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 for hours or even days.

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: Emergency treatment" and "Fatal anaphylaxis" and "Differential diagnosis of anaphylaxis in adults and children".)

DEFINITIONS AND INCIDENCE — There are four recognized temporal patterns of anaphylaxis: uniphasic, protracted, refractory, and biphasic [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].

Protracted anaphylaxis — A protracted or persistent anaphylactic reaction lasts hours to days without clearly resolving completely. The exact frequency of protracted episodes of anaphylaxis is unknown, although they appear to be uncommon. The literature consists only of case reports and small series [4-10]. Some experts have suggested that symptoms should persist for at least four hours [2].

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 [2]. The management of refractory anaphylaxis is discussed separately. (See "Anaphylaxis: Emergency treatment", section on 'Refractory anaphylaxis'.)

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. Biphasic reactions have been reported with an array of allergens, including ingested, injected, and intravenously administered substances, as well as in idiopathic anaphylaxis [11]. The time period between the resolution of the first reaction and the start of the second can range from 1 hour to up to 48 hours [11,12]. There are numerous series reporting biphasic events in both adults and children [7-11,13-47].

Estimates of the incidence of biphasic reactions in retrospective and prospective studies vary from 0.4 to 23 percent of all anaphylactic reactions [18,30,35,36,39]. Most studies have been done in emergency departments. A systematic review and meta-analysis estimated an overall rate of 5 percent, with a median time to onset of 11 hours [37]. In this study, patients presenting with initial hypotension or whose reaction was to an unidentified trigger were at increased risk for a biphasic reaction. Only a small number of fatalities have been reported [7,18,21,35,40]. A subsequent literature review designed to analyze only emergency department cases also found that the incidence was lower than in earlier reports and that many biphasic reactions were not "clinically significant" [12]. A subsequent review of European and Brazilian emergency department data found a similar (4.7 percent) incidence [48].

Other studies have reported the incidence of biphasic anaphylaxis in selected clinical settings.

●Biphasic reactions occurred in 10 and 23 percent of cases in two studies of patients receiving immunotherapy, both of which included adults and children [35,38,39].

●Rates of biphasic anaphylaxis were much lower in a study of children undergoing oral food challenges (1.5 to 2 percent) [15,34]. (See "Oral food challenges for diagnosis and management of food allergies", section on 'Safety'.)

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

CLINICAL CHARACTERISTICS — The following case reports vividly illustrate protracted and biphasic anaphylactic reactions [6,7,26].

Protracted reactions — A 33-year-old male developed hives in the groin, followed the next day by abdominal cramps and bloating, vomiting, angioedema of the lip, wheezing, tightness of the throat, and generalized hives [6]. He attributed these symptoms to clams eaten 14 hours before the onset of symptoms. On day 3, the gastrointestinal symptoms continued, and he developed transient lightheadedness. He presented to the hospital on day 4 with continued urticaria, gastrointestinal discomfort, and mild tachycardia. Evaluation was unrevealing, and he was treated with diphenhydramine, cimetidine, and intravenous fluids, with gradual improvement over the next two days. Serum tryptase samples drawn on the fourth and fifth days of illness were elevated, with return to normal when repeated several months later. Clam-specific immunoglobulin E (IgE) in the patient's serum was negative at the time of hospitalization but low-positive several months later.

Biphasic reactions — A 76-year-old atopic male sustained approximately 15 vespid stings [40]. Within 10 minutes, he developed urticaria, erythema, and hypotension (90/60 mmHg, measured by a family member). A clinician was called to his home. Upon evaluation, the patient had cutaneous signs and symptoms but no objective respiratory, central nervous system, or cardiovascular abnormalities, and his blood pressure had returned to normal (120/70 mmHg). He was treated with parenteral "antihistamine and glucocorticoid" and observed for 45 minutes in his home. The urticaria subsided, and the clinician left the home. Approximately 40 minutes after the departure of the clinician, the patient again developed urticaria, followed by angioedema of the neck. The symptoms worsened, and the clinician was called back. The patient died, despite attempts at resuscitation. The autopsy showed "generalized edema of the lungs, brain, glottis, and bowels, due to the severe characteristic systemic compromise of anaphylaxis."

Severity of recurrent symptoms — The case described above illustrates that the severity of recurrent symptoms is unpredictable, and the second phase of symptoms does not necessarily resemble the first [40]. The majority of studies found that recurrent symptoms are usually less severe than the initial symptoms [12,18,20,38,39,41]. Urticaria seems to be particularly common during the second wave of symptoms, and this is often the only symptom [21]. However, the second phase of an anaphylaxis episode can be more severe or even fatal, although fatalities appear to be rare [7,12,18,21,40,48].

Timing of recurrent symptoms — The period of time between resolution of initial symptoms and onset of recurrent symptoms varies substantially. In a study involving 103 patients who were contacted within 72 hours of an emergency department visit for anaphylaxis, the average time to onset of recurrent symptoms was 10 hours [21]. However, 40 percent of patients in this series had recurrent symptoms more than 10 hours after resolution of initial symptoms. Other studies have reported asymptomatic intervals ranging from 1 to 30 hours [13,20-22,27,42]. One study reported a biphasic reaction that occurred 72 hours after the resolution of initial symptoms, although this appears to be an exception to the usual temporal pattern [19].

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.

Theories of pathogenesis — The pathogenesis of biphasic anaphylaxis is not known, although several theories have been proposed:

●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 [41]. 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 [18,21,31,38]. 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 [31].

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.

Histologic findings in biphasic anaphylaxis do not support the above theory either. Studies of patients experiencing fatal biphasic reactions most often lack the characteristic inflammatory cell infiltrates in organs involved in the event [49]. The cell that accumulates in the tissues after fatal anaphylaxis is usually the eosinophil, and, in some reports, no cellular infiltrate is found at all.

Other theories of the pathogenesis of biphasic allergic reactions include the following:

●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 [50]. 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 [51]. 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 are significantly elevated in humans with severe or fatal anaphylaxis [52]. (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 counter-regulatory 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 [48].

●Uneven antigen absorption – A final theory about the pathogenesis of biphasic anaphylaxis implicates uneven antigen absorption. Some series reported that biphasic reactions were more common following oral allergen exposure, although intravenously administered antigens have also caused biphasic reactions [13,18].

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 [43].

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), as probable risk factors for biphasic reactions [43]. A subsequent retrospective review of over 9000 cases of anaphylaxis treated in emergency departments across Europe and Brazil also identified severity of the first phase of symptoms and the presence of multiorgan involvement as potential risk factors for biphasic reactions [48].

Inadequate or delayed epinephrine — Inadequate or delayed administration of epinephrine is associated with biphasic events [13,21,27,36,42-45].

●In a prospective study of 430 emergency department visits for anaphylaxis, approximately 5 percent of patients had clinically significant biphasic reactions [45]. 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) [43].

●The large European/Brazilian case series identified several other factors that 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 [48].

Prevention — 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) antihistamines (OR 0.71, 95% CI 0.47-1.06) or histamine 2 (H2) antihistamines, although certainty in the evidence was very low. Thus, the update to the American practice parameters suggested against administering antihistamines for the purpose of preventing recurrent anaphylaxis [43].

Antihistamines are sometimes given in the days following an episode of anaphylaxis to prevent or treat isolated urticaria that may persist or recur. The use of antihistamines for this purpose has not been studied and is not discouraged.

●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 and certainty in the evidence was rated as very low. Thus, the update to the American practice parameters suggested against administering glucocorticoids for the purpose of preventing recurrent anaphylaxis [43].

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. The use of glucocorticoids for this purpose has not been studied and is not discouraged.

Observation and admission

●Patients with protracted anaphylaxis clearly must be observed and treated for extended periods or admitted to a hospital.

●In contrast, the uncertain risk of biphasic anaphylaxis presents a clinical dilemma. The 2020 update to the American practice parameters suggested that patients with a severe initial presentation (ie, involving hypotension) 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 [43]. We suggest such individuals should be admitted to an observation unit or to a hospital. We typically admit such individuals for at least 24 hours, although the length of observation can be customized based upon patient risk factors and proximity to emergency medical care. In addition, patients should be discharged with an epinephrine autoinjector in hand whenever possible.

●There is no consensus about the optimal observation period following successful treatment for anaphylaxis, and studies have reached varying conclusions ranging from as soon as there is resolution of initial symptoms to 12 hours [12,23,30,31,46,53-56].

DISCHARGE CARE — When patients are discharged after anaphylaxis, important issues include ensuring that patients have access to an epinephrine autoinjector, understand how and when to use it, and have been 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 of discharge care are discussed 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, protracted, refractory, and biphasic. Most patients have uniphasic reactions, while biphasic reactions are estimated to occur in approximately 5 percent of patients. 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, and then a subsequent return of symptoms that again meet the criteria for anaphylaxis, without further exposure to antigen. The severity of recurrent symptoms in biphasic reactions is unpredictable. In most patients, recurrent symptoms are less severe than the initial symptoms. However, in a minority of patients, recurrent symptoms are more severe or even fatal. (See 'Clinical characteristics' above.)

●Possible risk factors for biphasic reactions – Risk factors for biphasic anaphylaxis have not been conclusively established, although available evidence suggests that a severe initial presentation (eg, hypotension), the need for more than one dose of epinephrine, and delayed initial administration of epinephrine may be risk factors. We suggest that patients with these characteristics be observed in a supervised setting (Grade 2C). We typically admit such individuals for at least 24 hours, although the length of observation can be customized based on patient risk factors and proximity to emergency medical care. (See 'Possible risk factors' above and 'Observation and admission' above.)

●Prevention:

•Prompt use of epinephrine may help prevent – 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 help prevent – Adjunctive therapies, such as glucocorticoids and antihistamines, have not been shown to have benefit in preventing recurrent symptoms, and we suggest against their use for this purpose (Grade 2C). However, there may be other situations in which administering these medications for a few days following anaphylaxis is helpful (eg, some patients with extensive angioedema or baseline asthma that worsened as part of their initial reaction). (See 'Prevention' above.)

●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 should be dispensed to the patient prior to discharge, or the patient should obtain an autoinjector within hours of discharge. (See 'Discharge care' above.)