Genital Angioedema to Higher Dose of Ibuprofen Abstract: Angioedema represents swelling of cutaneous and subcutaneous soft tissues that occurs as a result of an allergic or non-allergic reaction. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effect by reducing the production of prostaglandins through cyclooxygenase (COX-1) therefore shunting the arachidonic acid metabolism causing increased leukotriene production as well as increased bradykinin effect via B2 receptor, leading to the development of angioedema1. Here we report a case of isolated non-traumatic penile angioedema after an overuse of ibuprofen for dental pain.Background: Angioedema is the swelling of soft tissues due to vascular leakage, which occurs as a result of either an allergic or non-allergic reaction. The allergic angioedema is histamine induced and immunoglobulin E (IgE)- mediated whereas non-allergic angioedema is the result of bradykinin and/or leukotrienes build up2,3. Angioedema can result from a variety of causes including food, trauma, hereditary causes and pharmaceuticals such as NSAIDs and antibiotics use. Non-steroidal anti-inflammatory drugs exert their effect by reducing the production of prostaglandins through cyclooxygenase (COX-1), which shunts the arachidonic acid pathway leading to increased production of leukotrienes1. In addition, NSAIDs (particularly Ibuprofen) are known to increase the effect of bradykinin via the activation of B2 receptors in a dose-dependent manner4. These hypersensitivity reactions to NSAIDs have shown to present with mainly cutaneous manifestations, commonly limited to facial (periorbital) angioedema with or without urticaria1. Reactions typically range in severity from mild to moderate, although there is a risk of severe anaphylaxis. The underlying cause as to why some patients react to NSAIDs are not completely explained, however, predisposing factors have been identified in regards to cutaneous reactions. These factors include atopic diathesis, female sex, young adulthood and a history of chronic urticaria among others5. The prevalence of angioedema caused by NSAIDs is 0.1% – 0.3% in the general population; however, in patients with a history of chronic rhinitis, asthma, or urticaria, the prevalence could be up to 20%-30%3.The case described in this paper reports an isolated non-traumatic penile angioedema, which occured after an overuse of Ibuprofen in attempts to relieve dental pain.Case Presentation: A 53 year old male patient with no significant past medical history, presented with genital swelling to the emergency department (ED), refer to Figure 1. The patient reported right lower dental pain and facial swelling for a couple of days that became progressively worse. A day before presenting to the ED, he took 1600mg of Ibuprofen every 6 hours for pain. After the third dose, he experienced body itchin. The morning after, he felt pressure in his penis and when he checked he noticed the swelling. He denied penile trauma, penile discharge, penile rash, testicular pain, swollen lymph nodes and any sexual activity. He was able to urinate before and after the swelling commenced. The patient did not experience any shortness of breath, wheezing, hoarseness, drooling or chest pain. He denied history of any sexually transmitted diseases (STDs), he also stated that he was in a monogamous relationship and his last sexual encounter was a week before the symptom onset. He denied dysuria, hematuria, fever, chills, abdominal or flank pain, no vomiting or diarrhea. He denied using antibiotics or other medications.On examination of the genitourinary system, there was moderate edematous swelling in the genitalia region, specifically the penis shaft and scrotum, however no tenderness was present. There were no visible blisters or rash present on the circumscribed penis or scrotum. There was no associated edema present in the upper or lower extremities (Figure 1). On dental examination, the patient presented with right facial swelling with pain to palpation; specifically, his second tooth was tender with visible decay. The surrounding gingiva appeared swollen with no fluctuance. Laboratory test including complete blood count, urine analysis, urine culture as well as urine Gonorrhea/Chlamydia amplified assay which were all negative.For the treatment of the genital angioedema, the patient received Diphenhydramine, Famotidine, and Methylprednisolone with moderate improvement of the penile swelling. A genitourinary consult was obtained and concluded the angioedema of the penis and scrotal region to be due to ibuprofen hypersensitivity. A CT of the facial bone was obtained to evaluate for the presence of an abscess in the dental region. A small cystic focus in the inferior medial aspect of the right palatine tonsil, and a right-sided subperiosteal abscess along the outer cortex of the mandible were discovered. IV Antibiotics (Cephalexin) were commenced as a single dose to treat his odontogenic abscess. The patient was discharged on Amoxicillin-Clavulanate (Co-amoxiclav), Diphenhydramine, Famotidine, prednisone and acetaminophen/oxycodone. He did not return for a follow-up. Discussion: Non-steroidal Anti Inflammatory drug induced hypersensitivity reactions are known to often induce a mixed reaction involving multiple organs. Diagnosis of NSAIDs induced hypersensitivity, Ibuprofen in context, has been proven difficult as a result of the variable clinical presentations and the lack of reliable universal confirmatory tests6. A variety of NSAIDs have been known to trigger angioedema, however Ibuprofen is one of the most common causes amongst them12. According to a study conducted by the University of Toronto6, there are several subtypes of NSAIDs induced reactions based on clinical manifestations, timing (immediate or delayed), the presence of an underlying chronic disease such as asthma, and the mechanism by which the reaction occurred i.e. IgE mediated versus non-IgE mediated6. The study used a large cohort of patients aiming to characterize hypersensitivity reactions specifically to Ibuprofen.Angioedema and urticaria are among the most common adverse effects of NSAIDs7. Majority of NSAID-induced hypersensitivity reactions do not involve immunological mechanisms, thus are non-allergic. The more common non-allergic form of NSAID-induced angioedema can occur within 1 hour of ingestion and is precipitated by an increase in pro-inflammatory leukotriene production due to blockage of cyclooxygenase (COX), particularly COX-15,8. This reaction can occur upon the first administration of the drug. COX-2 inhibitors have been presented as safe alternatives in this patient population; however, a small percentage of patients with a cross-intolerance to multiple strong COX-1 inhibitors are intolerant to COX-2 inhibitors5,8.   The development of angioedema has shown to have a predilection for areas where the skin is lax rather than taut; this is especially for the face and the genitalia. The most common clinical presentation is facial angioedema; certain cases have presented with a combination of both cutaneous (urticaria and/or angioedema) and respiratory symptoms, which include upper respiratory tract oedema, rhinorrhea, cough, breathlessness and tearing5. Although hypersensitivity reactions to NSAIDs are common, their characteristics are defined poorly as a result of diverse clinical patterns that present in cases, which contribute to the complexity of diagnosis and treatment5.Genital angioedema may be hereditary, accounting for 5% of cases, or acquired by causes such as allergy, medications, sexually transmitted infections, or as a result of a malignancy or auto-immune related7. Given that this was the first and only episode of angioedema developing acutely in the shaft of his penis and scrotal region, it is unlikely that the cause was of hereditary nature in this patient. As both results concluded negative for Gonorrhea and Chlamydia, as well as the patient’s history of a monogamous relationship, the cause was not a sexually transmitted infection. Our patient did not consume any other food substances or materials, and did not have any known allergies. Based on circumstantial details we think the most likely cause of genital angioedema in this patient was hypersensitivity to Ibuprofen. This is supported by the time of onset of swelling after taking repeated high doses of Ibuprofen, the absence of associated symptoms, and no past medical history in relation to the presentation.The mechanism behind this patient’s clinical manifestations is proposed to be as a result of COX-1 inhibition; the role of IgE related mechanisms remains to be established5. It is generally described as ‘intolerance’ and most likely mediated by the diversion of the lipo-oxygenase pathway and overproduction of cysteinyl leukotrienes. It is important to remember to factor in that the patient exceeded the maximum daily intake of Ibuprofen for an adult male (upto 3200 mg/day), as side effects of Ibuprofen are dose-related.One possible explanation would be that the patient has a greater number of receptors activated by the effects of bradykinin and/or leukotriene present on the skin of his genital area. Bradykinin is known to play a significant role in the development of inflammation and pain. Its physiological actions have been directly linked to activation of B2 receptors, which lead to an intracellular cascade of events and the presenting features11. Though the combined presentation of urticaria and/or angioedema is typically seen in IgE mediated allergic reactions, drug induced isolated angioedema has been related to as a result of a kinin-dependent mechanism. Current literature has proposed Bradykinin to play a significant role in the pathogenesis of most forms of non-allergic angioedema without urticaria, especially in cases that present with angioedema alone12.Bradykinin induces vasodilation and increases vascular permeability, which is most likely due to the act of binding to the vascular B2 receptors. The effects of bradykinin have shown to be mediated by the administration of Ibuprofen leading to autocrine generation of arachidonic acid metabolites12. Ibuprofen had a 9-fold increase in activation of leukotriene pathway13. The dose dependent nature of bradykinin on effects such as vascular permeability, its release in response to Ibuprofen usage and the possible higher number of bradykinin stimulated vascular B2 receptors on the genital area, may have collectively been the cause as to why the patient developed isolated angioedema in the penile and scrotal region. However, a limitation of this case report is that there were no clinical studies conducted regarding complement factors, C1 esterase and C1Q to rule out hereditary causes of angioedema that may have been exacerbated by the overuse of the NSAIDs.References:Yadneshwar K, Sujata K. Adverse drug reactions to ibuprofen: a case report. International Journal of Basic and Clinical Pharmacology. 2016;:215–9. Available from: https://www.ijbcp.com/index.php/ijbcp/article/view/213Stone C, Brown NJ. Angiotensin-converting Enzyme Inhibitor and Other Drug-associated Angioedema. Immunology and Allergy Clinics of North America. 2017;37(3):483–95.Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet J, et al. Hypersensitvity to nonsteroidal anti-inflammatory drugs (NSAIDs) – classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy. 2011 Jul;66(7):818-99Baraniuk J, Silver P, Kaliner M, Barnes P. 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Available from: https://www.ncbi.nlm.nih.gov/pubmed/6427221Figure 1 Angioedmea of the shaft sparing the glans and ScrotumLateral view left sideAnterior viewLateral view right side