Background
Food allergy is a leading cause of anaphylactic reactions treated in emergency departments in the United States [
1],[
2], where it accounts for 31% of anaphylaxis cases [
3], and is a growing public health concern. Anaphylaxis is an acute potentially fatal systemic type I hypersensitivity reaction [
4]. The most cited working definition of food anaphylaxis (FA) was proposed by Sampson and colleagues in 2006 [
4],[
5]. FA is acute onset of an illness with involvement of skin/mucosal tissue, airway compromise, and gastrointestinal symptoms, or reduced blood pressure and associated symptoms [
1],[
5]. The most dangerous symptoms include breathing difficulties, a drop in blood pressure, and shock, which are potentially life-threatening. Given the increased awareness of food allergy by consumers and food manufacturers, frequency of accidental exposures appears to have been reduced [
6],[
7]. A recent study reported that the annualized reaction rate in milk, egg and peanut allergic children was 0.81 per year [
6]. However, extremely food-allergic children experience more frequent and potentially severe food-induced anaphylaxis (described herein as FSFA) despite attempted strict avoidance. Although the majority of food-induced reactions are triggered by ingestion; in extremely sensitive children severe reactions can also be triggered by inhalation [
8],[
9] and skin contact [
10],[
11]. Additional interventions that prevent frequent and potentially severe reactions while practicing food avoidance are urgently needed.
Traditional Chinese Medicine (TCM) is a medical system that primarily uses Chinese herbal medicines, acupuncture and acupressure. TCM has a long history of human use in China, Japan and Korea, and is beginning to play a role in the healthcare systems in the United States and other Western countries as a stand-alone or integrative practice. Unlike in Asia, the European Union and the UK [
12], Chinese herbal medicines in the U.S are classified as dietary supplements [
13]. In 2004, the US Food and Drug Administration (FDA) provided guidance for investigating botanical drug products including formulas comprised of multiple herbal constituents [
14]. Although preclinical and clinical studies are limited, several suggest that TCM herbal formulas may have potential for treating food allergies [
15],[
16]. Food Allergy Herbal Formula (FAHF)-1, FAHF-2, and butanol-extracted FAHF-2 (B-FAHF-2) (derived from the classical TCM formula
Wu Mei Wan) prevent systemic anaphylaxis in murine models of food allergies [
17]-[
19]; and have been US FDA approved as botanical investigational new drugs. Phase I clinical studies showed that FAHF-2 is safe, had an immunomodulatory effect on T cells and suppressed basophil activation [
20],[
21]. Herbal Formula-3 inhibited food allergy reactions in rats by stabilizing mast cells by modulating calcium mobilization [
22]. The traditional Japanese herbal medicine Kakkonto suppressed the occurrence of allergic diarrhea and decreased the number of mast cells in the proximal colons in a murine food allergy model [
23]. In addition, acupuncture has been reported to reduce wheal size following allergen skin tests and to reduce basophil activation in individuals with atopic dermatitis [
24],[
25]. In addition, we investigated the effects of extracts of 70 TCM herbs on cultured human B cells, and found that several directly suppressed IgE synthesis [
26]. Potential TCM effects on FSFA in children have not been previously investigated. This retrospective study of 3 pediatric patients with extraordinarily severe FSFA shows, for the first time, that a combined TCM therapy regimen prevented FSFA.
Discussion
This case study describes 3 FSFA patients who underwent TCM therapy with the goal of reducing the frequency and severity of their food induced anaphylactic reactions. In all cases, food allergy was diagnosed after ER visits due to anaphylactic reactions. Their FSFA generated significant stress for their families. P1 anaphylaxis episodes began in infancy, and increased in frequency and severity over time. P2 had a 3 year, and P3 had a 2 year period of anaphylaxis episodes that also increased in frequency and severity over time prior to TCM therapy. We therefore analyzed their reaction history during the 2-year period prior to starting TCM. We also conducted a separate analysis of frequency and severity of their reactions during the 3-month period immediately prior to starting TCM. All reported extraordinarily frequent and severe reactions during the 2-year pre-TCM period. Attempts to avoid ingestion of offending foods were not sufficient, because anaphylaxis in these patients could also be triggered by inhalation and skin exposure. The number of accidental reactions in these patients appeared to be 15–100 times higher than the recently reported rate of 0.8 reactions annually [
6]. This might be due to their extreme sensitivity to minute quantities of non-ingested allergen. All families denied that any episode was associated with acute stress, ruling out isolated panic disorder as responsible for the physiologic phenomena. Although the majority of clearly defined food induced reactions are triggered by ingestion, anaphylaxis due to non-ingested food allergen exposure has also been reported. For example, Vitaliti et al. [
8] described a child who developed anaphylaxis after inhaling lentil vapors. Tan et al. [
10] reported severe food allergy reactions following skin contact and inhalation of milk, egg or peanut in 5 children. Liccardi et al. [
11] reported a severe systemic allergic reaction in a 16-year-old boy induced by accidental skin contact with cow milk. A recent large cohort study reported that although 80.7% of food allergy reactions were triggered by ingestion, 12.9% were triggered by skin contact, and 1.2% by inhalation [
6]. Although the extremely severe FSFA in the patients described in the present report represents only a fraction of food allergy patients; this group of patients is most in need of therapy. All families expressed frustration about the lack of understanding by others, especially health care providers, regarding how sensitive their children were to food allergens.
This study is the first to demonstrate that comprehensive TCM therapy can prevent or markedly reduce FSFA and reduce antigen IgE levels. Mast cell and basophil IgE sensitization and subsequent activation following relevant antigen exposure are the key triggers of clinical anaphylactic reactions. Because FSFA clinical expression involves multiple organ systems, a combination of 4 TCM remedies was used for all 3 patients. The medicinal properties of herbs in each formulation have been studied in other contexts. Remedy A contains the 8 herbs in
Wu Mei Wan (from which FAHF-1 and FAHF-2 were developed), which originated from the classical herbal formula described in the book “Shang Han Lun” by Chinese physician Zhang Zhong-Jing (150 AD) used to treat gastrointestinal conditions and anaphylactic-like symptoms [
30]. FAHF-2 prevents anaphylaxis in animal model of food allergy, and suppresses IgE synthesis and mast cell and basophil activation in animal models [
17] and human basophil activation
ex vivo. Remedy A differs from FAHF-2 by not containing
Coptis chinesis (
C. chinesis) but instead a 50% higher dose of
P. chinesis extract than that of
C. chinesis in FAHF-2 [
31]. Both herbs are used similarly in TCM practice. In recent years,
C. chinesis has become increasingly expensive (7.5 times more expensive than
P. chinesis). Importantly
P. chinesis extract has been shown to inhibit IgE production in vitro [
26]. Remedy B, used to alleviate patients’ gastrointestinal symptoms, containing 6 herbs is based on modified
Xiang Sha Yang Wei Wan, the classical herbal formula described in the TCM book “Wan Bin Hui Chun” by Chinese physician Lon Tin Xian (1587 AD), which is used to reduce stomach ache and indigestion [
30]. In addition, since all patients were highly sensitive to food allergen skin contact, and since
P. chinesis compounds inhibit mast cell degranulation [
17] and IgE production, a
P. chinesis containing bath additive (Remedy C), and a cream (Remedy D) used to treat eczema [
32] were also utilized. Although all 3 patients had a remarkable response to TCM therapy, P1 required longer treatment than P2 and P3 before clinical improvement was evident. P1 experienced no reactions only during the final 6 months of a 2.5 year treatment period. P2 and P3 showed more rapid improvement, which became evident in the first 3 months of TCM therapy. Of most significance is that P2 reestablished full tolerance to almonds and other tree nuts, and continues to tolerate all nuts 6 months off TCM. In parallel with FSFA improvement, all patients’ chronic stomach discomfort resolved after approximately 3 months of TCM, and has not reoccurred. Their social activity and quality of life are improved: P1 resumed school and took a summer job, P2 resumed school sports and discontinued sertraline, and P3 no longer has a sleep disorder. Their FLIP scores are also reduced, most dramatically in P2 (from 39 to 0). In addition to the reported subjective clinical information, laboratory data were obtained from P1 and P3. These data showed that TCM therapy reduced both patients’ IgE levels, which is consistent with findings in animal food allergy models [
19], a cultured human B cell line [
26], and human PBMCs from food allergic children [
33].
Adherence to this type of combined TCM therapy is challenging because patients are required to adhere to a protocol that includes consuming many pills daily, as well as external treatment regimens. In contrast to a recent report showing that subjects exhibited poor adherence to a treatment protocol requiring consumption of a large number of pills in a phase II trial [
34], the patients in this study strictly followed the TCM protocol (documented by parents). Their motivation may be due to their extreme sensitivity and history of frequent reactions. We do not know if all remedies used by these patients were essential, and further study would be required to determine their individual effects.
Diagnosis of IgE-mediated food allergy requires evidence of both sensitization and clinical symptoms after exposure to the allergen. Either skin-prick testing or measurement of specific IgE levels is recommended for identifying foods that may provoke IgE-mediated allergic reactions [
35]. P1 has evidence of milk IgE sensitization and numerous well defined reactions to milk products by inhalation and skin contact, in addition to accidental ingestion. Although IgE testing was not performed, P2 exhibited systemic reactions (hives and vomiting) following skin testing with mixed tree nuts. This together with her history of well defined episodes of anaphylaxis made P2 qualified for this case review based on our FSFA criteria. Patient 3 had many positive skin test results and positive IgE levels. He also had a history of reactions to at least 13 foods before beginning TCM as illustrated in Figure
3.
Although it is widely known that mast cells are activated in the context of an allergic reaction by allergen-induced cross-linking of surface IgE/FcεRI (the high-affinity receptor for the Fc region of IgE), it should be recognized that many other stimuli and conditions can cause mast cell activation and result in anaphylaxis [
36]. Frequent anaphylaxis in a patient should prompt a clinician to include mast cell disorders in the differential diagnosis. Mast cell activation disorder (MCAD) has been distinguished into 2 major forms, clonal and nonclonal. Systemic mastocytosis (SM) and monoclonal mast cell activation disorder (MMAS), common forms of primary MCAD, implicate dysregulation of C-kit gene in a clonal population of mast cells, leading to increased physical burden of mast cells [
36]. Skin lesions (eg, urticaria pigmentosa), recurrent unexplained anaphylaxis, and unexplained cytopenias are clinical characteristics [
36]. Non-clonal mast cell activation syndrome (nc-MCAS, MACS) is a common form of idiopathic MCAD [
36],[
37]. Factors extrinsic to mast cells lead to recurrent, inappropriate release of mast cell mediators, including histamine and lipid mediators. The differential expression and release mediators of this multifaceted innate immune cell population leads to different hypersensitivity symptoms –chronic urticaria, pruritis, flushing, gastrointestinal distress (nausea, vomiting, abdominal pain, cramping, bloating), respiratory symptoms, cardiovascular compromise, and cognitive impairment such as poor concentration and memory and brain fog. Both primary and idiopathic MCAD usually have no objective evidence of food specific IgE allergy by ImmunoCAP® and percutaneous testing, which distinguishes them from IgE-mediated hypersensitivity reactions, a form of secondary MCAD [
36],[
37]. All 3 cases reported in this study had elevation of IgE and/or positive skin test to specific foods as well as well defined specific food exposure-induced reactions, which is in agreement with food induced anaphylaxis [
35]. In addition, none of these individuals exhibited urticaria pigmentosa, chronic urticaria, pruritis, flushing, stomach bloating, or brain fog. Thus MMAS or MACS was not entertained in these cases.
Patient 1 had severe symptoms as a result of cow's milk formula at 3 months of age. Food protein–induced enterocolitis syndrome (FPIES) is in the differential diagnosis for this age group. FPIES has a unique clinical expression that distinguishes it from IgE mediated food anaphylaxis. Acute FPIES manifests as profuse repetitive vomiting and lethargy, typically occurring 1–3 hours after ingestion of the offending allergen, and occasionally followed by diarrhea several hours later [
38],[
39]. 90% of children outgrew FPIES by 3 years of age. Diagnosis is primarily based on history because specific IgE and skin prick tests are typically negative [
39]-[
41]. Furthermore, FPIES reactions do not involve skin [
42]. P1 developed widespread hives, projectile vomiting, and difficulty breathing within minutes following ingestion of milk-based formula. It is highly unlikely that these symptoms would lead to a diagnosis of FPIES at time of presentation. This patient subsequently tested positive for milk specific IgE. Her milk allergy persisted to adolescence and became worse 2 years prior to TCM therapy despite attempted dairy product avoidance, and her reactions were often trigged by skin contact and inhalation of trace amounts of milk allergen. Her reactions were acute, starting with hives and progressing rapidly to respiratory reactions; in most severe events, cardiovascular changes were also seen. Overall, given the acute reactions, elevation of IgE, clinical expression and persistence of milk allergy, and skin and inhalation induced reactions to trace levels of milk protein, FPIES has not been considered.
Limitations of this study include the limited number of cases, possible recall bias and lack of knowledge of mechanisms underlying clinical effects. Patients did not undergo diagnostic food challenge because of fear of severe reactions, their convincing history of reactions, rescue medication use and ER visits. Food challenge is not necessary and may pose a potential risk in patients with FSFA. This is in agreement with previous publications [
10],[
27].
Competing interests
Xiu-Min Li received research support from the National Center for Complementary and Alternative Medicine (NCCAM)/the National Institutes of Health (NIH); Food Allergy Research and Education (FARE) and Winston Wolkoff Integrative Medicine Fund for Allergies and Wellness; received consultancy fees from FARE and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; received royalties from UpToDate; received travel expenses from the NCCAM and FARE; received practice compensation from the Ming Qi Natural Health Care Center, and is 42.5% shareholder of Herbs Springs, LLC. The other authors have declared that they have no competing interest.
Authors’ contributions
LS contributed to acquisition of data, analysis and interpretation of data, and drafted the manuscript. YS contributed to the conception and design, acquisition of data, analysis and interpretation of data, and helped draft the manuscript. JW helped to draft and revise the manuscript. PE contributed to the acquisition of data and interpretation of data and revision of the manuscript. MA contributed to conception and revision of manuscript. XML contributed to the conception and design, acquisition of data, analysis, interpretation of data, and revision of the manuscript. All authors read and approved the final manuscript.