3. Discussion
We report a case of perioperative grade 4 anaphylaxis to
amoxicillin/clavulanic acid with re-exposure to the molecule 72 hours
later without reaction. The patient had become sensitized to amoxicillin
during a treatment received one month before the event. Positive skin
tests and BATs carried out one month after the anaphylaxis confirmed the
sensitization. The absence of an allergic reaction when 1 gram of
amoxicillin/clavulanic acid was reintroduced orally 3 days after
anaphylaxis can be explained by a transient mast cell and potentially
basophil anergy and natural desensitization. A case of post-anaphylactic
re-exposure to amoxicillin/clavulanic acid has been reported in the
literature in a patient who took a 7-day course of oral AC without
reactions, 4 weeks after anaphylactic shock induced by 1.2 grams of
intravenous AC.9 The antigenic epitopes of beta
lactams are thought to be related to the R1 chain and while cefazolin,
piperacillin and cefotaxime can be used due to negative skin test, in
this patient cefadroxil, cefprozil and cefatrizine (with shared R1
chain)10 along with clavulanic acid should be avoided.
The use of penicillin and ampicillin will require further testing.
Tryptase was found 25 fold higher than baseline and histamine over 10
times higher within 60 min of the event, providing insight into the
mechanism of the reaction and the extent of mast cells and basophils
activation.
Several studies have evaluated mast cell anergy using skin
tests.11
In 1997, Goldberg and Cofino-Cohen1 performed SPTs,
IDTs and specific IgE on patients with a history of anaphylaxis to
hymenoptera venom, at 1 week and then 4-6 weeks after the incident. Of
the 38 patients tested, 9 had negative skin tests at the first visit but
positive specific IgE. The skin tests of these 9 patients became all
positive at the second visit. In 2013, Lafuente et al2 conducted a similar study (without specific IgE
testing) on 25 patients with perioperative anaphylaxis in whom the
offending allergen was identified. Ten of these patients had initial
skin tests (performed between 0 and 4 days after the incident) that were
negative and then positive at the second visit (4 to 8 weeks later).
Several factors such as the nature of the allergen, the severity of the
index reaction and the patient genetic factors are likely to influence
mast cells mediators depletion and skin test reactivity .
Several mechanisms are thought to be involved in post-anaphylactic mast
cell anergy (Figure 1 ): (i) mast cell re-granulation after
massive release of mast cell mediators; (ii) the activation of a
signalosome inhibiting mast cell activation ; (iii) changes in FcεRI
(high-affinity IgE receptor) availability and signalling following
internalization of the allergen/IgE/FcεRI complexes after anaphylaxis;
(iv) external factors such as the introduction of β-adrenergic therapies
blocking mast cell activation, as in the patient’s case.
After activation, mast cells do not undergo apoptosis and need time for
the biosynthesis of mediators, to regranulation and to become functional
again. Mast cell ”recovery” times can be variable: from 24-48h for IL-6
and IL-13 gene expression and release of
B-hexosaminidase;12, 13 to a few days for endocytosis
and granule recycling capacity.14 Hammel et
al15 observed a significant decrease in the size of
rat mast cells after strong IgE-dependent stimulation, followed by a
gradual recovery of the mast cells size and their granules over 4 to 5
weeks. Cytoskeletal changes also appear to be involved in mast cell
anergy. Seagrave et al showed that over-stimulated mast cells retained
degranulation capacity in an environment containing inhibitors of actin
polymerization,16 supporting the hypothesis that
cytoskeletal rearrangements and post-stimulation actin polymerization
would play an inhibitory role on hypothetical second degranulation.
The internalization of allergen/IgE/FcεRI complexes following
anaphylaxis leads to FcεRI membrane depletion, which can last several
days, explaining mast cell anergy despite the presence of specific IgE
and allergens.17
Repeated IgE mast cell activation with low dose allergens induces
profound quantitative and qualitative changes in FcεRI-dependent
signaling (known as FcεRI desensitization), resulting in a state of
unresponsiveness whose mechanisms have been analyzed in the induction of
rapid drug tolerance (acute drug desensitization) and involve the
activation of inhibitory phosphatases such as SHIP-1 (src homology
2-containing inositol phosphatase).18 The suppression
of mast cell responses secondary to exposure to increasing
concentrations of allergens is due to the activation of inhibitory
signaling pathways.19 An inhibitory signalosome with
SHIP-1,20 Lyn (src kinase family),21protein kinase C- δ (PKC- δ)22 and Cbl family proteins
such as Cbl-c23 (figure 1) has been proposed. As
allergen concentrations increase, the proteins making up this
signalosome are recruited. Mice or cells deficient in these various
enzymes or inhibitory proteins do not develop inhibition of mast cell
activation at supra-optimal allergen doses.20, 21, 22,
23, 24 The description of the change from positive to negative skin
test in a patient allergic to carboplatin after desensitization provides
evidence that mast cell inhibitory mechanisms do not need massive
release of mediators.25
Studies have shown that β-adrenergic receptor agonists inhibit
IgE-dependent histamine release by human mast cells,26and that exposing healthy volunteers to salmeterol and terbutaline
attenuates the cutaneous mast cell response for up to 24 hours
post-exposure.27 However, it is not known whether
these inhibitory effects follow a dose-response curve, nor whether they
are durable with molecules such as adrenaline, the first-line treatment
for anaphylaxis and used in large quantities in our patient’s case.
Systemic corticoids, on the other hand, do not appear to be involved in
inhibiting the mast cell response and the release of
mediators.28, 29
Post-anaphylactic mast cell anergy affects mast cells in all tissues,
which explains the negativity of skin tests and the absence of clinical
hypersensitivity reactions on re-exposure to the allergen in the days
and weeks following systemic mast cell activation. The duration of this
anergy has been defined as 4 to 8 weeks, based on studies of skin test
positivity after anaphylaxis. However, practitioners should be aware
that this duration may be longer in some patients, as suggested by the
recently published clinical case in which skin tests remained negative 8
weeks after the initial accident.9 The work-up carried
out 4 to 8 weeks after anaphylactic shock should be repeated if
negative. Clinicians may be able to explore this window of opportunity
allowing drug allergic patients to tolerate the culprit drug if given
within a short time after anaphylaxis while skin test is still negative.
4. Conclusion
Post-anaphylactic mast cell anergy is described here in a patient
allergic to amoxicillin/clavulanic acid, leading to natural
desensitization at the time of accidental reintroduction of the drug
within 3 days of the initial event. Research is needed to further
understand this window of opportunity in patients in need of first line
therapy.