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Biphasic allergic reactions in children - observation period

Three Part Question

[In patients under 16 years old with an acute allergic reaction] is [4 hours observation] sufficient to [exclude biphasic reaction?]

Clinical Scenario

29 month old boy had a representation with severe hives and vomiting 14 hrs from initial presentation with severe anaphylactic reaction to the Emergency department, you just wonder this child should be observed longer.

Search Strategy

Medline 1984 – 2014
(Exp allergy.ti,ab or anaphylaxis.ti.ab AND biphasic) (Limit to English Language and Humans and (Age Groups All Child 0 to 18 years))

Search Outcome

20 papers were identified using Medline. Five papers provided evidence that was relevant to the three-part question.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Lee J,Garrett JP,Brown-Whitehorn T,Spergel JM
1688 oral food challenges (OFCs) were analyzedA retrospective chart review (July 2007 - March 2011)Biphasic reactions were rare. 614 challenges (36.4%) were positive, and nine resulted in biphasic reactions (1.5% of positive chanllenges) 310 met anaphylaxis criteria, six resulted in biphasic reactions (1.9%). Retrospective chart review Study relied on parental calls on biphasic reactions, Possible missed cases who received care outside the study net work
The interval from resolution of initial reaction to onset of second reaction Ranged from 2 to 24 hrs
Lertnawapan R,Maek-a-nantawat W
208 cases of anaphylaxis were identifiedObservational study (2004 – 2008)The prevalence of anaphylaxis is increasing.Among 6.3 of the patients who developed biphasic reaction.Study setting Recall bias
The occurrence of biphasic reactions might be affected by early management and early recognitionof cases.The median times from onset to hospital arrival and the arrival to administration of epinephrine were also significantly longer in the biphasic group than the non-biphasic patients (p = 0.002 and p = 0.001, respectively).
Mehr S,Liew WK,Tey D,Tang ML
109 cases were includedRetrospective study over a 5 year durationUniphasic;BiphasicThere were 95 uniphasic (87%), 12 (11%) biphasic and two protracted reactions (2%). Its respective design Inability to measure biphasic reactions in non-hospitalized individuals. Potential inadequate or incomplete documentation
Children who received >1 dose of adrenaline and/or a fluid bolus for treatment of their primary anaphylactic reaction were at increased risk of developing a biphasic reaction.For the management of the primary anaphylactic reaction, children developing biphasic reactions were more likely to have received >1 dose of adrenaline (58% vs. 22%, P=0.01) and/or a fluid bolus (42% vs. 8%, P=0.01) than those experiencing uniphasic reactions
Ellis AK,Day JH
Prospective evaluation of 103 patientsProspective studyThe second-phase onset was 10 hours on average, but it occurred as late as 38 hours. Twenty patients (19.4%) experienced confirmed biphasic reactivity. Lacking evidence to determine course for Biphasic allergic reactions (5/20 - unknown cause)
Second phase reactivity has significant implications for clinical management of patients. Average time to onset of the second phase was 10 hours (range, 2-38 hours); 8 patients (40.0%) had their second phase occur more than 10 hours after the initial reaction.
Biphasic reactors in this study took significantly longer to achieve resolution of their initial symptoms Time to resolution of initial symptoms was significantly longer for biphasic reactors (112 vs 133 minutes; P = .03).


Anaphylaxis is the clinical syndrome representing a life threatening systemic allergic reaction. According to Stark BJ, Sullivan TJ. Arch Intern Med. 2001: Variants of the usual monophasic anaphylaxis syndrome include late onset anaphylaxis, biphasic anaphylaxis and protracted anaphylaxis. According to Sampson HA, Mendelson L, Rosen JP. N Engl J Med 1992, and Stark BJ, Sullivan TJ. Allergy Clin Immunol 1986: The biphasic reaction of anaphylaxis is a recurrence of anaphylactic symptoms after intial remission has occurred. Case series of these biphasic reactions reveal that recurrence can be severe enough to necessitate intubation and treatment with vasopressor agents. According to Mertes PM, Malinovsky JM, Mouton-Faivre C et al. And Weiler HA: Many contributing factors masking the actual incidence of anaphylaxis includes unawareness, nonidentification, especially in some circumstances such as the perioperative period: emergencies, and life saving or unconditional management and death with unidentified cause: and missed diagnosis of a case presenting mild symptoms. Mehr S,Liew WK,Tey D,Tang ML et al 2009 found for management of primary anaphylactic reaction, children developing biphasic reactions were more likely to have received > 1 dose of adrenaline (58% vs 22%, P = 0.01) and/or fluid bolus (42% vs 8%, P= 0.01) than those experiencing uniphasic reactions. The absence of either factor was strongly predictive of the absence of biphasic reaction (negative predictive value 99%), but the presence of either factor was poorly predictive of biphasic reaction (positive predictive value of 32%). Lertnawapan R,Maek-a-nantawat W et al 2011 reported the median time interval (minutes) from onset to administration of epinephrine was significantly longer in biphasic group than non- biphasic patients, 240 (IQR 122.5-380) vs 70v(IQR 40-135) minutes, p=0.002. Also the median time interval (minutes) from onset to hospital arrival was longer in the biphasic group than the non-biphasic group, p = 0.002. A variety of antigens led to biphasic reactions, the most common being foods (35.0%) and Hyemenoptera venom (25.0%).The occurrence rates of inciting antigens were not significantly different between uniphasic and biphasic reactions (P > .25); Ellis AK,Day JH et al 2006.

Clinical Bottom Line

The wide range of reported asymptomatic intervals make it difficult to determine appropriate clinical guidelines for duration of clinical observation. Patients with an episode of anaphylaxis to be observed for 8-24hrs to monitor for biphasic reactions and reactions may even occur later up to 72hours after resolution of primary event. All patients at risk of a biphasic reaction, clinicians must ensure any patients discharge from hospital following anaphylaxis has an emergency plan in place and injectable adrenaline available to ensure adequate management of any subsequent biphasic reaction.


  1. Juhee Lee, M.D., Jackie P.-D. Garrett, M.D., Terri Brown-Whitehorn, M.D., and Jonathan M.Spergel, M.D., Ph.D Biphasic reactions in children undergoing oral food challenges Division of Allergy and Immunology,Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania May-June 2013, 34:220-226
  2. Ratchaya Lertnawapan and Wirach Maek-a-nantawat Anaphylaxis and Biphasic Phase in Thailand: 4-year Observation. Japanese Society of Allergology 2011, Allergology International,2011;60:283-289
  3. S.Mehr, W.K.Liew, D.Tey, M.L.K.Tang Clinical predictors for biphasic reactions in children presenting with anaphylaxis Blackwell Publishing Ltd 2009; Clinical Et Experimental Allergy 39, 1390-1396
  4. Anne K. Ellis, MD, FRCPC, and James H. Day, MD, FRCPC Incidence and characteristics of biphasic anaphylaxis Division of Allergy and Immunology, Queens University, Kingston, Ontario. 2007;98:64-69
  5. Joyce M.Lee and David S. Greenes Biphasic Anaphylactic Reactions in Pediatrics 2000;106;762