Abstract
To The Editor:
S
Case Report
The patient, who was a male, preadolescent (11-year-old, sixth grader) was brought to our department with complaints of “anhedonia, irritability, tearfulness, insomnia at sleep onset, fatigue, school refusal, reduced appetite and concentration along with infrequent passive suicidal ideation.” Upon questioning, it was learned that the complaints had started 2 months earlier, that they were present for more days than not, and that they caused distress and impairment. The patient's previous functioning had been normal, and no stressors potentially related to onset could be identified. Past history, developmental milestones, and family history were normal. Physical and neurological examination findings were within normal limits. Routine biochemistry, hemogram, and thyroid function tests did not reveal pathology. Baseline evaluations with Children's Depression Inventory and Screen For Anxiety and Related Disorders revealed scores of 21 and 30 (both above thresholds), respectively. Clinical Global Impressions-Severity scale was judged to be 4 (Moderately Ill). As a result of evaluations, the patient was diagnosed with “Major Depressive Disorder (MDD), Single Episode, Moderate” according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria, and fluoxetine 10 mg/ day was started (American Psychiatric Association 2000). On the 4th day of treatment, the patient was brought to the emergency ward with complaints of “edema of hands, face, tongue, periorbital areas and scrota along with respiratory distress.” A consultation from the Department of Dermatology along with determination of complement levels, hemogram, and biochemistry led to a diagnosis of angioedema with mild symptoms of anaphylaxis. Examinations and questioning of the patient and parents ruled out pollens, foodstuffs, insect bites, cold, and light as etiological agents. Neither novel stressors nor infections were reported prior to onset of angioedema. The patient had not been using any other drugs or food supplements other than fluoxetine. Hereditary angioedema was ruled out by negative family history as well as lack of past history of allergies and intestinal colic. Complement levels also supported exclusion of hereditary angioedema.
The patient was started on prednisolone and pheniramine, and cessation of fluoxetine was suggested, because of the idiosyncratic nature of the reaction. The signs and symptoms remitted completely within 48 hours of treatment, and the patient was restarted on sertraline 12.5 mg/day under close supervision. At the 4th week of treatment there were no untoward effects of the treatment, and the dose was titrated to 25 mg/day.
Discussion
Here, a case of acquired angioedema is presented, in a Turkish preadolescent with MDD, that was thought to be caused by fluoxetine. Because of a lack of family history for similar reactions and normal C1, 2, and 4 levels as well as elevation of mast cell tryptase, all temporally coinciding with use of fluoxetine, the latter was thought to be the offending agent. An evaluation with the Naranjo algorithm revealed a score of 7, denoting a probable adverse effect caused by fluoxetine (Naranjo et al. 1981).
In clinical trials, 7% of patients were reported to develop rashes and/or urticaria, with most improving after cessation of fluoxetine and/or adjunctive antihistamines or steroids. Anaphylactic reactions, including bronchospasm, angioedema, laryngospasm, and urticaria have also been reported on rare occasions. The precise etiology and pathophysiology of these reactions are not known. The manufacturer suggests cessation of fluoxetine in presentations dominated by rash or other allergic phenomena for which an alternative cause cannot be identified (Prozac, manufacturer's insert).
Angioedema is classified as either hereditary or acquired, with the latter further divided into immunologic, nonimmunologic or idiopathic (Axelrod and Davis-Lorton 2011). Acquired angioedema is usually allergic while some cases may also occur as a result of drug exposure, especially to ACE inhibitors (Axelrod and Davis-Lorton 2011). Hereditary angioedema is caused by mutations in SERPING1 or F12 genes, which lead to abnormal activation of the complement system. The disorder is transmitted in an autosomal dominant form (Zuraw 2008). The disorder is diagnosed with clinical presentation. Mast cell tryptase levels may be elevated if the cause is acute allergic reaction. Depletion of C2 and 4 may show deficiency of C1 inhibitor. Antibodies against C1 esterase inhibitors may be formed in autoimmune disorders such as lymphoma. Also, consumption of vasodilators such as alcohol or cinnamon or use of nonsteroidal antiinflammatory drugs (NSAIDs) may cause angioedema in some patients. Regardless of cause, the final stages in angioedema involve elevation of bradykinin levels (Zuraw 2008; Axelrod and Davis-Lorton 2011).
It is known that serotonin and bradykinin play a role in inflammation and edema in addition to histamine, adenosine triphosphate (ATP), prostaglandins. and cytokines, and it may be argued that the angioedema observed in our patient may be related to the increased serotonin concentrations caused by fluoxetine. Supporting this position, sumatriptan, paroxetine, and various other SSRIs, as well as carcinoid tumors, were reported to cause angioedema (Dachs and Vitillo 1995; Mithani and Hurwitz 1996; Cederberg et al. 2004; Rodríguez Trabado et al. 2004; Krasowska et al. 2007). However, the lack of signs and symptoms of angioedema during a trial of sertraline argues against this preposition. Cederberg and colleagues (2004) report that some patients may be especially sensitive to minute changes in peripheral concentrations of serotonin and that chocolates and other foods increasing serotonin may cause adverse reactions. Although we asked the patient and his family detailed questions about foods consumed prior to the reaction and followed the patient for reemergence during the trial with sertraline to rule out this possibility, our findings may be affected by recall and report bias. Also, individual differences of the serotonergic system at dermis and mucosal surfaces may have played a role (Cederberg et al. 2004). A recent hypothesis to explain the predominance of skin reactions to oral or parenteral drugs proposes that drug molecules may interact in a labile and noncovalent way with T cell receptors and possibly with major histocompatibility molecules (“p-i reaction”) to activate the immune system and steer inflammatory cells toward the dermis (Hausman et al. 2010). This type of reaction is proposed to explain drug hypersensitivity reactions deemed to be “pseudo-allergic,” and it may also underlie the presentation in our patient.
There is only one other case of angiodema accompanying urticaria and a flu-like presentation 2 days after ingestion of high dose fluoxetine (Naranjo et a. 1981). Our case is unique in that the angioedema developed with therapeutic doses. The exact mechanism of angioedema in our patient could not be clarified, although mast cell degranulation in the presence of normal levels of immunoglobulin E (IgE) supports that it was pseudoallergic angioedema. Also, the resolution of the clinical picture has been the result of cessation of fluoxetine, application of pheniramine/prednisolone, or both. The presentation in our patient may also have been affected by his developmental stage (i.e., preadolescence) and MDD diagnosis. Regardless of cause, it may be prudent to follow children and adolescents at the start of treatment with SSRIs as well as during dose titrations, and caution them against foods that may potentially elevate serotonin. Our results should be clarified with further studies.
Footnotes
Disclosures
The authors have no conflicts of interest or financial ties to disclose.