Anaphylaxis has several described variants, including monophasic (one episode of symptoms), biphasic (a second episode after resolution of symptoms), late onset (occurring several hours after exposure to antigen) and protracted (in which symptoms took several hours to resolve despite treatment.) There have been multiple studies on the incidence of biphasic reactions which yielded differing results.
Stark and Sullivan described a 20% incidence of biphasic reactions in 25 patients. They found that patients experienced their second reaction 1-8 hours after the resolution of symptoms. Reactions were 2.8X more likely to be biphasic if the trigger was ingested or if the onset of symptoms was longer than 30 minutes after exposure. Laryngeal edema in the throat was also a risk factor. Severity of initial reaction or treatment administered did not correlate to whether or not the reaction was biphasic.
Douglas reported a 5.8% incidence rate of biphasic anaphylaxis. They found that higher doses of corticosteroids may have decreased the incidence of a second phase.
Lee and Greenes specifically investigated children. They found occurrence 1.3-28.4 hours after the resolution of initial symptoms. Most had wheezing and shortness of breath. Some had abdominal pain. Low blood pressure was rare. Importantly, they found that delay in administration of epinephrine was a predisposed patients to a second reaction. Patients who had only one reaction were administered epinephrine, on average, 48 minutes after exposure; those with two reactions, 190 minutes after. No other risk factors were identified.
18% of patients in the Brazil and MacNamara study were found to have biphasic anaphylaxis. Second phase occurred 4.5-29.5 hours later. They were unable to find clinical features that distinguished biphasic patients from uniphasic, but those with two phases did require more epinephrine to resolve initial symptoms.
Forest-Hay found that nine patients out of 91 had biphasic reactions. Eight of those had symptoms within six hours, a finding not seen in other studies.
A large study done by Smit on Hong Kong hospitals found a 5.3% incidence of biphasic reactions. They found that the time of treatment to onset of second phase averaged 7.6 hours. 12/15 biphasic patients had mild reactions. In particular, they found that biphasic reactors were less likely to have respiratory involvement (35% vs 77%.)
Ellis and Day found a 19.4% biphasic reaction rate. The second phase appeared 2-38 hours after the initial resolution. 40% of these patients had the second phase more than ten hours after the end of the first phase. The second phase could be milder than, similar to or more severe than the first. However, 40% had a lifethreatening second phase and 20% needed more treatment to resolve the second phase than the first. Biphasic patients had longer lasting initial reactions, were given less epinephrine and received less steroids. Late biphasic reactors (after 8 hours) took an average of 193 minutes to resolve their initial symptoms vs 112 minutes for uniphasic reactors. Importantly, no biphasic reaction was found in any patient who administered epinephrine and resolve symptoms within 30 minutes of onset. No biphasic if responded completed in less than 30 minutes. All patients received epi for treatment.
Delay in administration of epinephrine, inadequate dosing of epinephrine for first response, or need for large doses of epinephrine were found to suggest that biphasic anaphylaxis was more likely. Corticosteroid administration was not definitively found to prevent a second phase, but was generally considered to be beneficial. Previous cardiovascular history, older age, and use of beta blockers were risk factors for biphasic reactions. Oral ingestion of the trigger elevated the likelihood of a second stage, but it was also seen in parenteral and inhaled exposures. Hospital admission for 24 hours after resolution of symptoms is recommended.
Studies of mastocytosis patients have found that they are more likely to experience anaphylaxis, but true investigation of whether or not they are more likely to have biphasic reactions has been undertaken.
Tole, John and Phil Lieberman. Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors, and Observation Recommendations. Immunol Allergy Clin N Am 27 (2007) 309-326.
Douglas DM, Sukenick E, Andrade WP, et al. Biphasic systemic anaphylaxis: an inpatient and outpatient study. J Allergy Clin Immunol 1994; 93:977–85.
Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106: 762–6.
Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol 2007; 98(1):64–9.
Brazil E, MacNamara AF. ‘‘Not so immediate’’ hypersensitivity: the danger of biphasic anaphylactic reactions. J Accid Emerg Med 1998 ;15: 252–3.
Forrest-Hay A, Taylor C, Tolchard S. Biphasic anaphylaxis in aUKemergency department. Presented at Open Paper Presentations of the 2003 Scientific Symposium of the Resuscitation Council of the United Kingdom (abstract)
Smit DV, Cameron PA, Rainer TH. Anaphylaxis presentations to an emergency department in Hong Kong: incidence and predictors of biphasic reactions. J Emerg Med 2005;28(4): 381–8.