Pediatric idiopathic anaphylaxis: practical management from infants to adolescents

Abstract

Idiopathic anaphylaxis (IA) remains a frustrating challenge for both patients and physicians. The aim of this paper is to focus on IA in pediatric ages and suggest possible diagnostic algorithms according to specific age ranges (infants, children, and adolescents). In fact, in a variable percentage of patients, despite extensive diagnostic tests, the cause of anaphylactic episodes cannot be identified. Moreover, the lack of a unanimous IA definition requires a careful and detailed diagnostic workup. Prompt recognition of signs and symptoms, especially in younger children, and an accurate clinical history often allow a choice of the most appropriate diagnostic tests and a correct differential diagnosis.

Introduction

In children, “idiopathic anaphylaxis” (IA) is estimated to be present in 10% of all anaphylaxes after a complete allergy workup [1]. However, many differences in epidemiology have been reported by different studies (Table 1).

Table 1 Pediatric case series of idiopathic anaphylaxis (IA)

The term IA is usually used to refer to an acute event in which a patient presents the clinical features of anaphylaxis, but no specific cause of anaphylaxis is promptly recognized or identified later and all other diseases that imitate anaphylaxis are excluded along the diagnostic pathway. The term idiopathic anaphylaxis was used for the first time by Bacal et al. in 1978 [11]. One of the first case reports of IA in children was by Dykewicz et al. [12], followed by Ditto et al. [13]. The first pediatric case series on IA was published in 1997 by the same authors’ group [2] and included 22 children, all but one of whom were evaluated at the Division of Allergy and Immunology at Northwestern University (Chicago). These children were previously included in another study from the same group [14] that was later published as a pediatric case series [15]. In the 1997 case series, almost half of the children had other allergic diseases (asthma, rhinitis, food-dependent exercise-induced anaphylaxis, etc.), and 15 out of the 22 (68%) children were female. The children presented a wide variety of phenotypes and erratic responses to therapy. Three children presented with malignant idiopathic anaphylaxis (failure to respond to < 30 mg/day of prednisone or < 60 mg every other day), and one of these was lastly diagnosed with undifferentiated somatoform IA. Some authors suggest investigating this kind of IA when there is no response to any therapy. IA remains a frustrating challenge for both patients and physicians since, in a variable percentage of cases, despite extensive diagnostic tests, the cause of anaphylactic episodes could not be identified. In two very recent reviews on different types of anaphylaxis, the authors [16, 17] reported some possible underlying mechanisms explaining IA; however, most of them are not fully characterized yet. It is of the utmost importance to specify that, over the last few years, some changes in allergy nomenclature regarding IA have been proposed. As pointed out by Hammond [18], signs and symptoms of IA should be considered as a possible presentation of a mast cell disorder, as already proposed by Giannetti et al. [19] and by Akin [20]. Therefore, in managing a patient with a suspected episode of IA, clinicians should always include diagnostic tests for mast cell disorders. Certainly, the lack of a common and precise definition of anaphylaxis introduces further issues to the field. Even the main allergological scientific societies have not yet managed to agree on a unique definition of anaphylaxis (NIAID/FAAN 2006 [21]; EAACI 2020 [22]; EAACI PED [23]; WAO 2020 [24]; ASCIA 2021 [25]; AAAAI 2020 [26]). Furthermore, a uniform definition of AI is also still under discussion. Gulen and Akin [1] compared the typical clinical presentation of IA and mast cell activation syndrome (MCAS), from which it emerges that the involvement of the gastrointestinal system is an exclusive characterization of anaphylaxis if there is a “likely” or “known” cause. In the case of a suspected IA, when the cause remains unknown, cardiovascular symptoms (hypotension, syncope, collapse) or severe respiratory symptoms (laryngeal edema, wheezing, stridor) must accompany skin or mucosal involvement.

Finally, there are no specific diagnostic criteria for anaphylaxis in childhood; therefore, one must rely on adults’ criteria. This is a critical point of discussion since infants and toddlers are especially unable to articulate prodromal symptoms, such as abdominal pain or itching, and fuzziness or sleepiness could be misinterpreted as normal behavior. Of all proposed definitions of anaphylaxis by scientific societies, none provide a dedicated definition for pediatric age. Another critical point is that in most pediatric case series on anaphylaxis (whether enrolled in allergy clinics or in the emergency department [ED]), after a first skimming of food-drug-venom causes, often no further investigation was proposed or allergological referral programmed. Also, as listed in Table 1, not all studies reported a detailed diagnostic pathway through which the IA diagnosis has been formalized. Some studies calculated the percentage of IA only upon the ICD-9 coding at discharge from the ED; others had initially recruited a mixed-case series (adults or children). A clear example of these discrepancies could be observed by comparing the study by Calvani et al. [3], who reported 8.4% IA, and the European registry [4] with 21% IA. Both groups analyzed case series from selected patients already referred to allergy centers, and both had extended diagnostic pathways. In future studies, therefore, it is quite important to include a detailed diagnostic pathway and a long-term follow-up with repeated revaluations. Large studies are needed to define the exact incidence of IA better.

Pathogenesis

In the recent literature [1, 17], the different pathogenic mechanisms of IA were discussed to a great extent. Gulen T et al. [1] analyzed several features of IA and focused on pathogenesis and the “intriguing relationship between IA and MCAS and mastocytosis. Some factors seemed to confirm this connection, such as the main role of mast cells in IA, the commonly released mediators, and the response to therapies targeting mast cells.

In another study by Ivkovic-Jurekovic [27], other mediators seemed to be involved in IA. The authors demonstrated a reduced intestinal or serum activity of diamine oxidase (DAO) and histamine N-methyltransferase (HMT) in three children with IA, confirming their histamine intolerance. The authors also proposed the study of DAO and HMT gene polymorphism as a possible identification of a genetic predisposition but advised that more investigation needed to be done in this regard.

An increase in sensitivity to histamine was proposed by Tedeschi et al. [28]. They demonstrated a positivity of the autologous serum skin test and basophil histamine release assay in a patient as a confirmation of the presence of circulating histamine-releasing factors. However, this theory has not been investigated further.

The presence of autoantibodies against the Immunoglobulin E (IgE) receptor was another hypothesis, but studies did not confirm it [29].

Diagnosis

The importance of a precise and timely investigation of an anaphylaxis episode was discussed by Gonzales de Olano et al. [16].

Since the authors considered every anaphylaxis as “the end result of massive mast cell activation,” they suggested a possible workup, including all diagnostic tests to distinguish different mechanisms of anaphylaxis in the exposures to allergens, exercise, hormones, emotional stress, non-IgE-mediated activation, mastocytosis, and hereditary alpha tryptasemia (HaT).

In this paper, we seek to provide practical information on how to diagnose and manage IA among different age groups (infants, children, and adolescents) and differentiate the possible triggers based on age. Table 2 describes three different scenarios.

Table 2 Three different scenarios

Clinical history must be carefully collected, remembering to investigate specific aspects and focus on the role of cofactors (Table 3).

Table 3 Clinical History

Other anaphylaxis mimic disorders should be considered in the differential diagnosis of IA, for instance:

• a) Malignancies such as carcinoid syndrome, VIPoma, familial medullary thyroid carcinoma, and pheochromocytoma

• b) Bradykinin disorders, hereditary angioedema (HAE), ACE-I (angiotensin-converting enzyme inhibitors) induced angioedema

• c) Paradoxical vocal cord dysfunction

• d) Scombroid syndrome

• e) Vitamin supplements/energy drinks (nicotinic acid)

• f) Psychiatric diseases, such as Munchausen and Munchausen-by-proxy syndrome [61], undifferentiated somatoform IA [62], and anaphylaxis mimicries, such as psychiatric conditions and panic attacks, should be excluded if diagnostic tests are negative especially if the patient has a history of repeated hospital visits with no firm evidence of anaphylactic reactions.

Based on the possible diagnosis arising from the anamnesis and clinical examination, different types of tests could be performed (Table 4).

Table 4 Diagnostic work-up

In particular, clinical history should be focused on some peculiarities that differbetween infants, children, and adolescents (Fig. 1). For example, cofactors such as exercise, smoking, alcohol, and psychological distress should not be investigated in infants. On the contrary, other cofactors, such as teeth eruption and vaccinations, should be investigated in infants and children.

Fig. 1

Focused clinical history according to different age ranges

Acute management does not differ from classic anaphylaxis. Prompt use of adrenaline is mandatory when cardiovascular and respiratory involvement is recognized. Other medications could be used, such as second-generation antihistamines, steroids, or beta2-agonist inhalers, without delaying adrenaline administration. Education is a cornerstone of the chronic management of IA [54]. If a specific or aggravating factor has been identified and further confirmed, pediatric patients and their caregivers should be instructed on its avoidance, and in the case of food allergens, on reading labels and finding out ingredients. Adrenaline autoinjectors (AAIs) must be provided to patients and/or caregivers as soon as discharged, with a written action plan with detailed instructions on when and how to use AAIs and other drugs (oral second-generation antihistamines, oral steroids, beta2-agonistinhalers). Schools and sports coaches should be involved in AAI use, and formal instruction should be provided. Older pediatric patients should be the direct recipients of education on primary prevention and medical treatment of anaphylaxis. Yearly follow-up evaluations should be scheduled to keep track of IA evolution and to target therapy modifications, if necessary. Patients and caregivers should be advised to avoid all drugs that increase the risk of severe episodes, such as beta-blocking agents, ACE-Is, angiotensin receptor blockers, monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (e.g., amitriptyline) [94] If such drugs are necessary, patients should be aware that an impaired effect of adrenaline may occur. As reported by Carter et al. [58], the identification of possible cofactors has a pivotal role in the diagnosis, management, and prevention of further episodes of IA. According to this work, there is also an association between the severity of anaphylaxis and several intrinsic/extrinsic cofactors, age being the most important, followed by concomitant mastocytosis and insects as allergens.

Following diagnosis, it is important to properly classify all patients with IA in order to determine the correct treatment (Fig. 2). IA is commonly categorized as follows [29, 65, 95]:

Fig. 2

Steps approach of IA treatment

• 1) Frequency: infrequent, fewerthan six episodes/year or fewer than two episodes/two months; frequent, more than six episodes/year or more than two episodes/two months;

• 2) Severity: malignant, patient requires a high dose of steroids for disease control (60 mg of prednisone every other day or 30 mg prednisone daily); corticosteroid-dependent if the IA episodes are difficult to control without steroids;

• 3) Clinical scenario: generalized with urticaria and/or angioedema and systemic manifestations; angioedema-predominant with angioedema with laryngeal involvement and compromised airway, no other systemic manifestations.

In infrequent IA, there is usually no need for preventive therapy. If the patient is classified with frequent IA, it is reasonable to start a prophylactic therapy, as suggested by many authors, with prednisone and cetirizine daily. H1 receptor antagonists (commonly second-generation antihistamines) could be used with a dose of up to four times per day, as in chronic urticaria. H2 receptor antagonists could also be added to prevent gastric side effects in those who have been treated with oral steroids [54]. In children, particularly those with mild to moderate severity, H1 receptor antagonists and H2 receptor antagonists are preferred [54]. If IA is controlled, a tapering of steroids or an every-other-day scheme could be considered, maintaining daily cetirizine. If IA is not controlled, a step-back to daily prednisone should be made for 1 to 2 weeks [96]. Other suggested therapies, especially in malignant IA or when steroids are needed in high doses, could be adding montelukast (which seems to be effective in children with asthma) and cromolyn in children with gastrointestinal clinical manifestations [54]. Ketotifen could sometimes be helpful in controlling signs and symptoms of urticaria, thanks to its mast cell stabilizer effect [97]. Calcineurin inhibitors and Bruton tyrosine kinase inhibitors are studied in chronic urticaria, but there are no data on their performance on IA. Omalizumab has been proven to be an interesting therapeutic option in IA, generally at the same dosage as in chronic urticaria. Six months could be sufficient as a trial period to assess its efficacy. Kaminsky et al. [98] demonstrated its efficacy in 38 patients (age range 11–54) with IA who failed to respond to second-generation antihistamines and mast cell stabilizers. Of the patients, 63% showed a complete response, 28.5% showed a partial response, and three patients were considered non-responders. There is also additional experience in the pediatric age expressed as case reports but mostly in adolescents [98,99,100,101,102,103]. Furthermore, there are also a few case reports on the use of dupilumab in IA [104].

Nowadays, the diagnosis and management of IA still remain challenging for clinicians. Prompt recognition of signs and symptoms, especially in younger children, and an accurate clinical history often allow a choice of the most appropriate diagnostic tests and a correct differential diagnosis. It is important, however, to not forget about the rarer conditions that are becoming more frequently diagnosed thanks to the innovations. Over the past decades, the recognition and improvement of knowledge of several novel clinical entities mentioned above have led to a decrease in the percentage of IA, even in the pediatric age group. Nonetheless, further extensive research based on international data is needed, especially regarding those in the infant to adolescent age groups with IA, to improve its management worldwide.