Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors, and Observation Recommendations

doi:10.1016/j.iac.2007.03.011

Immunology and Allergy Clinics of North America

Volume 27, Issue 2, May 2007, Pages 309-326

https://doi.org/10.1016/j.iac.2007.03.011 Get rights and content

Biphasic anaphylactic reactions have been found to develop in as many as 20% of anaphylactic reactions. The biphasic reaction can be less severe, equally severe, or more severe than the initial reaction, ranging in degree from mild symptoms to fatal reactions. In this review, retrospective and prospective studies as well as case studies and case series are discussed in an attempt to gain insight on the incidence of biphasic reactions, the potential clinical characteristics suggestive of a uniphasic reaction developing into a biphasic reaction, and the recommendations for observation periods after an anaphylactic reaction.

Section snippets

Historical review

In 1902, Portier and Richet [1] attempted prophylaxis by means of immunization of dogs to sea anemone venom. The sensitized dogs had fatal reactions to subsequent nonlethal doses of the venom, however. This unexpected adverse outcome was termed by Portier and Richet [1] as anaphylaxis. Although a biphasic anaphylactic reaction was described by Duke [2] in 1925 and in two textbooks published in 1983 [3], [4], it was Popa and Lerner [5] who described the first case reports in 1984 and coined the

Clinical characteristics of the biphasic response

There have been several biphasic anaphylactic reaction studies and case reports [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. These evaluations are summarized in Table 1.

Popa and Lerner [5] reported three patients who developed systemic anaphylactic symptoms after exposure to rabies vaccine, rye grass extract immunotherapy, or yellow jacket sting. These patients were treated and had improved until 3.5 to 4 hours later, when they

Theories of biphasic pathogenesis

Several potential pathogenic mechanisms have been proposed as listed in Box 2.

The biphasic response was originally thought to be attributable to a temporarily ablated initial reaction, and therefore the result of insufficient treatment [3], [4], [5]. It was later hypothesized that the biphasic anaphylactic response, like that in the skin and respiratory tract, was the result of the secondary influx of cells into the site(s) of the reaction [5]. There are several lines of evidence that mitigate

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Cited by (141)

Anaphylaxis: Emergency Department Treatment
2023, Immunology and Allergy Clinics of North America
Anaphylaxis: Emergency Department Treatment
2022, Emergency Medicine Clinics of North America
Emergency medicine updates: Anaphylaxis
2021, American Journal of Emergency Medicine
Anaphylaxis is a potentially deadly condition that requires emergent therapy. While frequently treated in the emergency department (ED), recent evidence updates may improve the diagnosis and management of this condition.
This paper evaluates key evidence-based updates concerning the diagnosis and management of anaphylaxis for the emergency clinician.
The presentation of anaphylaxis can vary. Current diagnostic criteria can be helpful when evaluating patients for anaphylaxis, though multiple criteria exist. While the most common causes of anaphylaxis include medications, insect venom, and foods, recent literature has identified an IgE antibody response to mammalian galactose alpha-1,3-galactose, known as alpha-gal anaphylaxis. Epinephrine is the first-line therapy and is given in doses of 0.01 mg/kg (up to 0.5 mg in adults) intramuscularly (IM) in the anterolateral thigh. Intravenous (IV) epinephrine administration is recommended in patients refractory to IM epinephrine and IV fluids, or those with cardiovascular collapse. Antihistamines and glucocorticoids should not delay administration of epinephrine and do not demonstrate a significant reduction in risk of biphasic reactions. Biphasic reactions may affect 1–7% of patients with anaphylaxis. Risk factors for biphasic reaction include severe initial presentation and repeated doses of epinephrine. Disposition of patients with anaphylaxis requires consideration of several factors.
Emergency clinicians must be aware of current updates in the evaluation and management of this disease.
Characterizing Biphasic Food-Related Allergic Reactions Through a US Food Allergy Patient Registry
2021, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
Our results agree with previous data16 and highlight the importance of informing patients and families about the increased risk for a biphasic food-related allergic reaction after a severe initial reaction. This is consistent with previous study results indicating that most biphasic reactions are similar to the original reaction in severity and can range in symptoms from mild to fatal.9,11,13 Moreover, this study provides incidence estimates because less severe secondary reactions may go unreported since they are often managed at home by self-administered treatment and do not result in a visit to the ED or physician's office.
Understanding about patient-reported biphasic food-related allergic reactions is currently sparse.
To characterize patient-reported biphasic food-related allergic reactions among a national food allergy registry.
We used two patient registry surveys established by Food Allergy Research and Education. Variables were described with proportions and 95% confidence intervals (CIs); unadjusted results were stratified by respondent type. Multivariable logistic regression evaluated the adjusted odds of reporting a biphasic reaction.
The incidence of reported biphasic reactions was 16.4% (95% CI, 15.3-17.7). A total of 12.8% of parent or guardian respondents (95% CI, 12.5-14.3) and 21.8% of self-respondents (95% CI, 19.7-23.8) indicated a biphasic reaction during their most recent food-allergic reaction. Among respondents with a mild initial reaction, 7.4% reported a biphasic reaction, compared with 30% with a very severe initial reaction. When the initial reaction was mild, 69.6% of parent or guardian respondents (95% CI, 47.2-85.4) and 52.0% of self-respondents (95% CI, 38.0-35.7) with a biphasic reaction reported a mild secondary reaction. When the initial reaction was very severe, 36.3% of parent or guardian respondents (95% CI, 26.4-47.5) and 42.9% of self-respondents (95% CI, 31.1-55.5) with a biphasic reaction reported a very severe secondary reaction. Female sex, Black race, reaction age 5-12 and 26-66 years, initial moderate, severe, or very severe reaction, and one or more annual reactions were associated with increased odds of a biphasic reaction.
This study characterizes the incidence of patient-reported biphasic reactions and provides valuable information on the probable severity of a biphasic food-related allergic reaction. Further research is necessary to understand the epidemiology of food-related biphasic reactions.
Characteristics of Anaphylactic Reactions: A Prospective Observational Study in Japan
2020, Journal of Emergency Medicine
Anaphylaxis is a systemic, life-threating, allergic reaction in which the clinical features may vary in different populations or due to the allergic triggers. Moreover, the timing and characteristics of biphasic anaphylactic reactions remain unclear.
The purpose of this study was to investigate the clinical characteristics of anaphylaxis cases assessed and treated in Japanese hospitals.
This was a prospective observational study of anaphylactic reactions treated in the Emergency Department (ED) of two medical centers from June 2016 to May 2019. All patients diagnosed with anaphylaxis were enrolled in this study. Data collected included patient demographics, symptoms and signs, treatment, clinical course, and suspected triggers. Descriptive statistics and univariate methods were used in the analyses.
We enrolled 302 patients. The median age was 32 years (interquartile range 13–37) and the sample included 182 (60.3%) women. Of the 302 patients, 179 (59.3%) had a history of allergic reactions. The dermatologic, respiratory, gastrointestinal, and cardiac systems were involved in 297 (98.3%), 248 (82.1%), 150 (49.7%), and 55 (18.2%), respectively. Nineteen patients (6.3%) experienced biphasic anaphylactic reactions. Epinephrine use was associated with a lower incidence of biphasic anaphylactic reaction (odds ratio 0.3, 95% confidence interval 0.1–0.9). Time to recurrence of symptoms ranged from 2 to 48 h (median: 10 h).
In this prospective ED study, foods were the most common triggers of anaphylaxis, and epinephrine administration was associated with a decreased occurrence of biphasic anaphylactic reactions. Over half of patients experiencing biphasic anaphylactic reactions developed symptoms more than 10 h after presentation.
Risk Factors for Severe Anaphylaxis in Children
2020, Journal of Pediatrics
Citation Excerpt :
In addition, all the children with a clinically important biphasic reaction required at least another dose of epinephrine. The reported incidence of biphasic reactions varies from 0.18% to 23%,13,17-22 attributable to a wide variety of definitions used for anaphylaxis and biphasic reactions. Nevertheless, the majority of studies have found that recurrent symptoms are usually less severe than the initial symptoms,18-21 urticaria often being the only finding.22
To identify risk factors associated with severe anaphylaxis in children.
We carried out a multicenter prospective observational study including children less than 18 years old diagnosed with anaphylaxis in 7 Spanish pediatric emergency departments (EDs) between May 2016 and April 2018. Children were considered to have severe anaphylaxis if they met one or more of the following criteria: requirement for 2 or more doses of epinephrine, clinically important biphasic reaction, endotracheal intubation, intensive care unit admission, and/or death.
We included 453 episodes of anaphylaxis. Of these, 61 were classified as severe anaphylaxis (13.5%, 95% CI [10.6-16.9]): 53 (11.7%) required more than 1 dose of epinephrine, and there were 14 (3.1%) cases of clinically important biphasic reactions, 2 (0.4%) intubations in the ED, and 6 (1.3%) admissions to the intensive care unit. No patients died. In the multivariable regression, we identified 5 independent risk factors for severe anaphylaxis: history of asthma (P = .002; OR 2.705, 95% CI [1.431-5.113]), onset of the symptoms less than 5 minutes after the allergen exposure (P = .002; OR 2.619, 95% CI [1.410-4.866]), non-well appearance (P = .005; OR 2.973, 95% CI [1.380-6.405]), tachycardia (P = .014; OR 2.339, 95% CI [1.191-4.959]), and hypotension (P = .036; OR 3.725, 95% CI [1.087-12.762]).
Childhood anaphylaxis is usually well controlled in the ED. Children with a history of asthma, rapid onset of the symptoms, who are non-well appearing, or have tachycardia or hypotension upon arrival to the ED are more likely to have severe episodes.

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Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors, and Observation Recommendations

Section snippets

Historical review

Clinical characteristics of the biphasic response

Theories of biphasic pathogenesis

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Emerg Med

J Emerg Med

Am J Emerg Med

Ann Allergy Asthma Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Pathol

De l'action anaphylactique de certains venins

C Roy Soy Biol (Paris)

Allergy, asthma, hayfever, and urticaria