Multiphasic anaphylaxis in the emergency and intensive care setting

Authors: Margret Ann Schneider, Hans de Groot, Jan-Willem Geerts

Abstract

Anaphylaxis, the most severe form of an allergic reaction, is a potentially life-threatening systemic reaction requiring prompt and effective management. A subset of cases shows a recurrence of symptoms despite adequate care and full clinical response. These biphasic or even multiphasic courses provide a unique challenge for clinicians, especially as reported incidence varies, risk factors are unclear and clear management strategies are lacking in current guidelines. This is especially true for multiphasic anaphylaxis presenting with multiple relapses into anaphylaxis despite adequate response to standard treatment with epinephrine. Due to the relatively rare occurrence of multiphasic anaphylaxis, case reports providing examples of clinical management can provide an important source of insight into this clinical problem.

In this study, we present the case of a woman in her 60s presenting with multiphasic anaphylaxis to clarithromycin, with subsequent analysis showing a high likelihood of systemic mastocytosis, though she did not meet formal diagnostic criteria.

Background

Anaphylaxis is a severe and—especially in anaphylactic shock—potentially life-threatening allergic reaction, and a common cause of presentation to emergency care.13 However, a subset of cases shows a biphasic or even multiphasic course, characterised by initial anaphylactic reaction to a trigger, followed by resolution of symptoms, that is, an asymptomatic phase and then recurrence of symptoms without re-exposure to the allergen. This reaction is usually observed within the first 24 hours after initial allergen exposure, but reports include symptom recurrence up to 78 hours later.^4^ Reported incidence of biphasic anaphylaxis varies widely, ranging from 0.4% to 23.3%,^4 5^ though most data points towards an incidence between 4% and 6%.^4^ Due to the possibility of relapse, a period of observation after anaphylaxis is commonly advised even if symptoms initially resolve fully. However, definitions of biphasic anaphylaxis are at times inconsistent and treatment guidelines vary, with the role of corticosteroids being brought into question in recent years. Multiphasic anaphylaxis, presenting with multiple episodes of symptom recurrence, presents a special challenge with regard to treatment and observation protocols. In this study, we present the case of a woman in her 60s presenting with a multiphasic anaphylactic reaction to clarithromycin.

Case presentation

A woman in her 60s, with a known allergy to beta-lactam antibiotics, presented to the emergency department (ED) with anaphylaxis following oral clarithromycin 500 mg.

The patient’s medical history included diabetes mellitus type 2, hypertension, psoriasis and depression. Her weight was 104 kg. Her medication in use was metformin (two times a day 500 mg), gliclazide (once daily 80 mg retard), hydrochlorothiazide (once daily 25 mg), omeprazole (once daily 20 mg) and sertraline (once daily 100 mg). Her last dose of hydrochlorothiazide was taken in the morning, over 12 hours before ED presentation.

The patient had presented with a mild allergic reaction to amoxicillin in her adolescence, which was limited to facial swelling without oropharyngeal swelling, rash, hypotension or dyspnoea, and furthermore had previously displayed a strong local skin reaction to a wasp sting, but without any systemic symptoms. However, the following clinical admission was the patient’s first episode of anaphylaxis.

5 days before ED presentation, she was prescribed clindamycin for erysipelas by her general practitioner. After 5 days of clindamycin use, she developed a (not further described) rash on her abdomen. This was interpreted as a late allergic reaction to clindamycin, for which her general practitioner switched the antibiotic regime to clarithromycin, to which she had had no previous exposure.

She subsequently presented to ED with pruritus, flushing, increased transpiration, agitation and a feeling of swelling in her throat. Symptoms started 1 hour after oral intake of the first dose of clarithromycin, with symptoms worsening progressively over time. She sought medical help 1 hour after first development of symptoms. Her vital signs at initial ED presentation showed hypotension and hypoxaemia (non-invasive blood 74/50 mm Hg, peripheral oxygen saturation 88% at room air, respiratory rate 22 breaths per minute), with initial clinical examination showing facial swelling, new-onset generalised erythema and urticaria over her entire body and increased transpiration and agitation. No swelling of the tongue or throat was observed and cardiac and lung auscultation was normal. Blood glucose was 12.7 mmol/L and her ECG showed a sinus rhythm. She promptly received care for a suspected severe allergic reaction, consisting of intramuscular injection of 0.3 mg epinephrine via auto-injector and slow intravenous injection of 2 mg clemastine, for treatment of the skin reaction following local guidelines. Additionally, she received supplemental oxygen (15 L via non-rebreather mask) and 500 mL of normal saline (sodium chloride 0.9% solution) during initial stabilisation. Supplementary oxygen could be stopped again after good clinical response to epinephrine injection; however, it had to be temporarily restarted during subsequent anaphylactic episodes. Clarithromycin was discontinued with no additional doses taken beyond the single initial dose of 500 mg orally.

Initially, a good response to this therapy was observed, with blood pressure returning to normal levels and facial swelling as well as redness decreasing. The patient was admitted to the acute internal ward, where increased monitoring by specialised nursing staff is provided, though without telemetry control. However, despite an initial good response, the patient developed recurrent episodes of symptoms fitting anaphylactic shock within the first 12 hours of admission. The patient was admitted to the intensive care unit (ICU) after the first relapse of anaphylactic shock for further monitoring. Each episode required intramuscular administration of epinephrine to resolve (figure 1) with a total of four anaphylactic episodes including the primary ED presentation. The first two epinephrine doses were administered by auto-injector containing 0.3 mg epinephrine intramuscularly and the second two doses were administered by individually prepared doses of 0.5 mg epinephrine intramuscularly. Though the dosage of the auto-injectors available at our clinic is lower than the recommended 0.5 mg, the use of auto-injectors is our preferred method in time-sensitive settings (as during the initial stabilisation of a new patient on the ED) or in settings where emergency treatments, such as for anaphylaxis, are not highly routine and where hesitancy due to unfamiliar medication might otherwise delay treatment. Treatment was supplemented by corticosteroids after the first recurrence of anaphylaxis, due to the traditional role of corticosteroids in the prevention of biphasic anaphylaxis. She received both 30 mg of prednisone intravenously daily for 5 days as well as 8 mg of dexamethasone intravenously once, due to differences in recommendations in our hospital’s general ward anaphylaxis protocol and intensive care anaphylaxis protocol. Furthermore, she received 2 mg of clemastine intravenously twice for treatment of cutaneous symptoms and an additional 500 mL of normal saline solution during the second episode of anaphylaxis. Interestingly, the intensity of symptoms lessened with each episode of anaphylaxis, ranging from deep hypoxaemia with cyanosis, hypotension and severe dyspnoea at first to dyspnoea, recurrence of rash and pruritus during the last episode.

The department of allergology was consulted early on for specialised treatment advice. In this study, two alternative treatment courses were considered. First, continuous administration of epinephrine via intravenous pump was considered, pre-emptively treating anaphylaxis instead of waiting for symptom recurrence. Alternatively, in light of the slowly decreasing symptom intensity, an expectant approach was considered to see if symptoms would resolve spontaneously. Both approaches provided serious risks, underpinned by the lack of literature providing treatment guidance in multiphasic cases.

Outcome and follow-up

Ultimately, neither treatment approach was necessary as the patient did not show further symptom relapse after this point. After approximately 24 hours without renewed anaphylaxis, she was transferred back to a standard care ward. She was ultimately discharged from the hospital after 3 days of admission. She was started on the antihistamine levocetirizine as a new standard medication and given and taught to use an epinephrine auto-injector (0.3 mg). She has since had no further episodes of anaphylaxis.

Due to the atypical and prolonged clinical course, further analysis into underlying causes was instigated. This analysis revealed a high probability of systemic mastocytosis, which, however, did not conform to the requirements of a formal diagnosis (only two WHO minor criteria, major criteria not assessable due to limited material obtained in the bone marrow biopsy, see figure 2). Tryptase levels during the third anaphylactic episode, as well as baseline tryptase levels, were increased and remained increased during follow-up via the allergologist, as shown in table 1.

Unfortunately, tryptase levels were not determined during the initial workup of the first anaphylactic episodes, meaning that the recommended intervals for tryptase level evaluation were not adhered to. Guidelines recommend a minimum of two, ideally three tryptase samples, taken at specific intervals.^3^ An initial sample is recommended as soon as feasible without delaying treatment, followed by a second sample 1–2 hours (but within 4 hours) of the onset of symptoms, when tryptase levels usually peak and a third sample taken a minimum of 24 hours after full clinical resolution to establish baseline tryptase levels.^3^ In the case presented, the first tryptase sample was taken 1 hour after the third anaphylactic episode and the second sample was taken 27 hours after the last recurrence of anaphylaxis.

No allergy confirmation test was performed, as risking renewed serious anaphylaxis through, for example, skin testing was not deemed proportional, underpinned by the relative ease with which further exposure can be avoided. Further relevant findings which are in line with systemic mastocytosis included hepatomegaly in abdominal sonography and possible neuropsychiatric symptoms including depression and memory problems.

Discussion

Anaphylaxis itself is a fairly well-defined clinical diagnosis, characterised by the sudden onset and rapid progression of symptoms involving the airway, breathing, circulation and/or gastrointestinal tract and typically accompanied by cutaneous or mucosal manifestations such as urticaria, angioedema or flushing. While identification of a likely allergen supports the diagnosis, it is not always possible to determine a specific trigger.^1 3^

Complex presentations, such as biphasic or refractory anaphylaxis, are less well defined, although recent efforts have aimed to establish consensus definitions here as well.^6^ The Resuscitation Council UK defines biphasic anaphylaxis as a recurrence of symptoms several hours after apparent symptom resolution in the absence of further allergen exposure.^3^ Differentiating true biphasic reactions from sustained anaphylaxis with transient response to epinephrine or ongoing allergen absorption (eg, from residual food or slow-release medication) can be challenging.^3^ Refractory anaphylaxis, by contrast, refers to persistent anaphylaxis with no or insufficient response to correctly administered epinephrine.^3^

Guideline recommendations concerning biphasic anaphylaxis primarily address clinical monitoring. Despite this, optimal observation duration remains debated. Traditional observation periods range from 4 to 6hours following symptom resolution.^7^ The Dutch Nederlands Huisartsen Genootschap (NHG)^1^ and the World Allergy Organisation^2^ guideline note that approximately half of biphasic reactions occur within 6–12 hours after the initial event, but neither provides a specific monitoring recommendation.^1 2^ The UK guideline 2021,^3^ in contrast, does propose a three-tier risk-stratified approach to monitoring.^3^ Consensus monitoring strategies are clearly needed to meet the challenge of balancing healthcare resources (large group of single episode anaphylaxis) with patient safety requirements (risk of complications in small and difficult to identify biphasic group).

Advice for advanced medication strategies in biphasic and multiphasic courses is noticeably and troublingly lacking. Management of biphasic and multiphasic anaphylaxis largely mirrors standard anaphylaxis treatment, consisting of prompt intramuscular epinephrine combined with appropriate supportive care.13 The recommended epinephrine dosage in guidelines is 0.01 mg/kg of body weight, with a maximum total dose of 0.5 mg.^2^ This is often simplified to 0.5 mg for adults,13 as a majority of adults weigh above 50 kg. However, it is striking to note that many auto-injectors, such as those used to treat the first two anaphylactic episodes in our presented case, contain only 0.3 mg of epinephrine, even if intended for use in adults. Epinephrine auto-injectors play an essential role in the preclinical setting, but can be beneficial even in medical settings, as they can minimise treatment delay and reduce treatment hesitancy with personnel that only rarely comes in contact with vasoactive agents such as epinephrine. However, the use of a 0.3 mg epinephrine auto-injector, while not uncommon, leads to a potentially critical underdosing in adults over 50 kg. A 2025 retrospective study showed that patients who initially received 0.3 mg epinephrine needed escalation of care, such as additional epinephrine injections, significantly more often than those who initially received 0.5 mg epinephrine.^8^ Breaking down barriers, such as practitioner comfort with the historically recommended 0.3 mg dosage and the high availability of 0.3 mg auto-injectors, and improving adherence to the recommended epinephrine dosages could critically improve anaphylaxis treatment.

Traditionally, the use of corticosteroids was recommended, in part to prevent biphasic reactions.^9^ However, mounting evidence demonstrates no benefit and even potential harmful effects, leading to a recent shift away from the use of steroids in anaphylaxis.^10 11^ A 2017 systematic review^12^ examined 22 studies with only one of these studies supporting the use of corticosteroids and 21 studies showing no evidence that corticosteroids reduce the risk of biphasic anaphylaxis.^12^ Furthermore, recent studies emphasise the relevance of side effects,^13^ with one 2019 study even showing an increased likelihood of ICU/hospital ward admission after prehospital corticosteroid treatment.^14^ Consequently, most contemporary guidelines advise against routine corticosteroid administration, although their use in clinical practice persists.13

Biphasic anaphylaxis is rare but clinically highly relevant. The absence of reliable predictors complicates risk stratification and monitoring decisions. Suggested predictors include delayed epinephrine administration, severe initial presentation, multiple epinephrine doses and prior biphasic reactions.^3 4 7^ However, reliable predictors allowing targeted monitoring are not yet available.

Systemic mastocytosis, involving an abnormal increase in mast cells, excessive mediator release and multiorgan inflammation, predisposes patients to severe anaphylaxis. 1517 However, given the rarity of both conditions, to our knowledge, there is currently no research specifically addressing the role of systemic mastocytosis in biphasic anaphylaxis. Further research into mast cell disorders and biphasic anaphylaxis may provide valuable insights for future management.

Fortunately, anaphylaxis mortality is low, especially in regions with timely access to emergency medical care. Furthermore, fatal outcomes of biphasic anaphylaxis are even rarer, despite their apparent inherent danger.^3^ However, notwithstanding these reassuring statistics, anaphylaxis remains a common emergency demanding prompt treatment and adequate monitoring. While initial emergency medical care is the focus of research and of guidelines, subsequent medical care and monitoring is of course also of great importance. A clearer understanding of complex anaphylaxis courses, such as biphasic anaphylaxis, could pave the way to a more targeted, patient-centred and resource-efficient anaphylaxis management.

The rarity of biphasic and especially multiphasic anaphylaxis and the barriers inherent to research in emergency situations make the development of true evidence-based strategies a great challenge. Expert-based consensus guidelines with clear management recommendations are a deeply valuable option in such situations; however, the development of expert-based recommendations is also hampered by the lack of available data. In light of the rarity of these complex anaphylaxis courses, a registry of such cases, including salient patient, suggestions for possible management strategies, as given in our case report, and outcome data, could provide the backbone for data-driven expert-based recommendations.