Abstract
Background
Rates of anaphylaxis in early childhood are rising, yet there remains a paucity of data on age‐specific presentations and outcomes. While prompt treatment is essential, symptoms can differ from older children. Observation after stabilization is routinely used; however, no infant and toddler‐specific data guide the duration of monitoring. Identifying predictors of biphasic anaphylaxis could help guide observation times.
Objective
To characterize symptoms of anaphylaxis in infants and toddlers, analyze predictors for biphasic anaphylaxis and get more insight into required observation times in this age group.
Methods
Anaphylaxis cases aged 0–2 years presenting to a major Emergency Department (ED) were reviewed over two 5‐year‐periods. We analyzed clinical features, allergens, and management, comparing uniphasic and biphasic presentations.
Results
Of 567,595 total ED presentations aged 0–16 years, 243 cases of 0–2‐year‐olds (infants/toddlers) presented with anaphylaxis (72/236,217 in 2003–2007; 171/331,378 in 2013–2017). Symptoms included urticaria (85.8%), angioedema (67.8%), wheeze/persistent cough (57.7%), vomiting (42.3%) and flushing (21.8%). Symptoms unique to infants/toddlers were pallor/hypotonia (33.5%) and persistent crying (13.8%).
Biphasic anaphylaxis occurred in 4.6%, was exclusively food‐induced and more common among infants (p = .048). Predictors for biphasic anaphylaxis were lower systolic blood pressure (p = .011), pallor/hypotonia (p = .046), use of fluids (p < .001), and greater severity (p = .014). Timeframe for recurrence of anaphylaxis was 70–330 min.
Conclusion
Increased awareness of age‐specific symptoms is essential for timely recognition and optimal care of infant/young toddler anaphylaxis. Cardiovascular signs, fluid resuscitation, and reaction severity may help predict recurrent anaphylaxis in 0–2‐year‐olds and identify which patients need observation beyond 4 h versus those safe for earlier discharge.
Keywords: anaphylaxis, anaphylaxis management, anaphylaxis severity, anaphylaxis symptoms, biphasic anaphylaxis, food allergy, infant anaphylaxis, predictors for biphasic anaphylaxis
Abbreviations
- AAI
adrenaline autoinjector
- AD
atopic dermatitis
- EAACI
European Academy of Allergy and Clinical Immunology
- ED
Emergency Department
- EDIS
Emergency Department Information System
- FAAN
Food Allergy and Anaphylaxis Network
- GP
General Practitioner
- ICD‐10
International Classification of Diseases, Tenth Revision
- NIAID
National Institute of Allergy and Infectious Diseases
- PED
Pediatric Emergency Department
- PICU
Pediatric Intensive Care Unit
- SSU
Short Stay Unit
Key message.
Anaphylaxis in infants and young toddlers aged 0–2 years can present with phenotypes that differ from those seen in older children; greater awareness of these age‐specific symptom patterns is crucial for timely recognition and appropriate management. Predictors of biphasic anaphylaxis in infants/young toddlers include cardiovascular compromise, the need for fluid resuscitation, and greater initial severity. While prolonged hospital stays can strain health systems and families, early discharge must be balanced against the risk of recurrence. A 4 h observation time seems sufficient for most infants/young toddlers, whereas in those with cardiovascular impairment, >4 h appears safer.
1. INTRODUCTION
Anaphylaxis is a serious allergic (hypersensitivity) reaction that can progress rapidly and may cause death, requiring timely recognition. Adrenaline remains the first‐line of treatment. 1 The rate of anaphylaxis presentations to the Emergency Department (ED) is rising globally, with particularly marked increases reported in young children. 2 , 3 , 4 , 5 , 6 Despite this, standard definitions of anaphylaxis by the World Allergy Organization (WAO), the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network (NAIFAN/FAAN) do not specify signs and symptoms unique to children aged 0–2 years, 7 , 8 , 9 although more recent practice parameters and guiding principles acknowledge them. 1 , 10 , 11
Age‐specific features for anaphylaxis in infants and young toddlers include non‐specific symptom patterns—such as persistent crying, drooling, or abrupt non‐specific behavioral changes—that differ from the typical signs seen in older children and adults. 11 , 12 , 13
Frequently, the first allergic or anaphylactic reaction occurs during the introduction of solid foods. This transitional period can itself produce behavioral responses (for example, refusal, spitting, irritability or persistent crying) that are difficult to distinguish from allergic reactions or anaphylaxis, generating uncertainty and anxiety for families and contributing to both over‐representation and delayed or absent presentation to medical services. The child's limited ability to verbalize symptoms further complicates timely recognition, diagnosis, initiation of treatment, and follow‐up care. 11 , 13 , 14
Hence, improved characterization of symptom patterns in infants and young toddlers with anaphylaxis is essential to support earlier recognition, optimize acute management, determine appropriate observation periods and reduce the risk of representation and hospital admission. However, despite this need, there remains a global paucity of data describing the clinical phenotypes of infant and toddler anaphylaxis. In Australia—where the prevalence of infant food allergy is among the highest in the world 15 —no published studies to date have specifically focused on these age‐specific symptoms.
When anaphylaxis is suspected, ambulance attendance or ED presentation is common to ensure access to critical care and to also permit post‐treatment monitoring for biphasic reactions—delayed recurrences of anaphylaxis that occur without re‐exposure to the inciting trigger after initial resolution. Biphasic anaphylaxis, however, remains relatively uncommon, and most evidence is derived from adult cohorts. 16 , 17 , 18 Pediatric data are limited, 19 , 20 , 21 and no dedicated series have focused on very early childhood. Australia mandates at least 4 h of observation for all age groups after the onset of anaphylaxis as part of national healthcare standards while some international bodies suggest up to 12–24 h. 17 However, prolonged hospital stays for infants and toddlers place particular strain on families because of developmental and logistical challenges unique to early life. Moreover, with rising numbers of infant and young toddler presentations for anaphylaxis to EDs, 2 , 4 , 5 , 6 pressures on the healthcare system are increasing. As such, identifying predictors of biphasic anaphylaxis in this age group could help clinicians triage patients and determine who would benefit most from extended (>4 h) observation versus earlier discharge.
This study aims to characterize symptom patterns and management of anaphylaxis in children aged 0–2 years in an Australian cohort, with a specific focus on the clinical features and predictors of biphasic anaphylaxis, to inform age‐specific care pathways and guideline development.
2. METHODS
2.1. Data collection
Children aged 0–2 years presenting with anaphylaxis to the tertiary Pediatric Emergency Department (PED) at Princess Margaret Hospital (PMH) in Perth, Western Australia, over a 10‐year period (2003–2007 and 2013–2017) 4 were identified using the ED Information System (EDIS) and International Classification of Diseases, Tenth Revision (ICD‐10) codes. PMH was the sole pediatric tertiary hospital and had the only dedicated pediatric ED in the state of Western Australia during this time.
All ICD coding was performed electronically by medical staff and subsequently verified manually via review of patient charts by two independent allergists who collected information on signs of acute allergy and anaphylaxis on standardized forms. Children >2 years of age and/or those who did not clearly fulfill criteria for anaphylaxis were excluded (Figure S1). Other exclusion criteria were no documentation on examination findings or symptoms before presenting to the PED or within the PED, reactions secondary to medications administered in the ED or comorbidities requiring tailored management decisions. For multiple presentations each visit was one encounter. Anaphylaxis was defined according to the Australasian Society for Clinical Immunology and Allergy (ASCIA) criteria. 22
Data collected included baseline characteristics (e.g., gender, weight, history of any atopy, intercurrent infection, vital signs, features of anaphylaxis, severity of anaphylaxis (grading according to Muraro et al. 23 ), suspected allergens, pre‐hospital and in‐hospital management, referrals to an allergist/immunologist, and prescription of an adrenaline autoinjector). At the time of data collection, ASCIA recommended a minimum weight of 10 kg for the prescription of an 150 mcg adrenaline autoinjector (AAI). For infants weighing <10 kg, consultation with an immunologist was required to determine the appropriateness of prescribing an AAI. Overtreatment was defined as administering adrenaline after signs of anaphylaxis had already resolved. Undertreatment was related to situations were (1) Adrenaline was available but not administered (defined as “mismanagement”) or (2) anaphylaxis signs were present in a setting where adrenaline was available but not given (defined as “suboptimal” treatment).
Biphasic anaphylaxis was defined as the presence of one or more anaphylactic symptoms occurring between 1 and 48 h after complete resolution of initial symptoms in the absence of further allergen exposure. 24 This included cases who experienced their biphasic reaction while in the PED and patients who were discharged but returned to the PED because of a anaphylactic episode. Characteristics of biphasic anaphylaxis were compared to uniphasic anaphylaxis. Cases who received a significant adrenaline overdose due to drug errors (n = 4) were excluded from analysis. Data from both time periods (2003–2007 and 2013–2017) were pooled to increase statistical power for this comparison. Ethics approval was granted by the Ethics and Research Governance Committee at Princess Margaret Hospital for Children in Perth, Australia (GEKO, approval number 33427).
2.2. Statistical analysis
Continuous data were described using means and standard deviations and compared between 2003–2007 and 2013–2017 using independent t‐tests, unless when skewed in distribution. For non‐normally distributed data, medians and interquartile ranges (IQR) were reported and compared using the Mann–Whitney U test. Categorical variables were described using frequencies and proportions. Comparisons between groups were made using Chi‐square except where expected cell counts were <5, in which case Fishers exact test was used. A p‐value of <0.05 was considered statistically significant.
3. RESULTS
Across both time periods (2003–2007 and 2013–2017), a total of 1603 out of 567,595 children (0–16 years) were coded for anaphylaxis. Of these, 298 cases (18.6%) were aged 0–2 years, and 239 (80.2%) were confirmed cases of infant anaphylaxis (Table 1 and Figure S1).
TABLE 1.
Baseline characteristics, history of any atopic disease, intercurrent illness and vital signs in infants and young toddlers (0–2 years) between 2003–2007 and 2013–2017.
| Total numbers | Summary data | Comparison | |||
|---|---|---|---|---|---|
| Total population | 2003–2007 | 2013–2017 | p‐value | ||
| Total | 243 | n = 72 | n = 171 | ||
| Weight in kg | 0.271 | ||||
| Mean (SD) | 240 | 9.7 (2.2) | 10.0 (2.5) | 9.6 (2.0) | |
| Gender | 0.090 | ||||
| Female | 243 | 87 (35.8%) | 20 (27.8%) | 67 (39.2%) | |
| Male | 156 (64.2%) | 52 (72.2%) | 104 (60.8%) | ||
| Age in years | 0.499 | ||||
| 0 to < 1 years | 243 | 143 (58.8%) | 40 (55.6%) | 103 (60.2%) | |
| 1 to < 2 years | 100 (41.2%) | 32 (44.4%) | 68 (39.8%) | ||
| Age in months | 0.217 | ||||
| 0– < 6 m | 243 | 22 (9.1%) | 10 (13.9%) | 12 (7.0%) | |
| 6– < 12 m | 121 (49.8%) | 30 (41.7%) | 91 (53.2%) | ||
| 12– < 18 m | 47 (19.3%) | 16 (22.2%) | 31 (18.1%) | ||
| 18– < 24 m | 53 (21.8%) | 16 (22.2%) | 37 (21.6%) | ||
| History of any atopy a | 0.934 | ||||
| No | 239 | 92 (38.5%) | 28 (38.9%) | 64 (38.3%) | |
| Yes | 147 (61.5%) | 44 (61.1%) | 103 (61.7%) | ||
| Intercurrent infection | 0.395 | ||||
| No | 243 | 197 (81.1%) | 56 (77.8%) | 141 (82.5%) | |
| Yes | 46 (18.9%) | 16 (22.2%) | 30 (17.5%) | ||
| Vital signs | |||||
| Heart Rate b | 0.903 | ||||
| Mean (SD) | 236 | 146.1 (22.4) | 145.8 (22.4) | 146.2 (22.5) | |
| Blood Pressure (syst) c | 0.850 | ||||
| Mean (SD) | 154 | 102.4 (19.7) | 103.2 (25.9) | 102.3 (18.5) | |
| Blood Pressure (diast) c | 0.092 | ||||
| Mean (SD) | 152 | 62.2 (17.2) | 57.1 (14.6) | 63.5 (17.6) | |
| Respiratory Rate b | 0.976 | ||||
| Mean (SD) | 231 | 35.3 (7.8) | 35.3 (9.1) | 35.2 (7.2) | |
| Oxygen Saturation d | 0.330 | ||||
| Mean (SD) | 229 | 98.4 (2.9) | 98.7 (2.0) | 98.3 (2.8) | |
Any medically diagnosed history of eczema, food allergy and/or recurrent wheeze. Recurrent wheeze is defined as ≥ 2 wheezy episodes.
Heart Rate and Respiratory Rate/min.
Blood Pressure in mmHg.
Oxygen Saturation in %.
3.1. Baseline characteristics
Population characteristics are summarized in Table 1. Males were overrepresented. Intercurrent infection was noted in 18.9% of cases. Comparing both time periods, there was no difference in the history of atopic diseases (eczema, food allergy, recurrent wheeze). Vital signs were recorded for the majority of children, with no significant differences in heart rate (HR), blood pressure (BP), respiratory rate (RR), and oxygen saturation (Table 1).
3.2. Age‐specific symptoms of anaphylaxis in 0–2 year old children and presumed allergens
Mucocutaneous symptoms were observed in 95.8% (229/239) of cases, respiratory in 81.6% (195/239), gastrointestinal in 43.1% (103/239), neurological in 18.8% (45/239), and cardiovascular symptoms in 33.9% (81/239). BP was recorded in 154 infants/toddlers, with hypotension identified in four cases (2.6%) (Figure 1).
FIGURE 1.
Allergic symptoms of children 0–2 years of age presenting to the Paediatric Emergency Department with anaphylaxis. Features of anaphylaxis were recorded in n = 239 children 0–2 years of age (n = 4 with significant adrenaline overdose were excluded for calculation due to potential influence on clinical progression); *Blood pressure measured in n = 154 patients, n = 4 (2.6% were hypotensive).
A presumed trigger was identified in 230/243 cases. Three were attributed to antibiotics and one to bee venom (Table 2). The vast majority of anaphylaxis cases (226/243, 93.0%) were food‐induced. In four patients, the specific food trigger remained unclear. Egg was the most commonly implicated presumed allergen (74/226, 32.7%). No significant differences were found in symptoms and triggers between the two time periods (Table 2). Novel food triggers, such as coconut, sesame and soy, were observed only in the 2013–2017 cohort.
TABLE 2.
Management of anaphylaxis and presumed allergens in infants and young toddlers (0–2 years of age).
| Total numbers | Summary data | Comparison | |||
|---|---|---|---|---|---|
| Total population | 2003–2007 | 2013–2017 | p‐value | ||
| (n = 72) | (n = 171) | ||||
| Groups of Triggers | 0.422 | ||||
| Food | 230 | 226 (98.3%) | 63 (96.9%) | 163 (98.8%) | |
| Insect | 1 (0.4%) | 1 (1.5%) | 0 (0.0%) | ||
| Drug | 3 (1.3%) | 1 (1.5%) | 2 (1.2%) | ||
| Suspected Food Allergens | 0.185 | ||||
| Egg | 222 | 74 (33.3%) | 23 (36.5%) | 51 (32.1%) | |
| Dairy | 46 (20.7%) | 20 (31.7%) | 26 (16.4%) | ||
| Peanut | 41 (18.5%) | 11 (17.5%) | 30 (18.9%) | ||
| Tree nut | 32 (14.4%) | 6 (9.5%) | 26 (16.4%) | ||
| Kiwi | 2 (0.9%) | 1 (1.6%) | 1 (0.6%) | ||
| Seafood | 4 (1.8%) | 1 (1.6%) | 3 (1.9%) | ||
| Wheat | 11 (5.0%) | 1 (1.6%) | 10 (6.3%) | ||
| Banana | 2 (0.9%) | 0 (0.0%) | 2 (1.3%) | ||
| Coconut | 2 (0.9%) | 0 (0.0%) | 2 (1.3%) | ||
| Sesame | 6 (2.7%) | 0 (0.0%) | 6 (3.8%) | ||
| Soy | 2 (0.9%) | 0 (0.0%) | 2 (1.3%) | ||
| Adrenaline timing from onset | 0.770 | ||||
| Median (IQR in min) | 108 | 40.0 (20.0–60.0) | 40.0 (22.5–62.5) | 40.0 (20.0–75.0) | |
| Anaphylaxis management | 0.008 | ||||
| Optimal | 243 | 129 (53.1%) | 30 (41.7%) | 99 (57.9%) | |
| Suboptimal a | 74 (30.5%) | 36 (50.0%) | 38 (22.2%) | ||
| Mismanagement b | 40 (16.5%) | 6 (8.3%) | 34 (19.9%) | ||
| Adrenaline given, not indicated | 0.999 | ||||
| 243 | 2 (0.8%) | 0 (0.0%) | 2 (1.2%) | ||
| Adrenaline indicated, not given b | 0.007 | ||||
| 243 | 40 (16.5%) | 19 (26.4%) | 21 (12.3%) | ||
| Anaphylaxis symptoms resolved by time of arrival to ED | 0.093 | ||||
| 243 | 147 (60.5%) | 48 (66.7%) | 99 (57.9%) | ||
| Adrenaline given in ED | 0.128 | ||||
| 243 | 92 (37.9%) | 22 (30.6%) | 70 (40.9%) | ||
| Antihistamine given in ED | 0.013 | ||||
| 243 | 112 (46.1%) | 42 (58.3%) | 70 (40.9%) | ||
| Salbutamol given in ED | 0.999 | ||||
| 243 | 15 (6.2%) | 4 (5.6%) | 11 (6.4%) | ||
| IV fluids given in ED | 0.056 | ||||
| 243 | 12 (4.9%) | 6 (8.3%) | 6 (3.5%) | ||
| Oxygen given in ED | 0.200 | ||||
| 243 | 7 (2.9%) | 4 (5.6%) | 3 (1.8%) | ||
| Glucocorticosteroids given in ED | <0.001 | ||||
| 243 | 70 (28.8%) | 48 (66.7%) | 22 (12.9%) | ||
| Disposition | 0.020 | ||||
| Home | 243 | 55 (22.6%) | 14 (19.4%) | 41 (24.0%) | |
| SSU | 152 (62.6%) | 38 (52.8%) | 114 (66.7%) | ||
| PICU | 3 (1.2%) | 1 (1.4%) | 2 (1.2%) | ||
| Ward | 33 (13.6%) | 19 (26.4%) | 14 (8.2%) | ||
| Discharged with AAI | 0.348 | ||||
| Yes | 243 | 169 (69.5%) | 47 (65.3%) | 122 (71.3%) | |
| AAI not dispensed | 0.049 | ||||
| AAI indicated but not dispensed | 75 | 29 (38.7%) | 14 (53.8%) | 15 (30.6%) | |
| Weight too low | 46 (61.3%) | 12 (46.2%) | 34 (69.4%) | ||
| Referral to Immunology | 242 | 0.999 | |||
| 240 (99.2%) | 71 (100.0%) | 169 (98.8%) | |||
Signs and symptoms of anaphylaxis present in a setting where adrenaline was indicated but not given as it was not available.
Signs and symptoms of anaphylaxis present in a setting where adrenaline was available but not given.
3.3. Medical treatment and adrenaline autoinjector dispension
Table 2 details treatment across the full cohort including the years 2003–2007 and 2013–2017. In 147 of 243 cases, symptoms had resolved on arrival at the PED. Adrenaline was administered in 92 cases in the PED. Overtreatment (adrenaline given when not indicated) occurred in two infants (0.8%), while undertreatment (adrenaline not administered although indicated and available) occurred in 40 cases (16.5%). Upon discharge, 169 patients (69.6%) were prescribed an AAI. In 46 cases (18.9%), no AAI was dispensed due to body weight <10 kg.
3.4. Comparing uniphasic and biphasic anaphylaxis cases: Possible predictors for biphasic anaphylaxis in children 0–2 years of age
Biphasic anaphylaxis occurred in 11 of 239 cases: 4/72 (5.5%) in 2003–2007 and 7/167 (4.2%) in 2013–2017, with most requiring ward admission. There was a male predominance (81.8%), and the majority (9/11) were ≤12 months old (Tables 3 and 4). All recurrent anaphylactic events took place in our PED, and there were no representations for biphasic anaphylaxis.
TABLE 3.
Demographics, observational measurements and clinical features comparing cases of uniphasic and biphasic anaphylaxis in infants and young toddlers.
| Total number (n) a uniphasic/biphasic | Uniphasic n = 228 | Biphasic n = 11 | p‐value | |
|---|---|---|---|---|
| Demographics | 228/11 | |||
| Gender (male) (%) | 146 (64%) | 9 (81.8%) | 0.337 | |
| Age in months (median; IQR) | 10 (7.0–17.0) | 7.0 (4.0–11.0) | 0.048 | |
| Weight in kg (median; IQR) | 9.7 (8.3–11.3) | 8.7 (6.9–9.5) | 0.064 | |
| Hx of eczema (%) | 129 (56.6%) | 5 (45.5%) | 0.542 | |
| Hx of recurrent wheeze (%) | 32 (14%) | 1 (9.1%) | 0.999 | |
| Hx of anaphylaxis (%) | 28 (12.3) | 0 (0%) | 0.371 | |
| Observational Data | Median (IQR) | Median (IQR) | ||
| HR per min | 225/11 | 142 (130–160) | 154 (146–163) | 0.050 |
| BP systolic in mmHg | 145/9 | 102 (91–116) | 80 (74–99) | 0.011 |
| BP diastolic in mmHg | 143/9 | 61 (51–75) | 50 (38–64) | 0.099 |
| RR per min | 221/9 | 32 (28–40) | 38 (34–41) | 0.092 |
| SaO2 in % | 218/11 | 99 (98–100) | 98 (97–99) | 0.104 |
| Allergic Features | 228/11 | n (%) | n (%) | |
| Urticaria | 194 (85.1) | 10 (90.9) | 0.999 | |
| Angioedema | 154 (67.5) | 8 (72.7) | 0.999 | |
| Flushing | 50 (21.9) | 2 (18.8) | 0.825 | |
| Vomiting | 97 (42.5) | 4 (36.4) | 0.764 | |
| Diarrhea | 13 (5.7) | 1 (9.1) | 0.493 | |
| SOB | 74 (32.5) | 5 (45.5) | 0.512 | |
| Stridor | 33 (14.5) | 1 (9.1) | 0.998 | |
| Hypoxia | 17 (7.5) | 3 (27.3) | 0.054 | |
| Swollen tongue | 15 (6.6) | 0 (0) | 0.999 | |
| Hoarse voice | 35 (15.4) | 3 (27.3) | 0.388 | |
| Wheeze/persistent cough | 132 (57.9) | 6 (54.5) | 0.999 | |
| Drooling | 42 (18.4) | 0 (0) | 0.220 | |
| Paleness/hypotonia | 73 (32.0) | 7 (63.6) | 0.046 | |
| Hypotension | 3 (1.3) | 1 (9.1) | 0.173 | |
| Persistent cry | 31 (13.6) | 2 (18.2) | 0.652 | |
| Irritability/clinginess | 17 (7.5) | 0 (0) | 0.999 | |
| Symptom Categories b | 228/11 | |||
| Cutaneous | 219 (96.1) | 10 (90.9) | 0.382 | |
| Gastrointestinal | 99 (43.4) | 4 (36.4) | 0.761 | |
| Respiratory | 185 (81.1) | 10 (90.9) | 0.694 | |
| Cardiovascular | 74 (32.5) | 7 (63.6) | 0.048 | |
| Neurological | 43 (18.9) | 2 (18.2) | 0.935 | |
| Severity c | 227/11 | |||
| 1 (mild) | 46 (20.2) | 1 (9.1) | 0.230 | |
| 2 (moderate) | 162 (71.1) | 6 (54.5) | 0.591 | |
| 3 (severe) | 19 (8.3) | 4 (36.4) | 0.014 |
Abbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate.
Significant adrenaline overdose was given in n = 4; cases omitted for calculation of features of uniphasic/biphasic anaphylaxis due to potential influence on clinical progression.
≥ one sign out of symptom category present.
Grading of anaphylaxis according to Muraro et al. 23 .
TABLE 4.
Characteristics of infants and young toddlers presenting with biphasic anaphylaxis to a Pediatric Emergency Department over 10 years.
| No | Age (months) | Weight (kg) | Sex | Hx of atopy | Transport | Trigger | Allergen exposure to first ana sx (mins) | Onset of ana to ED arrival (mins) | Arrival to first adrenaline dose (mins) | Sx of initial ana | Sx of biphasic/ 2nd reaction | Severity c of initial ana | Time to biphasic/recurrent reaction (mins) | Treatment for initial ana | Treatment for biphasic/2nd reaction | Disposition | LOS (hr) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 (2003–2007) | |||||||||||||||||
| 1 | 15 | 11.6 | M | No | Private | Cashew | <5 | 60 | 15 | U, A, W, PC | W | 1 | 75 | A, St | A | Ward | 24 |
| 2 | 4 | 6 | M | Eczema | Private | Dairy | <5 | ND | ND | U, Fl, C, W, HV, HO, PC | S | 3 | 90 | A, O, AH, St | A | SSU | 12 |
| 3 | 11 | 12 | M | No | SJA | Egg | <5 | 45 | 25 | U, A, SOB, S | SOB | 2 | 90 | A, St | A | SSU | 13 |
| 4 | 3 | 7 | M | Eczema | SJA | Dairy | <5 | ND | 10 | U, A, HV, W, P, F | U, SOB | 3 | 205 | A, F, AH, St | A | Ward | 24 |
| Period 2 (2013–2017) | |||||||||||||||||
| 5 | 13 | 8.7 | M | Recurrent wheeze | Private | Egg | 10–20 | 90 | ND | U, A, C, P, F | W | 3 | 70 | A, V | V | SSU | 5 a |
| 6 | 6 | 8.5 | F | Eczema | Private | Egg | 5–10 | 15 | 15 | U, P, F, SOB | SOB | 3 | 90 | A, F | A | Ward | 30 |
| 7 | 7 | 8.8 | M | No | Private | Egg | 90 | ND | ND | V, P, F | P, F | 2 | 90 | A, F | A | Ward | 30 |
| 8 | 11 | 9 | M | No | Private | Peanut | 20–30 | 40 | 40 | U, A, FL, P, F, HT | HT | 3 | 120 | A, F, O, St | A | PICU | 48 |
| 9 | 7 | 9.5 | M | No | SJA | Banana | <5 | 20 | 20 | U, A, V, P, C, HV, W | W | 2 | 80 | A, V | A,V | SSU | 6 |
| 10 | 4 | 6.7 | M | ND | SJA | Dairy | 5–10 | 60 | 45 | U, A, V, D, P, F, SOB |
U, P, F I/C |
2 | 120; then 210 b | A, F, St |
A A |
Ward | 24 |
| 11 | 11 | 6.9 | F | ND | Private | Peanut | 20–30 | 110 | ND | U, A, C | C | 2 | 75 | A, St | A | SSU | 8 |
Abbreviations: A, Adrenaline; A, Angioedema; ana, Anaphylaxis; C, Persistent Cough; D, Diarrhea; F, Floppy; F, Fluids; FL, Flushing; H, Antihistamines; HO, Hypoxia; HT, Hypotension; HV, Hoarse Voice; hx, History; I/C, Irritability/Clinginess; LOS, Length of Stay; ND, no data; O, Oxygen; P, Pale; PC, Persistent Crying; S, Stridor; SOB, Shortness of Breath; SSU, Short Stay Unit; St, Steroids; Sx, Symptoms; TS, Tongue Swelling; U, Urticaria; V, Ventolin; V, Vomiting; W, Wheeze.
Patient discharged against medical advice.
Patient had 2nd anaphylaxis 120 min after symptoms in primary anaphylaxis resolved, and 3rd anaphylaxis 210 min after symptoms of 2nd episode resolved.
Grading of anaphylaxis according to Muraro et al. 23 .
Comparing the two time periods (2003–2007 and 2013–2017) with regards to demographics of uniphasic and biphasic reactors, there were no significant differences in gender, atopic history, intercurrent infection, or history of previous anaphylaxis; however, biphasic reactors were generally younger (median 7.0 months; IQR 4.0–11.0) than children with uniphasic anaphylaxis (median 10 months; IQR 7.0–17.0, p = .048) (Table 3). All biphasic anaphylaxis cases were food‐induced and occurred during the child's first allergic episode. Cooked egg was the most frequently implicated allergen (4/11) (Table 4).
Comparing uniphasic and biphasic cases by focussing on the primary reaction, cardiovascular signs such as paleness/hypotonia (p = .048) and a lower systolic BP (p = .011) were significantly more common in biphasic reactors in which anaphylaxis was also more severe 23 (p = .014) (Table 3). There was a trend towards a higher HR (0.050) in the primary reaction of biphasic reactors. The time interval between the initial and recurrent episodes was 70–330 min. The latter is related to a child (see patient 10 in Table 4) who had 3 distinct episodes of anaphylaxis. Recurrent reactions were generally milder (Table 4).
No adrenaline was administered by caregivers prior to ED arrival in any of the biphasic reactors (Tables 4 and 5). On presentation, symptoms had resolved less frequently in biphasic than in uniphasic cases (p = .026). There was no significant difference in time to adrenaline administration from onset. Compared with uniphasic reactors, biphasic cases more often received at least one dose of adrenaline (p = .050), and there was a trend towards requiring two doses (p = .060) for the initial reaction. Use of oxygen (p = .026), steroids (p = .015), and i.v. fluids (p < .001) was significantly higher in biphasic cases. AAI dispensing did not differ between biphasic and uniphasic groups (Table 5).
TABLE 5.
Uniphasic anaphylaxis versus biphasic anaphylaxis in infants and young toddlers: Treatment administered and follow‐up management.
| Uniphasic (n = 228) | Biphasic (n = 11) | p‐value | |
|---|---|---|---|
| Median (IQR) | Median (IQR) | ||
| Time to first dose adrenaline a | 30 (15;45) | 45 (20;75) | 0.83 |
| n (%) | n (%) | ||
| Adrenaline i.m. administered (≥1 dose) | 136 (59.9) | 10 (90.9) | 0.050 |
| Site of initial adrenaline dose | |||
| Paramedics | 80 (57.6) | 5 (45.5) | 0.533 |
| Other Hospital | 20 (14.4) | 5 (45.5) | 0.020 |
| GP | 21 (15.1) | 1 (9.1) | 0.990 |
| Anaphylaxis resolved on arrival in ED | 141 (61.8) | 3 (27.3) | 0.026 |
| Adrenaline indicated, not given | 38 (16.7) | 3 (27.3) | 0.407 |
| Medication given in ED | |||
| Adrenaline | 80 (35.1) | 10 (90.9) | <0.001 |
| Antihistamine | 109 (47.8) | 3 (27.3) | 0.226 |
| Ventolin | 12 (5.3) | 2 (18.2) | 0.129 |
| Steroids | 62 (27.2) | 7 (63.6) | 0.015 |
| Fluids | 7 (3.1) | 5 (45.5) | <0.001 |
| Oxygen | 4 (1.8) | 2 (18.2) | 0.026 |
| ≥2 doses adrenaline in total for 1st reaction | 79 (34.6) | 7 (63.6) | 0.060 |
| Disposition | |||
| Home | 54 (23.7) | 0 (0) | 0.129 |
| Short Stay Unit | 146 (64) | 5 (45.5) | 0.220 |
| PICU | 1 (0.4) | 1 (9.1) | 0.090 |
| Ward | 27 (11.8) | 5 (45.5) | 0.008 |
| Discharged with AAI | 160 (70.2) | 8 (72.2) | 0.999 |
| Referred to Immunologist | 225 (98.7) | 11 (100) | 0.936 |
n = 107.
4. DISCUSSION
To our knowledge this is the first Australian study and the largest series investigating age‐specific symptoms of confirmed anaphylaxis in 0–2‐year‐old children (n = 243) presenting to ED. It is also the largest series to address the issue of biphasic anaphylaxis in this age group. We analyzed data of infants and young toddlers presenting with anaphylaxis to the sole tertiary PED in Western Australia over 10 years: 2003–2007 and 2013–2017.
Identifying anaphylaxis in very early childhood presents a well‐known challenge due to developmental differences including reduced communication skills (contributing to delayed recognition of clinical signs) and distinct symptom patterns compared to older children. 5 , 25 Consistent with our findings, smaller studies in children aged 0–2 years have also reported non‐specific symptoms such as vomiting, pallor, drowsiness, irritability, persistent crying, and somnolence. 26 , 27
Respiratory symptoms were more frequently reported in our cohort (81.6%) than in most previous studies. 12 , 26 , 27 , 28 This may be influenced by intercurrent infections (18.8%), supporting the concept of a variable anaphylaxis threshold in the context of airway inflammation and altered immune responses. 29
In contrast, cardiovascular symptoms were less frequently found (23%), with hypotension noted only in 2.6%. This aligns with recent data 30 but differs from earlier studies where hypotension was not described. 26 , 27 Rates may be underreported due to difficulties in obtaining an accurate blood pressure measurement in younger children 13 , 31 and because hypotension is a late sign in early childhood, typically preceded by tachycardia 1 with pallor, hypotonia, and diaphoresis—all symptoms reported in our cohort. However, unlike ASCIA anaphylaxis guidelines which include paleness and hypotonia in infants and toddlers, 22 and recently published guiding principles and practice parameters, 1 , 10 , 11 none of these additional signs are mentioned in the NIAID/FAAN clinical criteria for anaphylaxis 32 or the WAO criteria, 8 , 9 which are currently used for all ages, including infants and toddlers. The same applies to neurological signs (e.g. irritability/clinginess, persistent crying).
We propose that age‐specific neurological symptoms—present in 18.8% of our cohort—warrant consideration as a separate organ system when defining symptom patterns in anaphylaxis in infants and young toddlers. These symptoms may reflect end‐organ hypoperfusion but also play a key role in recognition and management. Only one other study has assessed neurological symptoms in children aged 0–2 years, reporting a slightly lower rate (11.6%) 28 likely due to under‐recognition or variation in definitions. A French study comparing preschool children with <1‐year‐olds reported a higher rate (61.5%); however, while the authors, similar to our study, included irritability/restlessness and persistent crying as neurological signs, their infant group was younger and the definition included hypotonia (which belongs to the group of cardiovascular signs in our cohort). 33 Evaluating neurological symptoms in 0–2‐year‐olds is challenging, as they are often subjective and depend on caregiver reports to identify deviations from baseline behavior. Additionally, these symptoms do not form part of the standardized NIAID/FAAN clinical criteria or WHO criteria, 8 , 9 and they may have been observed but not formally documented within the current study.
Biphasic anaphylaxis is a well‐known complication of anaphylaxis. However, studies of biphasic anaphylaxis concerning children are limited to a very few, 19 , 20 , 21 , 34 with only a few scattered single reports involving infants and young toddlers. 12 , 19 , 33 In our cohort, children with biphasic anaphylaxis were younger than those with uniphasic anaphylaxis (median 7 months; IQR 4–11 vs. median 10 months; IQR 7–11 vs., p = .048). Our rate of biphasic anaphylaxis was 4.6% (11/239), which is similar to reported cases in another Korean study of 0–2‐year‐olds (4.7%) 28 but slightly lower than in studies focused on older children (6%–15%). 19 , 20 , 34 Overall, the incidence of biphasic anaphylaxis varies widely across the literature, ranging from 0.4% to 21%, depending on the study design, the population examined, and the specific definition of anaphylaxis employed in each study. 16 , 24 This lack of clear and objective definitions likely contributed to wide variability in reported rates and variability in features and predictors. Dribin et al. used Delphi methodology to develop a consensus definition for biphasic anaphylaxis; but expressed uncertainty about its applicability to infants and toddlers because symptoms may be more difficult to detect. 24
Although none of our anaphylaxis cases re‐presented to our PED with a secondary anaphylaxis, we cannot rule out loss to follow‐up. Therefore, our rate may be underestimated, as some biphasic or recurrent reactions could have occurred post‐discharge without being reported. This suggests that while biphasic anaphylaxis is a recognized concern, the true incidence may be underestimated. Prospective studies with extended follow‐up would be valuable.
In our infant/young toddler cohort, all biphasic anaphylaxis cases were reported as food‐induced, in contrast to the Korean study, where most were drug‐induced. 28 While we provided detailed descriptions of biphasic cases, their study lacked further characterization. Further research into the triggers and mechanisms of biphasic anaphylaxis in 0–2‐year‐olds is required to gain more insight.
Our data indicate that infants and young toddlers with biphasic anaphylaxis did not differ from uniphasic cases in terms of respiratory involvement. However, they more frequently exhibited cardiovascular manifestations during the initial reaction, including pallor and hypotonia, along with lower systolic blood pressure. Although no other studies have specifically examined biphasic anaphylaxis in infants and young toddlers, several investigations including children up to 18 years report consistent findings. These studies likewise found no difference in respiratory signs but identified cardiovascular involvement as a risk factor for biphasic anaphylaxis, 19 , 20 , 21 suggesting that while age‐specific symptoms for anaphylaxis may vary between very young and older children, predictors of biphasic anaphylaxis appear broadly similar. Hence, infants and young toddlers who present with cardiovascular impairment may warrant closer monitoring, early intervention, and prolonged hospital observation due to a potentially higher risk of biphasic anaphylaxis. 21 , 35 Further research on specific predictors could help guide tailored management strategies in infants and young toddlers.
We found that severe reactions were associated with an increased risk of biphasic anaphylaxis, consistent with previous studies in older children 19 , 20 , 21 and a prospective adult study linking biphasic reactions to a prolonged inflammatory response. 36 As described elsewhere in the literature, 19 , 20 , 37 we also observed that primary reactions tended to be more severe than secondary ones. All secondary reactions in our cohort occurred in hospital, where early recognition and prompt treatment are expected. This may have mitigated their severity and influenced our findings.
In terms of treatment and management, there was a trend that compared with uniphasic cases our biphasic anaphylaxis cases required more doses of adrenaline for the primary reaction, likely due to more severe presentations. Consistent with Mehr et al. 19 fluids were administered more frequently in biphasic cases, probably due to fluid depletion from cardiovascular compromise.
As biphasic anaphylaxis is a key reason for post‐recovery hospitalization, clearer guidance is needed on observation times, which vary globally—from 1 h to over 12 h in adults, and even overnight stays in children. 17 In Australia, including at our ED, the mandated observation period is 4 h. Scientific consensus on optimal observation duration, especially age‐adjusted, remains lacking. A meta‐analysis found that the median time from resolution to biphasic onset ranged from 1.75 to 17 hours, 17 and a consensus paper suggests recurrence can occur 1–48 h from complete resolution of initial symptoms. 24 In our infant/young toddler cohort, the interval for recurrent anaphylaxis ranged from 1.25 to 5.5 h. This shorter interval is supported by a recent publication in older children (median age 7.9 years; IQR 3.3–13.1) suggesting that an observation period of 4 h might be sufficient for children with cardiovascular involvement who appear well. 21 However the condition of a patient who initially appeared well may change even after 4 h. Age‐related physiological differences—such as falling adrenaline levels, allergen absorption, and immune responses—may contribute to different timeframes. Anaphylaxis health costs and ED overcrowding with its adverse effects on patient morbidity and mortality are two examples where reduced ED length of stay may have broader healthcare benefits for the community. While prolonged hospital stays can strain health systems and families, early discharge (before 4 h) must be balanced against the risk of recurrence. Developing and validating a clinical decision rule to identify infants and young toddlers safe for discharge within 4 h would be beneficial.
Before discharge, all families should receive education on biphasic anaphylaxis. To support earlier discharge while ensuring safety, hospitals might consider dispensing (rather than just prescribing) an adrenaline device, which is standard practice in our PED.
A major strength of this study is that our hospital as the sole tertiary PED in the state captures a large and diverse population, with over 70,000 annual ED visits. However, although we present a large anaphylaxis cohort in 0–2‐year‐olds, including the largest case series in biphasic infant/young toddler anaphylaxis, this is a retrospective single‐centre study, which can result in incomplete or missing data and reporting bias. Even though our medical staff in ED is trained to ask and report on symptoms of an allergic reaction and anaphylaxis in infants and young toddlers, we acknowledge that symptoms may not have been recorded in a standardized manner and hence underreporting of certain symptoms may have occurred. This especially includes unspecific signs described in 0–2‐year‐olds, such as mottling, licking of lips and impaired mental status/sleepiness.
Although we present the largest series on biphasic anaphylaxis in infants and toddlers, our numbers are very limited and more research is required to gain more robust data on predictors for biphasic anaphylaxis in this age group. Furthermore, we could not account for biphasic or recurrent reactions occurring in children discharged home. However, given the proximity of most families to medical services, we would expect at least some re‐presentations if secondary or recurrent reactions had occurred. While our findings provide valuable insights into the nature of biphasic anaphylaxis in 0–2‐year‐olds, further research is essential to fully understand the prevalence and management of these reactions in a broader context. Hence, future prospective studies should aim to incorporate multi‐centre data to enhance the robustness of the conclusions drawn from this initial investigation.
In conclusion, our findings emphasize the need for improved characterization of anaphylaxis in infants and young toddlers and to adapt diagnostic definitions and clinical guidelines to improve management and outcomes. Although prolonged hospitalization can place strain on families and health systems, decisions regarding early discharge (<4 h observation time) must be carefully balanced against the risk of recurrence. While a 4‐h observation period seems sufficient for most infants/toddlers experiencing anaphylaxis, greater severity, cardiovascular signs and/or fluid resuscitation may be useful predictors of biphasic/recurrent anaphylaxis in 0–2‐year‐olds. Hence, infants/young toddlers presenting with these signs may benefit from an extended (>4 h) inpatient observation time. While this will apply to the minority of 0–2‐year‐olds with anaphylaxis, most could likely safely be sent home earlier (<4 h observation time). Future prospective, multicentre studies with longer post‐discharge follow‐up would be beneficial to confirm our findings.
AUTHOR CONTRIBUTIONS
Kristina Rueter: Conceptualization; methodology; investigation; writing – original draft; data curation; validation; formal analysis. Brennan Ta: Methodology; software; data curation; investigation; project administration; visualization; writing – review and editing. Natasha Bear: Validation; formal analysis; writing – review and editing. Michaela Lucas: Conceptualization; writing – review and editing. Susan L. Prescott: Conceptualization; supervision; writing – review and editing.
FUNDING INFORMATION
No funding to declare.
CONFLICTS OF INTEREST STATEMENT
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Supporting information
Figure S1: Flowchart: Infant/young toddler anaphylaxis cases presenting to the PED between 2002–2007 and 2013 to 2017. *In Australia adolescents >16 years of age present to an adult or mixed ED. **significant adrenaline overdose included (n = 4): omitted for calculation of features of allergic reaction/anaphylaxis due to potential influence on clinical progression.
ACKNOWLEDGMENTS
The authors thank Dr. Natasha Moseley, Dr. Kareena Easton, and Professor Meredith Borland very much for supporting the data collection. Open access publishing facilitated by The University of Western Australia, as part of the Wiley ‐ The University of Western Australia agreement via the Council of Australasian University Librarians
Rueter K, Ta B, Bear N, Lucas M, Prescott SL. Characteristics of uniphasic and biphasic anaphylaxis in infants and young toddlers: An analysis of clinical signs, predictors and management. Pediatr Allergy Immunol. 2026;37:e70438. doi: 10.1111/pai.70438
Editor: Vicki McWilliam
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: Flowchart: Infant/young toddler anaphylaxis cases presenting to the PED between 2002–2007 and 2013 to 2017. *In Australia adolescents >16 years of age present to an adult or mixed ED. **significant adrenaline overdose included (n = 4): omitted for calculation of features of allergic reaction/anaphylaxis due to potential influence on clinical progression.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.