although the former
profile requires avoidance of only group 1, the later requires a more
thorough study, that may include several drug challenges, until one
tolerable glucocorticoid is found.128 Stomatitis has been reported
for both topic and inhaled formulations.129
Dental materials and other allergens
Latex
Despite growing knowledge on its allergenicity, use of latex is still
widespread in dentistry. It may be present in gloves, endodontic
rubber stoppers, rubber dams, orthodontic rubber bands, face
masks with latex ties, mixing bowls, bite blocks, anesthetic
cartridges, and so on.130 Patients submitted to surgery at a very
early age (eg, spina bifida), health care and latex industry
workers, patients submitted to multiple surgeries, and atopic
individuals show a higher risk for latex IHR.131 However,
specific risk factors differ depending on the components to which
the patient is sensitized and genetic factors may also play a
role.132 Those allergic to latex may display the so called latex-
fruits syndrome caused by crossreactivity between latex and fruit
components – Hev b 6, with banana, avocado, and chestnut; Hev
b 5 with kiwi; and Hev b 7 with potato or eggplant.133 IHR
caused by latex may range from mild rhinitis to anaphylaxis.133
On the contrary, latex also causes type IVc not due to the
aforementioned components, but rather to additives and
accelerator compounds used in its manufacturing.134
Alternative materials should be used whenever latex allergy is
suspected. However, alternative materials, such as vinyl, or nitryl
display a less favorable elastic modulus, which may be significant
namely in orthodontics.135
Other oral hygiene products
Toothpastes and mouthwashes contain a wide variety of
flavors, fragrances, preservatives, adjuvants, and fillers that
allow the active substance to exert its action. Despite the fact
that the prevalence for allergy to these oral hygiene products has
not been established, these are considered to be relatively
common causes for both allergic and irritative contact
stomatitis and cheilitis.136 Flavors (eg, essential oils, cinnamon)
are the most frequently involved components in contact
reactions.20,137 Also, rare cases of IgE-dependent anaphylaxis
have been described.138 Although underreported in the
literature, hypersensitivity reactions may develop following
use of products containing iodopovidone, eugenol, cow milk
proteins, and ethanol, among many others.
Metals
Metals are a vital component of prosthodontics, both tooth- and
implant-supported, and orthodontics. Among those used in
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dentistry, chromium, cobalt, and nickel deserve special attention,
because they are widely used in removable (ie, partial/total acrylic
resin dentures or skeletal dentures) and fixed prosthodontics (ie,
crowns and bridges). Two of the most used metals, nickel and
cobalt, are consistently referred to as the most frequent elicitor,
and one of the top 15 most frequent elicitors of contact
dermatitis, respectively.57 In the oral cavity, hypersensitivity to
metals is also common, namely in women,57 and mostly
manifests as oral lichenoid lesions.22 Although often used as
alternatives, hypersensitivity to gold, molybdenum,139 titani-
um,140 or even zirconium21 has been described, being especially
common for gold.141
Acrylic resins
Acrylic resins are present in a wide number of dental appliances
such as partial/complete removable dentures, orthodontic
appliances, and temporary crowns, among others. Prevalence
of contact allergy to acrylates rounds 1% in general popula-
tion,57 having been reported to be the main cause of occupational
allergic dermatitis in dental health workers.4
Acrylic resins are available as a powder/solid prepolymerized
polymethacrylate that is to be mixed with liquid methacrylate
monomers, before shaping, to obtain a rigid and fitted acrylic
polymer.142 Polymerization may occur through chemical activa-
tion following simple mixture of liquid and solid components, as
in self-cured resins, or following exposure to a physical activator,
that is, heat, or UV light.142 Contact stomatitis to acrylic resins is
mainly caused by unpolymerized methacrylate monomers, being
most frequent with self-cured materials.143 Such reactions are
usually mild, and most patients tolerate appliances, following
proper polymerization.4 There are, however, exceptional cases in
which symptoms persist, requiring the use of alternatives
materials (eg, polyamide).144
Composites and epoxy resins
Composite resins and other epoxy resins are widely used in
restorative dentistry, both as restorative and adhesives, and
cements in orthodontics and prosthodontics. Several monomers
take part in these materials, most of which are methacrylates – for
example, bisphenol A-glycidyl methacrylate (bis-GMA), ethoxy-
lated bisphenol A-glycol dimethacrylate, triethylene glycol
dimethacrylate, hydroxyethyl methacrylate, and urethane dime-
thacrylate.145 Bis-GMA is the most widely studied, with a
sensitization prevalence rounding 1.8%.57 However, many other
compounds may be included in composites, namely quinones,
eugenol, and formaldehyde all of which are known elicitors for
contact stomatitis.146
Approach to suspected drug hypersensitivity in the
dental office
Both immune- and nonimmune-mediated IHR usually occur
seconds to 60 minutes postexposure. However, in some patients,
reactions may occur up to 6 hours. Furthermore, following an
initial episode, patients may suffer from a later recurrence, with
variable severity.147 Clinical findings are usually quite suggestive,
since they often present with a local or generalized pruritus,
accompanied by urticaria, or even angioedema. These may be
accompanied by bronchospasm with wheezing, laryngeal edema
with stridor, emesis, crampy abdominal pain, diarrhea, syncope,
or even anaphylactic shock, caused by a generalized vasodila-
Rama and Cernadas Porto Biomed. J. (2020) 5:6
tion.148 Diagnosis of anaphylaxis is established in the presence of
(1) urticaria/angioedema joined by respiratory symptoms, or
cardiovascular symptoms; (2) involvement of 2 systems in any
combination of mucocutaneous, respiratory, cardiovascular, or
gastrointestinal symptoms; or (3) reduced blood pressure;
following exposure to a plausible allergen.149 Any of these
should prompt the administration of epinephrine, through
intramuscular injection on the lateral aspect of the thigh, of a
1:1000 formulation (1 mg/mL), on a dosage of 0.01 mg/kg. This
procedure may be repeated twice and the patient should always
be referred to the emergency room. Serum tryptase levels should
always be assessed.
NIHR manifest in distinct timings, according to their specific
type. Maculopapular exanthems may manifest in the first day,
hours after the last administration, or even after suspension of an
antibiotherapy course. Severe cutaneous adverse reactions
usually occur later, occurring 4 to 28 days following drug
exposure, for SJS/TEN, usually 2 to 6 weeks for DRESS, and 1 to
11 days for AGEP.150 Clinical findings may be quite specific, but,
aside from fever which commonly occurs in all of them, they are
not always easy to find. SJS and TEN manifests as variable skin
detachment, usually with bullae and may involve mucous
membranes. AGEP is characterized by the presence of widespread
nonfollicular sterile micropustules. Cutaneous characterization
for DRESS may be more difficult to define, as it may manifest
with erythroderma, facial angioedema, maculopapular rash, or
even purpura. Mucous membranes may also be involved. DTH
usually require a thorough investigation and may require
hospitalization. However, in an outpatient clinic setting,
suspected drug(s) should be stopped immediately. As a rule, all
suspected NIHR with fever should be urgently referred to a
tertiary care facility, where differential diagnoses (eg, viral
exanthems, chronic spontaneous urticaria, erythema multiforme,
burns, cytotoxic effects, and acute graft-versus-host disease)
should be considered.150
When there is a suspicion for drug hypersensitivity, patients
should be tested for potential allergens. Positive drug provocation
tests remain as the criterion standard for the diagnosis of drug
hypersensitivity.151 However, this procedure is not risk free and
there are situations in which it is contraindicated – SJS/TEN,
DRESS, drug-induced organ injury (cytopenias, pneumonitis,
hepatitis, and nephritis), vasculitis, and serum sickness–like
reactions.152 In such situations, when there is a suspicion of an
IgE-dependent mechanism, the diagnosis may be based on skin-
prick testing, intradermal testing, and specific serum IgE dosing.
Clinical symptoms compatible with DTH reactions should be
assessed through late-reading intradermal tests, patch testing,
and/or lymphocyte transformation tests,153,154 except for SJS/
TEN in which intradermal tests are considered contraindi-
cated.155
Hypersensitivity reactions to materials should be studied
through patch testing and, when confirmed, should prompt
removal of the offending material. The dental series used for
patch testing usually includes amalgam, amalgam alloying
metals, ammoniated mercury, ammonium tetrachloroplatinate,
benzoyl peroxide, bis-GMA, urethane dimethacrylate, ethylene
glycol dimethacrylate, eugenol, hydroxyethyl methacrylate,
hydroquinone, menthol, methyl methacrylate, palladium chlo-
ride peppermint oil, potassium dicyanoaurate, N,N-dimethyl-p-
toluidine, sodium thiosulfatoaurate, and triethylene glycol
dimethacrylate.146 When lesions persist despite of removal, a
short course of topical or even oral glucocorticoids may be
applied.21
6
Porto Biomedical Journal
Conclusions
Drug hypersensitivity reactions are not common on the dental
practice but may carry dire consequences. Furthermore, dental
practitioners often prescribe/administrate some of the drugs that
are often responsible for these reactions.
Dentists should not only be aware of their existence, but also
know how to treat severe immediate reactions (ie, anaphylaxis).
These are mostly caused by antibiotics and NSAIDs, but may be
caused by other drugs including CHX and should prompt the
immediate administration of intramuscular adrenaline. Also,
dentists should be able to recognize severe cutaneous adverse
reactions (ie, in the presence of skin detachment/bullae and/or
fever), and the need to refer them to urgent care. In order to avoid
false drug allergy labeling, all patients with a suspected drug or
material hypersensitivity reaction should be referred to an
allergist/immunologist to be thoroughly investigated.
Opposed to drug hypersensitivity, hypersensitivity reactions to
dental materials are frequently addressed by dentists. As such,
dentists should not only know the most frequent elicitors, but
also their safest alternatives, whenever removal is indicated.
Acknowledgments
None.
Conflicts of interest
The authors declare no conflicts of interest.
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