24 The Open Allergy Journal, 2010, 3, 24-28 1874-8384/10 2010 Bentham Open Open Access Biphasic Anaphylaxis: A Review of the Incidence, Characteristics and Predictors Anne K. Ellis* Division of Allergy & Immunology, Department of Medicine, Queen’s University, Kingston, ON, Canada Abstract: While it has been recognized for over a quarter century that anaphylactic reactions have the potential to follow a biphasic course, reports on the incidence of biphasic anaphylaxis are conflicting, and the search for reliable predictive factors of such responses has been challenging. Further adding to the complexity of this clinical entity are the widely vari- able durations of the asymptomatic window, and the similarly variable reports on second phase severity. This review aims to provide the health care professional with a better understanding of the true incidence, nature, and risk factors for this type of reactivity by consolidating and summarizing the available literature on the topic of biphasic anaphylaxis. As our body of evidence builds, patterns are emerging to suggest that those patients with an initial presentation requiring more than one dose of epinephrine, those who have life-threatening initial presenting features, and those who otherwise take longer to stabilize, are in this higher risk group, and would be more likely to benefit from prolonged in hospital observa- tion. Conversely, patients who respond rapidly to the immediate administration of epinephrine may be at lower risk, but this finding requires confirmation by others. Further prospective evaluations of biphasic anaphylaxis will greatly aid our understanding of this condition. Keywords: Anaphylaxis, biphasic, late phase response, predictors, allergy. INTRODUCTION Anaphylaxis is a serious allergic reaction that is rapid in onset and potentially fatal [1]. It results from immunologi- cally induced mast cell and/or basophil mediator release after exposure to specific antigen in previously sensitized persons [2]. A recent epidemiological review indicated that anaphy- laxis occurs in 1.2% to 15% of the US population, and that an estimated 1500 deaths a year may be attributed to anaphy- laxis [3]. Variants of the usual monophasic anaphylaxis syndrome include late onset anaphylaxis, biphasic anaphylaxis, and protracted anaphylaxis [4]. While biphasic reactions are a recognized complication, many updated reviews on the topic of anaphylaxis fail to mention the potential for a second phase of reactivity [5-7], or significantly downplay the pos- sibility [8]. Yet as time has progressed, this entity is increas- ingly being described and acknowledged in the medical lit- erature [9], and additionally is being described as a compli- cation that occurs more frequently than has been traditionally recognized [10,11]. This review will provide an overview and update on the latest research findings in the literature on the entity of biphasic anaphylaxis, with particular emphasize on its clini- cal characteristics, the incidence rate, and risk factors or pre- dictors of these types of reactions. Articles were identified for inclusion in this review via a MEDLINE search of the literature for studies published between January 1970 and *Address correspondence to this author at the Division of Allergy & Immu- nology, Doran 1, Kingston General Hospital, 76 Stuart Street, Kingston, ON K7L 2V7, Canada; Tel: 613.548.2336; Fax: 613.546.3079; E-mail: ellisa@queensu.ca December 2009 on biphasic response using the keywords anaphylaxis, biphasic, biphasic anaphylaxis, and late phase reaction. Review articles identified also underwent a refer- ence search for other publications of relevance. Studies pub- lished in abstract form only were not included as per the re- strictions of this journal. EPIDEMIOLOGY AND INCIDENCE OF BIPHASIC ANAPHYLAXIS The first case reports of biphasic anaphylactic episodes were reported by Popa and Lerner [12]. They described three individuals who, after successful treatment and resolution of symptoms, experienced a second phase of anaphylactic reac- tivity that onset after an asymptomatic window of 3 to 4 hours. Since this case series was published, several retrospective series were reported suggesting that the incidence rate of these biphasic reactions were generally low (Table 1). Doug- las et al. performed a retrospective analysis of the records from their outpatient service of patients receiving immuno- therapy in addition to a chart review of emergency depart- ment (ED) and hospital admissions for anaphylaxis [13]. They described an overall incidence rate for these reactions of 5.8%. Subsequent retrospective analyses continued to report relatively low incidence rates, such as 2% (from Cian- feroni et al.’s review of 113 inpatients [14]), 3% (from Brady et al.’s ED review [15]), and 6% (from Lee and Gree- nes pediatric inpatient series [16]). The most recently pub- lished retrospective analyses further suggests relatively low incidence rates of 5.3% and 11% for biphasic responses [17,18]. The only retrospective series with an appreciably higher reported incidence was from Brazil and MacNamara’s re-