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.