Biphasic and protracted anaphylaxis

INTRODUCTION — 

Most episodes of anaphylaxis begin quickly, escalate, and then resolve completely, particularly when appropriate treatment is administered. However, some anaphylactic reactions resolve and recur hours later or do not resolve completely despite adequate treatment.

Atypical patterns of anaphylaxis, the incidence of atypical patterns of reactions, and proposed risk factors for these reactions will be reviewed here. The diagnosis and treatment of anaphylaxis, fatal anaphylaxis, and other topics related to anaphylaxis are discussed separately:

●(See "Anaphylaxis: Acute diagnosis".)

●(See "Anaphylaxis: Emergency treatment".)

●(See "Fatal anaphylaxis".)

DEFINITIONS AND INCIDENCE — 

There are four recognized temporal patterns of anaphylaxis: uniphasic, biphasic, persistent or protracted, and refractory [1,2]. In each pattern, symptoms must fulfill the diagnostic criteria for anaphylaxis (figure 1).

Uniphasic anaphylaxis — Uniphasic anaphylactic reactions are the most common type, accounting for an estimated 80 to 94 percent of all episodes. A uniphasic response typically peaks within hours after symptom onset and then either resolves spontaneously or after treatment, usually within several hours [3].

Biphasic anaphylaxis — Biphasic reactions are characterized by an initial reaction that meets criteria for anaphylaxis, followed by an asymptomatic period of one hour or more, and then a subsequent return of symptoms meeting the criteria for anaphylaxis without further exposure to antigen. An expert consensus and guideline recommendations are to consider reactions up to 48 hours after resolution as biphasic [1,2].

Incidence in emergency departments — Most studies examining the incidence of biphasic reactions have been done in emergency departments (EDs). A meta-analysis estimated an overall incidence of 5 percent, with a median time to onset of 11 hours, based on over 4000 patients in 27 observational studies [4]. A subsequent review of European and Brazilian ED data found a similar (4.7 percent) incidence [5].

Other settings — Other settings in which anaphylaxis is encountered with regularity include allergy clinics and radiology departments.

●Allergy clinics:

•Biphasic reactions occurred in 10 and 23 percent of anaphylaxis cases in two studies of patients receiving immunotherapy, both of which included adults and children [6,7].

•Rates of biphasic anaphylaxis were much lower in a study of children undergoing oral food challenges (1.5 to 2 percent) [8,9]. (See "Oral food challenges for diagnosis and management of food allergies", section on 'Safety'.)

●Radiology departments – Biphasic events occurred in 10.3 percent of cases in a retrospective study of reactions due to the administration of radiocontrast [10].

Note that reported rates of biphasic reactions in allergy clinics and radiology departments are higher as compared with those in the ED. It is possible that this is due to route of exposure of the antigen. Data suggest that risk of biphasic reactions is higher with more severe presentation, such as widened pulse pressure, and this is typically seen more often with parenteral route of exposures, such as with subcutaneous allergy immunotherapy and radio contrast media. This is supported by the lower rate of biphasic reactions with oral food challenges in the allergy clinic setting. Biphasic reactions are discussed in more detail below. (See 'Biphasic reactions' below.)

Persistent or protracted anaphylaxis — A persistent or protracted anaphylactic reaction lasts hours to days without clearly resolving completely. Some experts have suggested that symptoms should persist for at least four hours, regardless of treatment [1]. The exact incidence of protracted episodes of anaphylaxis is unknown, although they appear to be uncommon. In one study, the incidence of protracted anaphylaxis in patients undergoing radiologic procedures was 4.1 percent [10]. The literature consists only of case reports and small series [10-16].

Refractory anaphylaxis — Refractory anaphylaxis can be defined as continued symptoms of anaphylaxis despite appropriate epinephrine dosing and symptom-directed treatment (eg, intravenous fluids for hypotension), and one expert panel suggested that the term be applied to reactions that had been treated with at least three doses of epinephrine or initiation of an epinephrine infusion [1]; however, other groups have suggested that this be applied after receipt of two doses of epinephrine [17]. There is clearly overlap between persistent/protracted anaphylaxis and refractory anaphylaxis. The management of refractory anaphylaxis is discussed separately. (See "Anaphylaxis: Emergency treatment", section on 'Refractory anaphylaxis'.)

BIPHASIC REACTIONS — 

The remainder of this topic will focus on biphasic anaphylaxis since more data are available regarding biphasic compared with protracted reactions, and biphasic reactions occurring after a patient has been discharged pose the greatest clinical dilemma for the treating clinician.

Cause and severity — Biphasic reactions have been reported in both adults and children and with an array of allergens, including ingested, injected, and intravenously administered substances, as well as in idiopathic anaphylaxis [4,6-10,14-16,18-46]. The clinical presentation of the biphasic symptoms can be similar to or different from the initial presenting symptoms.

Most studies report that recurrent symptoms are usually less severe than the initial symptoms [6,7,23,25,40,47]. A literature review focused on emergency department (ED) cases found that biphasic reactions were usually not "clinically significant" [47]. Urticaria seems to be particularly common during the second wave of symptoms, but isolated urticaria without other symptoms does not meet criteria for anaphylaxis [26]. However, the second phase of an anaphylaxis episode can be more severe or even fatal, although only a few fatalities have been reported [5,14,23,26,39,47].

Timing of recurrent symptoms — Expert consensus and guideline recommendations are to consider reactions up to 48 hours after resolution as biphasic [1,2]. Consistent with this, the time between the resolution of the first reaction and the start of the second can range from 1 hour to up to 48 hours [18,30,41,47].

The average time to onset of recurrent symptoms was 10 hours in a study involving 103 patients who were contacted after an ED visit for anaphylaxis [26]. However, 40 percent of patients in this series had recurrent symptoms more than 10 hours after resolution of initial symptoms.

Theories of pathogenesis — The pathophysiology of biphasic anaphylaxis is not fully known and is likely to involve similar mediators as anaphylaxis in general (see "Pathophysiology of anaphylaxis"). Theories about why there is a recurrence of symptoms in biphasic cases include the following:

●Influx of inflammatory cells – One theory propounds that the biphasic response, like allergic responses seen in the skin and the respiratory tract following allergen challenge, is due to the influx of inflammatory cells that occurs in response to cytokines and chemotactic factors released during the initial response [40]. Mast cell degranulation is responsible for the initial symptoms in the skin following injection of allergen or in the lung following inhalation of allergen. This is followed over the next two to eight hours by a highly reproducible influx of other inflammatory cells, including eosinophils, basophils, and lymphocytes. These cells are responsible for delayed swelling at the site of skin testing and the late-phase asthmatic response. In keeping with this theory is the observation that the severity of anaphylactic events correlates with the level of inflammatory mediators that have chemotactic and/or inflammatory potential, such as interleukin (IL) 6, IL-10, and complement components C3a and C4a [6,23,26,34]. In addition, the frequency of biphasic reactions have been found to correlate with the levels of mast cell tryptase, histamine, and the cytokines IL-6, IL-10, and tumor necrosis factor (TNF) receptor [34].

However, the above model does not account for the variability seen in biphasic anaphylactic responses. Recurrent symptoms can occur as early as one hour and as late as three days after resolution of the first reaction, and this period is highly variable from patient to patient. Furthermore, histologic findings in patients experiencing fatal biphasic reactions have shown increases in eosinophils and mast cells in the spleen but not in the presumed target organs [48].

●Second wave of mast cell degranulation – The biphasic response may be related to a second wave of mast cell degranulation. In some murine models of anaphylaxis, it was noted that orally administered antigens could result in biphasic degranulation of mast cells [49]. Peak periods of mediator release consistently occurred at 30 minutes and 72 hours after a single oral challenge. An inflammatory infiltrate was apparent by 72 hours. However, this model would not explain cases of biphasic anaphylaxis in humans that occur quickly (ie, one to eight hours after resolution of the first response).

●Late synthesis of platelet-activating factor – In a murine model of penicillin-induced anaphylaxis, it was found that a late-occurring synthesis of platelet-activating factor (PAF) was responsible for a second delayed reaction [50]. This was in part due to release of TNF-alpha from mast cells during the initial reaction because inhibition of TNF-alpha resulted in ablation of both the late-phase response and the late increase in PAF. The role of PAF in murine anaphylaxis is well established. Also, serum PAF levels have been reported to be elevated in humans with severe or fatal anaphylaxis [51]. (See "Pathophysiology of anaphylaxis".)

●Effects of therapies "wearing off" – Another theory suggests that biphasic responses have no unique pathogenesis but simply represent a protracted event that undergoes a temporary remission and then recurs as treatments or endogenous counterregulatory mechanisms "wear off." In this theory, the biphasic reaction is simply a form of a protracted reaction with only two phases. However, it seems unlikely that this explanation would account for episodes occurring as late as 24 hours or later after the event. Another argument against this hypothesis is the large number of predisposing characteristics and cofactors distinguishing biphasic from uniphasic events, implying qualitative distinctions [5].

●Uneven antigen absorption – A final theory about the pathogenesis of biphasic anaphylaxis implicates uneven antigen absorption. For example, one early series examining biphasic reactions reported that biphasic reactions were more common following oral allergen exposure, [23]. However, this does not appear to be the case in most other series, suggesting that antigen absorption is probably not a significant factor.

Possible risk factors — Based on available data, it is not possible to predict with confidence which patients will develop a biphasic response. A systematic review that formed the basis of a 2020 update to the practice parameter of the North American Joint Task Force identified 32 studies, mostly observational and retrospective, that evaluated risk factors for biphasic anaphylaxis [42]. Other meta-analyses and studies have also addressed this issue [4,5,44]. The table summarizes possible risk factors for biphasic anaphylaxis (table 1).

Severe initial symptoms — The systematic review underlying the practice parameter update identified the need for more than one dose of epinephrine (odds ratio [OR] 4.82, 95% CI 2.70-8.58) and severe initial symptoms, such as hypotension (OR 2.11, 95% CI 1.23-3.61) or a widened pulse pressure, as probable risk factors for biphasic reactions [42].

Other studies of adults and children have also found that more severe initial reactions, such as those with respiratory or cardiovascular symptoms, were associated with higher rates of biphasic reactions [4,5,52].

Inadequate or delayed epinephrine — Inadequate or delayed administration of epinephrine is associated with biphasic events [19,26,30,38,41-44,53].

●In a prospective study of 430 ED visits for anaphylaxis, approximately 5 percent of patients had clinically significant biphasic reactions [44]. The median time from anaphylaxis onset to an initial epinephrine dose was longer for patients with biphasic than uniphasic reactions (78 versus 45 minutes, respectively).

●In the 2020 systematic review, >60 minutes to first epinephrine dose was also found to be associated with biphasic anaphylaxis based on eight retrospective studies (very low certainty; OR 2.29) [42].

Other possible risk factors — Other risk factors emerge from additional case series, but these may be only relevant in certain cohorts as they do not seem consistent across studies. For example, in one of the largest anaphylaxis series to date, conducted throughout Europe and Brazil, several other factors were associated with an increased risk of biphasic reactions: anaphylaxis triggered by peanut/tree nut or an unknown elicitor, exercise as a cofactor, chronic urticaria as a comorbidity, a prolonged interval between contact with the elicitor and the start of primary symptoms, and antihistamine treatment with or without glucocorticoids [5]. An unknown trigger was a possible risk factor in other studies as well [4,37].

Prevention — Because delay in receipt of epinephrine was a risk factor in most case series, prompt treatment with epinephrine that results in complete resolution of symptoms is believed to be the most effective means of preventing biphasic anaphylaxis. Adjunctive therapies, such as antihistamines and glucocorticoids, have not been shown to have benefit in preventing recurrent symptoms.

●Antihistamines are useful in acute anaphylaxis for the management of pruritus and urticaria. However, they should not be given before or instead of epinephrine. In addition, the 2020 systematic review did not identify a significant benefit in the prevention of biphasic anaphylaxis from histamine 1 (H1) receptor antihistamines (OR 0.71, 95% CI 0.47-1.06) or histamine 2 (H2) receptor antihistamines, although these data come from observational studies with low numbers of events. Thus, the update to the American practice parameters suggested against administering antihistamines for the purpose of preventing recurrent anaphylaxis [42]. However, antihistamines are often given in the days following an episode of anaphylaxis to prevent or treat isolated urticaria that may persist or recur.

●Glucocorticoids are sometimes administered in the treatment of anaphylaxis, although they are not believed to impact acute symptoms, because mast cells are relatively resistant to their pharmacologic effects and the onset of action is slow (four to six hours). It has been theorized that glucocorticoids may help prevent biphasic reactions by suppressing the later inflammatory changes that variably follow. However, the 2020 systematic review did not identify a significant benefit in the prevention of biphasic anaphylaxis from glucocorticoids (OR 0.87, 95% CI 0.74-1.02), and, for patients under 18 years of age, treatment with glucocorticoids was associated with a slightly increased risk of biphasic anaphylaxis (OR 1.55, 95% CI 1.01-2.38), although confounding based on reaction severity could not be ruled out. Thus, the update to the American practice parameters suggested against administering glucocorticoids for the purpose of preventing recurrent anaphylaxis [42], as have other expert groups [46,54,55]. (See "Anaphylaxis: Emergency treatment".)

In contrast, glucocorticoids are sometimes given to patients following anaphylaxis who have developed extensive facial/oropharyngeal angioedema or significant asthma symptoms for the purpose of speeding the resolution of these specific symptoms in the ensuing days.

OBSERVATION AND ADMISSION — 

Guidelines have attempted to provide more specific guidance about the need for admission or prolonged observation following treatment for anaphylaxis. In particular, most have advocated for decreased observation time for low-risk patients to promote more cost-effective and patient-centered care.

●After persistent, protracted, or refractory – Patients with persistent/protracted and refractory anaphylaxis clearly must be observed and treated for extended periods or admitted to a hospital.

●After uniphasic – In contrast, there is no consensus about the optimal time to observe a patient after successful treatment of uniphasic anaphylaxis, and the uncertain risk of biphasic anaphylaxis presents a clinical dilemma. It is our approach to consider patients to be at low risk for recurrent symptoms if they had uniphasic anaphylaxis, received epinephrine in a timely manner, and responded promptly to a single dose with resolution of symptoms. For such patients, observation for one to two hours after the complete resolution of symptoms is generally sufficient. Possible risk factors for biphasic anaphylaxis should also be considered (table 1), as well as practical issues, such as distance from care or presence/lack of supervision.

Studies addressing length of observation after anaphylaxis treatment have reached varying conclusions ranging from as soon as there is resolution of initial symptoms to as long as 12 hours [33,34,45,47,56-59]. One of the largest of these was a retrospective study of over 5000 children presenting to multiple emergency departments (EDs) with anaphylaxis [52]. The study found that the risk of requiring an additional dose of epinephrine was <2 percent at 115 minutes after the initial dose for all patients and <2 percent after 161 minutes for patients with initial cardiovascular symptoms (eg, presyncope, hypotension). Given that 95.3 percent of patients in the cohort would have been safely discharged two hours after receiving the first epinephrine dose and that 98.1 percent of patients would have been safely discharged four hours after the first epinephrine dose, the authors felt that a two-hour observation was reasonable for most pediatric patients, with a four-hour observation for those with cardiovascular symptoms.

Various guidelines and practice parameters suggest the following:

•The 2020 update to the American anaphylaxis practice parameters suggested that a one-hour observation time after full resolution of symptoms may be reasonable for most anaphylaxis cases. However, patients with a severe initial presentation (ie, involving hypotension or widened pulse pressure) or the need for more than one dose of epinephrine to treat initial symptoms should be observed longer because they may be at increased risk for a biphasic reaction; although the amount of observation time was not specified, a six-hour observation time was suggested [42]. This guidance was evaluated in one small, retrospective study from a single pediatric ED suggesting that shortening observation times for patients without these risk factors for biphasic reactions is reasonable, but extending observation times in higher-risk patients would still not have picked up most cases of biphasic reactions [60].

•The UK concise clinical guidance for anaphylaxis recommends the following periods of observation after the resolution of symptoms [46]:

-Two hours for patients with a prompt (10 to 15 minutes) and complete response to a single dose of epinephrine given within 30 minutes of the onset of symptoms if the patient already has epinephrine for self-administration and will be supervised.

-At least six hours if the patient required two doses of epinephrine or has a history of a biphasic reaction.

-At least 12 hours if the patient had a severe reaction, required more than two doses of epinephrine, has severe asthma, or had respiratory compromise during the reaction or a trigger that could have ongoing absorption (eg, slow-release medication, food).

•The 2022 European guidelines suggest monitoring for 6 to 8 hours if patients had respiratory compromise and at least 12 to 24 hours for patients with hypotension [54]. In addition to severity, factors that should prompt longer observation include needing more than one dose of epinephrine to treat the initial reaction, an unknown trigger, or a trigger that could have ongoing absorption (eg, food). No specific time range is provided for longer observation.

DISCHARGE CARE — 

When patients are discharged after anaphylaxis, important issues include ensuring that patients:

●Understand that anaphylaxis is potentially life threatening (see 'Information for patients' below)

●Have access to epinephrine for self-administration (autoinjector or nasal spray) and fill the prescription on the way home if they do not already possess one

●Understand how and when to use epinephrine

●Are informed that symptoms can recur up to three days after the initial episode and, in some cases, can be more severe than the initial symptoms

Issues surrounding discharge care after anaphylaxis are discussed in more detail separately. (See "Anaphylaxis: Emergency treatment", section on 'Discharge care'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anaphylaxis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Anaphylaxis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Anaphylaxis treatment and prevention of recurrences (Beyond the Basics)" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patterns of anaphylaxis – There are four recognized temporal patterns of anaphylaxis: uniphasic, biphasic, persistent/protracted, and refractory. Most patients have uniphasic reactions, while biphasic reactions are uncommon and refractory and protracted reactions are rare. (See 'Definitions and incidence' above.)

●Characteristics of biphasic reactions – Biphasic reactions are characterized by an initial reaction that meets criteria for anaphylaxis (figure 1), followed by an asymptomatic period of 1 to 48 hours (72 hours by some definitions), and then a subsequent return of symptoms that again meet the criteria for anaphylaxis, without further exposure to antigen. Biphasic reactions are estimated to occur in up to 5 percent of anaphylaxis cases, with a mean time to recurrent symptoms of approximately 11 hours; however, rates may differ by setting of study and route of exposure to the allergen. In most patients, recurrent symptoms are less severe than the initial symptoms. However, in a minority of patients, recurrent symptoms are more severe. Fatalities from biphasic symptoms are rare. (See 'Biphasic reactions' above.)

•Possible risk factors – Risk factors for biphasic anaphylaxis have not been conclusively established, although available evidence suggests that a severe initial presentation (eg, hypotension or widened pulse pressure), the need for more than one dose of epinephrine, and delayed initial administration of epinephrine may be risk factors. (See 'Possible risk factors' above and 'Observation and admission' above.)

•Prevention:

-Prompt use of epinephrine may help prevent biphasic reactions – Prompt treatment with epinephrine is believed to be the most effective means of treating anaphylaxis and preventing biphasic reactions. (See 'Prevention' above.)

-No evidence that glucocorticoids or antihistamines prevent biphasic reactions – Neither glucocorticoids nor antihistamines have been shown to help prevent recurrent symptoms, and we suggest against their use for this purpose (Grade 2C). However, antihistamines may be given to prevent recurrence of urticaria, and there may be situations in which administering glucocorticoids for a few days following anaphylaxis is helpful (eg, some patients with baseline asthma that worsened as part of their initial reaction). (See 'Prevention' above.)

●Observation after successful treatment – The clinical details of each case must inform decisions about how long to observe a patient after treatment for anaphylaxis or when admission is appropriate. (See 'Observation and admission' above.)

•Patients with uniphasic anaphylaxis who received epinephrine in a timely manner and responded promptly to a single dose with resolution of symptoms are low risk for recurrent symptoms, and observation for one to two hours after the complete resolution of symptoms is generally sufficient.

•For patients with possible risk factors for biphasic reactions (table 1) or for those with persistent, protracted, or refractory anaphylaxis, longer observation or hospital admission is warranted, depending upon the specific clinical features present.

●Discharge care – Patients who are discharged following anaphylaxis should be informed about the possibility of recurrent symptoms for up to three days after the initial symptoms. If possible, an epinephrine autoinjector or nasal spray should be dispensed to the patient prior to discharge, or the patient should obtain a device within hours of discharge. (See 'Discharge care' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Phillip L Lieberman, MD, who contributed to earlier versions of this topic review.