A Rare Case of Anaphylaxis to Methimazole in a Patient With Graves’ Disease

We present the case of a patient with Graves’ Disease (GD) who developed anaphylaxis to methimazole (MMI) necessitating hospitalization, emergent treatment and ultimately urgent total thyroidectomy. While the most common adverse reactions to thionamides include hepatotoxicity, agranulocytosis, pruritis, and urticaria, delayed anaphylaxis has been reported. A 25-year-old woman was diagnosed with GD two years prior to presentation during an admission for syncope. She was started on MMI 10 mg twice a day and propranolol 10 mg three times a day, which she took for roughly one year until she ran out of medication and was lost to follow-up. She remained off MMI until she re-presented several months later grossly thyrotoxic, complaining of fatigue, heat intolerance, unintentional weight loss, blurry vision, and palpitations. Labs were significant for TSH <0.02 mIU/L (normal 0.3-4.7), free T4 >7 ng/dL (normal 0.8-1.7), free T3 >2900 pg/dL (normal 222-383), and thyroid stimulating immunoglobulin (TSI) >500 (normal ≤122). She was restarted on propranolol and MMI 10 mg twice a day which was quickly increased to 20 mg twice a day. Two weeks after restarting MMI, the patient presented to the ER with a diffuse pruritic rash and was treated with antihistamines and steroids. She clinically improved and was discharged in stable condition. Two days later, her symptoms recurred along with flushing, facial/lip swelling, and dysphagia. She presented to our hospital with evidence of angioedema and difficulty breathing. Based on her presentation, anaphylaxis was diagnosed, and she was given intramuscular epinephrine. She was also started on glucocorticoids, H1/H2 blockers and montelukast and was admitted to the ICU for close monitoring. Over the next few days, her symptoms improved. As there was no other recent novel exposure, her anaphylactic reaction was attributed to MMI. Given the life-threatening nature of the reaction, there was concern for trialing propylthiouracil (PTU) due to its known cross-reactivity with MMI. Thus, treatment with propranolol, steroids and potassium iodide was initiated with improvement in her thyroid labs. As the patient would be unable to tolerate anti-thyroid agents in the future, it was decided to pursue definitive treatment with total thyroidectomy given the presence of eye disease. Anaphylaxis secondary to MMI is very rare, and less than a handful of cases have been reported. However, they seem to share two key features: their occurrence with higher doses of MMI (≥40 mg daily), and a delayed onset of presentation (2-4 weeks from exposure). The mechanism is unknown, although it is unlikely to be IgE-mediated given its time course. Current ATA guidelines recommend against using MMI or PTU in patients who have developed serious side effects to the other agent. Our case highlights the importance of close monitoring and timely follow-up after initiating anti-thyroid drugs.

Association between lone star tick bites and increased alpha-gal sensitization: evidence from a prospective cohort of outdoor workers

Background Alpha-gal is an oligosaccharide implicated in delayed anaphylaxis following red meat consumption. Exposure to tick bites has been correlated with development of an allergic response to alpha-gal. However, evidence prospectively linking exposure to a single tick species and an immune response to alpha-gal is lacking. Methods We used serum samples from a prior study cohort of outdoor workers in North Carolina, USA, with high exposure to the lone star tick, Amblyomma americanum, to prospectively evaluate the relationship between tick bites and anti-alpha-gal IgE antibodies. Results Individuals who reported exposure to one or more tick bites were significantly more likely to have a positive change in anti-alpha-gal IgE compared to individuals with no reported tick bites. This relationship was not dependent on time. A trend toward increasing number of tick bites and increased anti-alpha-gal IgE levels was observed but not statistically significant. Conclusion To our knowledge, this is the first study to prospectively link documented exposure to A. americanum bites and increased sensitization to alpha-gal in a cohort of outdoor workers. Our results support the role of A. americanum as likely agents for eliciting an allergic response to red meat, and highlight the importance of preventing tick bites.

Vaccination with Alpha-Gal Protects Against Mycobacterial Infection in the Zebrafish Model of Tuberculosis

The alpha-Gal syndrome (AGS) is associated with tick bites that can induce in humans high levels of IgE antibodies against the carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) present in glycoproteins and glycolipids from tick saliva that mediate primarily delayed anaphylaxis to mammalian meat consumption. It has been proposed that humans evolved by losing the capacity to synthesize α-Gal to increase the protective immune response against pathogens with this modification on their surface. This evolutionary adaptation suggested the possibility of developing vaccines and other interventions to induce the anti-α-Gal IgM/IgG protective response against pathogen infection and multiplication. However, the protective effect of the anti-α-Gal immune response for the control of tuberculosis caused by Mycobacterium spp. has not been explored. To address the possibility of using vaccination with α-Gal for the control of tuberculosis, in this study, we used the zebrafish-Mycobacterium marinum model. The results showed that vaccination with α-Gal protected against mycobacteriosis in the zebrafish model of tuberculosis and provided evidence on the protective mechanisms in response to vaccination with α-Gal. These mechanisms included B-cell maturation, antibody-mediated opsonization of mycobacteria, Fc-receptor (FcR)-mediated phagocytosis, macrophage response, interference with the α-Gal antagonistic effect of the toll-like receptor 2 (TLR2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)-mediated immune response, and upregulation of pro-inflammatory cytokines. These results provided additional evidence supporting the role of the α-Gal-induced immune response in the control of infections caused by pathogens with this modification on their surface and the possibility of using this approach for the control of multiple infectious diseases.

Recurring Anaphylaxis: A New Line of Questioning for your HPI

Anaphylaxis is a serious life-threatening allergic reaction that typically has an immediate onset. It can present as flushing, angioedema, shortness of breath, rash and result in death if not treated immediately. In the past ten years, an emerging cause of delayed anaphylaxis has been identified. An IgE antibody to a mammalian oligosaccharide epitope (alpha-gal, or galactose-alpha-1,3-galactose) has been linked to both immediate and delayed onset anaphylaxis. The immediate form is associated with the first exposure to cetuximab; whereas the delayed onset occurs after ingestion of mammalian meat such as beef and pork. The presentation can develop 2-6 hours after ingestion. This IgE antibody to alpha-gal is strongly suggested that Lone Star tick bites have been the culprit. It is imperative when caring for an anaphylaxis patient of unknown etiology, to consider a line of questioning to not only include recent tick bites, but also last 2-3 meals ingested to identify if mammalian meat may have been the trigger.