Delayed symptoms and orthostatic intolerance following peanut challenge

Clinical reactions to Oral Food Challenge (OFC) in peanut‐allergic individuals have been well‐characterised, but rates and phenotypes of symptom recurrence beyond the first hour after objective symptoms are less well‐characterised.


| INTRODUC TI ON
Oral Food Challenges (OFC) are important as a means to distinguish between asymptomatic IgE-sensitisation and clinical reactivity. 1 Patient selection has an important impact on the likelihood of reaction at OFC. Previously, OFC were used primarily as a mean to confirm tolerance, and thus associated with a lower rate of positive reactions. However, as allergen immunotherapy increasingly becomes an option for the management of food-allergic patients, more OFC are performed where the outcome is much more like to cause a clinical reaction.
Biphasic reactions are defined as the recurrence of symptoms (after initial resolution) without re-exposure to the trigger. 2 Reported rates of biphasic reaction range from <1% to 20% in the community setting. 3 A recent systematic review and meta-analysis reported a rate of 4.7%, with median time of onset to biphasic symptoms of 11 h. 4 However, lower rates have been reported for OFC conducted under medical supervision. [5][6][7] Anecdotally, we observed a number of patients following OFC where further symptoms seemed to occur following discharge, triggered by the consumption of food after OFC. We therefore prospectively evaluated the frequency of recurring clinical symptoms following allergic reactions in patients undergoing OFC, and whether these might be associated with consumption of a light meal prior to discharge as part of our OFC protocol.

| ME THODS
We prospectively monitored peanut-allergic individuals who underwent double-blind, placebo-controlled food challenge (DBPCFC) as part of screening procedures for two studies: a peanut immunotherapy trial (the BOPI study, Clinical Trials.gov identifier NCT02149719) in young people aged 8-17 years, and in peanut-allergic adults

| Participants
Participants with a diagnosis of peanut allergy were recruited from local allergy clinics, and nationally (through patient support groups and for the TRACE study, though advertisements in local media).
Informed written consent was obtained from participants, or in the case of young people under the age of 16 years, their parent/guardian with written assent from the participant. Exclusion criteria are as previously described. 8,9 Individuals with peanut allergy caused by pollen food allergy syndrome were excluded; individuals with previous anaphylaxis were not excluded unless the reaction required admission to intensive care.

| Procedures
Skin prick testing (SPT) was performed on commercially available extracts of peanut, soya and birch pollen (ALK-Abello) using singlepoint lancets, according to national guidelines. Histamine (10 mg/ml) was used as a positive control. Total and allergen-specific IgE was measured with the ImmunoCap system (Thermo Fisher).
DBPCFC were conducted according to international PRACTALL consensus criteria. 1 All subjects underwent peanut DBPCFC challenge over two separate days, at least 14 days apart. Children participating in the BOPI study received, on each day, increasing doses every 30 min of peanut protein (Defatted roasted peanut flour (Golden Peanut Company; 12% fat) at the following doses: 3 mg, Adult participants in the TRACE study underwent a similar challenge at the baseline screening challenge, using the following dosing regimen: 3 µg, 30 µg, 300 µg, 3 mg, 30 mg, 100 mg, 300 mg and 1000 mg, until stopping criteria were met. 9 The challenge matrix used defatted roasted peanut flour (Golden Peanut Company; 12% fat) incurred at the appropriate dose into a water-continuous dessert base matrix, adapted from that developed within the EuroPrevall project for DBPCFC and hydrated prior to use. 11 For both study groups, the order of active/placebo challenge was determined by computer randomization. Members of the study team were blinded as to the challenge assignment, aside from the technician preparing the challenge material. Anaphylaxis was retrospectively assigned according to the World Allergy Organisation (WAO) 2020 clinical criteria. 12 Participants were monitored for at least 2 h following the challenge, and ate a light meal (e.g. sandwich, salad) after the first 60 min of observation. Participants were contacted on the day after discharge to determine whether any delayed symptoms had occurred which would meet the definition for a biphasic reaction. Symptoms of orthostatic intolerance were defined as the occurrence of skin changes (eg pallor) and light-headedness on standing which resolved with supine positioning. Orthostatic hypotension was defined as a symptomatic decrease in systolic blood pressure of >20 mmHg and/or a decrease in diastolic blood pressure >10 mmHg on standing. 13

| Statistical analysis
Non-parametric data are presented as medians. Fisher's exact test was performed to evaluate the associations between binary variables. Statistical analyses were conducted using Graphpad Prism (version 8.4.2). All statistical tests were two-tailed, and a p-value <.05 was considered significant.

| RE SULTS
One hundred and thirty-five participants (67 adults, 68 children) underwent DBPCFC to peanut (Figure 1), of whom 121 (57 adults, 64 children) met challenge-stopping criteria and thus had confirmed peanut allergy. Baseline characteristics are shown in Table 1.
Thirty-three (27%) participants had progression or recurrence of symptoms beyond an hour following acute objective clinical reaction (due to the presence of symptoms consistent with PRACTALL consensus criteria 1 ) ( Table 2). Individual patient symptoms are described in the Table S1. The recrudescence of symptoms following reaction was more common in the paediatric cohort (p = .04). In 27 cases, symptoms occurred during or within 30 min of eating a light meal, around 1 h after stopping the challenge. There were 2 biphasic reactions that occurred independent of further consumption of food, one of which met WAO criteria for anaphylaxis. Anaphylaxis as the stopping symptom at challenge was associated with lower risk of symptom recurrence (OR 0.18, 95% CI 0.04 to 0.82, p = .02).

| DISCUSS ION
In these two cohorts of children and adults with IgE-mediated peanut allergy undergoing DBPCFC, we observed a significant proportion of participants who exhibited symptom progression/recurrence more than 1 h after stopping the challenge. Only 2 subjects experienced a classic biphasic reaction (ie onset of new symptoms following complete resolution of initial phase reaction, without an obvious further trigger), equating to a rate of 1.7%. This is consistent with reported rates in the literature following OFC. [5][6][7] However, we observed a much larger number of participants who experienced "recurrent symptoms,"-that is, progression or recrudescence of symptoms at least 1 h after stopping the OFC, which was often Anaphylactic shock occurs as a result of a profound loss of venous tone and fluid extravasation, causing a mix of hypovolemic and distributive shock, which results in a reduced cardiac output. 14,15 There are a number of reports in the literature of fatal outcomes due to anaphylaxis, where the apparent precipitant was a change in posture (for example, from the supine to standing position); 16,17 it was proposed that the change in posture might result in an inability to compensate for reduced venous return to the heart, in the context of peripheral vasodilatation. 16 We recently demonstrated that significant changes in cardiovascular function, including decreased stroke volume, are common and occur during even non-anaphylaxis reactions in adults undergoing peanut-induced allergic reactions. 17 Of note, we observed evidence of cardiovascular compensation-in particular, an increase in heart rate which maintained cardiac output, despite the fall in stroke volume; this mild tachycardic response was evident at rest, with patients supine, indicative of a reduction of circulating blood volume. 18 In contrast, in our participants with features of an orthostatic drop in blood pressure, we did not observe any obvious tachycardia at rest (with patients semi-recumbent), as shown in the exemplar case described in Box 1 and Figure 2. Thus, while the fall in stroke volume previously described during allergic reactions to peanut may be relevant, 18 we have no direct evidence for this and other mechanisms may be relevant. For example, the allergic reaction may have caused a disturbance in normal postural circulatory reflexes, akin to the blunting of postural reflexes which is often observed during anaesthesia. 19 Orthostatic hypotension is associated with a decrease in heart rate variability, 20,21 and previous studies in both children and adults have reported reduced heart rate variability following food-induced allergic reactions, independent of severity. 18,22 Thus, these episodes could potentially represent a more mild form of the postural decompensation Anaphylaxis as initial reaction 0 0 Detected at >1 h following stopping of FC 5 3 Anaphylaxis as initial reaction 0 0 TA B L E 2 Description of further symptoms experienced following reaction at DBPCFC seen in some cases of fatal anaphylaxis. The mechanism is likely to differ from typical hypotensive anaphylaxis, because of the absence of a clinically relevant tachycardia when supine and in the delayed-onset cases, an absence of other concurrent signs or symptoms of acute allergic reaction. We, therefore, propose that isolated orthostatic intolerance following an acute allergic reaction does not imply anaphylaxis per se. In support of this, we did not identify any factors (such as anaphylaxis) associated with the occurrence of orthostatic intolerance, although this observational report was not powered to assess risk factors for this.
Blumchen et al reported that 8% of young people undergoing OFC to peanut exhibited symptom progression from initial objective symptoms (which met stopping criteria for challenge) to more severe ones later, 23 a similar rate to that observed in the two cohorts studied here.
However, in our study, reaction progression was usually associated with food consumption. This suggests that some biphasic reactions may in fact be due to further allergen absorption triggered by postprandial gut motility, rather than representing a true "immunologically biphasic" reaction. There is evidence from animal models of food allergy that acute allergic reactions impact upon gastric motility, 24,25 and this is supported by anecdotal data from human anaphylaxis. 26  Finally, while the participants in this study may not be completely representative of peanut-allergic consumers in the wider peanutallergic population, it would seem prudent that patients who have F I G U R E 2 Cardiac observations for representative case of orthostatic hypotension following challenge (see Box 1. HR, heart rate (per min); sBP and dBP, systolic and diastolic bloods pressure (mmHg); RR, respiratory rate (per min). Two episodes of significant orthostatic hypotension were noted with no evidence of haemodynamic instability prior. Measurements plotted in red were taken while patient standing rather than supine/ semi-recumbent  Adrenaline 300 mcg was self-administered using an autoinjector, which resulted in rapid symptom resolution. He subsequently ate lunch an hour later after reaction and then discharged after a total of 2 h observation, completely asymptomatic.
On exiting the hospital, he felt the urgent need to pass a bowel motion. Unfortunately, the toilet was occupied and while waiting, he felt dizzy and fainted. Help was summonsed and on arrival, he was sitting on the toilet, conscious and communicating normally. There was no evidence of haemodynamic compromise. Blood pressure was 106/59 mmHg (semi-recumbent) with a heart rate of 80; however, on standing, he had marked orthostatic hypotension (BP 69/28, HR 120 after 4 min, decreasing further to BP 46/35 after a further minute at which time he was symptomatic (dizzy). On lying supine, symptoms fully resolved with blood pressure normalised (BP 103/48, see Figure 2). had a systemic allergic reaction are assessed for symptoms of orthostatic intolerance (including the measurement of standing blood pressure, if indicated) prior to discharge from a medical facility.

ACK N OWLED G EM ENTS
We thank our study participants, including those who were recruited through the TRACE Peanut study (funded by the UK Food Standards Agency); we are grateful to the study investigators (Chief investigator A Clark) and the Food Standards Agency for their support; and to the members of our independent data monitoring commit-