No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Distinct patterns of cow's milk allergy in infancy defined by prolonged, two-stage double-blind, placebo-controlled food challenges
Abstract
The clinical manifestations of cow's milk allergy (CMA) are highly variable, and challenges usually identify only immediate, IgE mediated reactions.
To clearly identify CMA of immediate and delayed types using a two-stage, double-blind, placebo-controlled food challenge (DBPCFC), and to prospectively compare the clinical history and analyses of specific IgE antibodies to milk in predicting outcome of DBPCFC.
A total of 69 patients (33 girls, 36 boys) were recruited for study based on a history highly suggestive of CMA and resolution of symptoms on a bovine protein-free diet. After skin-prick tests (SPTs) and search for allergen-specific serum IgE antibodies by enzyme allergosorbent test (EAST), a two-stage DBPCFC was performed over several days.
Of 16 patients (mean age 36.9 months) classified as probable immediate reactors based on the history, 10 (62.5%) had a positive DBPCFC with similar patterns to historical adverse reactions (< or = 2 h after milk exposure). The other 53 (77%) patients (17.3 months) had a history of probable delayed type CMA presenting with predominantly gastrointestimal symptoms from 2 h and up to 6 days after milk exposure. Of these, 15 (28.8%) had a positive DBPCFC, again with a symptom pattern similar to the history. Sensitivity/specificity of SPT was similar to that of EAST for both immediate (70/83% and 62/83% respectively, NS) or delayed (0/97% and 0/97%) CMA confirmed by DBPCFC.
Using our two-stage, prolonged DBPCFC, we clearly identified two groups of children with CMA, reflecting different pathogenesis of either immediate-type IgE-dependent, or delayed-type IgE-independent allergy. Although useful in immediate reactors, IgE antibody determination cannot predict the outcome of DBPCFC in delayed reactors. A thorough clinical history was the most helpful tool to predict the type of response in challenge positive patients.
... The distribution of eliciting doses (ED) was based on the No Observed Adverse Effect Levels (NOAEL) and Lowest Observed Adverse Effect Levels (LOAEL) of milk-allergic participants (mostly children) available in milk challenges from the literature (Baehler et al., 1996;Blom et al., 2013;Gushken et al., 2013;Hill et al., 1988;Høst and Samuelsson, 1988;Keet et al., 2012;Lam et al., 2008;Longo et al., 2008;Morisset et al., 2003;Nørgaard and Bindslev-Jensen, 1992;Okada et al., 2015;Orhan et al., 2009;Caminiti et al., 2009;Patriarca et al., 2002;Rolinck-Werninghaus et al., 2012;Skripak et al., 2008;Staden et al., 2007;Vlieg-Boerstra et al., 2008;Winberg et al., 2015;Dambacher et al., 2013;Ebrahimi et al., 2017;Devenney et al., 2006;Eller et al., 2012;Fiocchi et al., 2003;Flinterman et al., 2006;Goldberg et al., 2015) (Appendix Table 1). Only discrete doses triggering objective symptoms were considered (n = 1078). ...
... The ED values (mg milk protein) to elicit reactions in 1, 5, 10 and 25% of the allergic population (ED 01 , ED 05 , ED 10 , ED 25 ) were estimated using Weibull, Log Normal & Log Logistic distributions as recommended in previous risk characterization/assessment (Remington et al., 2015;Taylor et al., 2009). The ED obtained (mg) were then compared to published ED (Houben et al., 2020) and the lowest NOAEL-NOAEL values reported in the clinical studies (Baehler et al., 1996;Blom et al., 2013;Okada et al., 2015;Orhan et al., 2009; (Remington et al., 2013), and Spanjersberg et al. (2007). The model simulates the amount of pre-packaged food (e.g., dark chocolate, cookies, or baked goods) a milk-allergic consumer would eat, the level of milk contamination, and the likelihood the allergic consumer would consider the PAL, to compute a distribution of estimated exposure doses. ...
... Distribution parameters of the probabilistic risk assessment. Variable (unit) Distribution/Equation ( (Baehler et al., 1996;Blom et al., 2013;Gushken et al., 2013;Hill et al., 1988;Høst and Samuelsson, 1988;Keet et al., 2012;Lam et al., 2008;Longo et al., 2008;Morisset et al., 2003;Nørgaard and Bindslev-Jensen, 1992;Okada et al., 2015;Orhan et al., 2009;Caminiti et al., 2009;Patriarca et al., 2002;Rolinck-Werninghaus et al., 2012;Skripak et al., 2008;Staden et al., 2007;Vlieg-Boerstra et al., 2008;Winberg et al., 2015;Dambacher et al., 2013;Ebrahimi et al., 2017;Devenney et al., 2006;Eller et al., 2012;Fiocchi et al., 2003;Flinterman et al., 2006;Goldberg et al., 2015) Bernouilli (p = 0.011) Clarke et al., 2020 χ : Probability of having an allergic reaction at a given exposure. ...
The risk of having an allergic reaction in milk-allergic individuals consuming products with precautionary allergen labelling (PAL) for milk has been rarely studied in products such as dark chocolate, cookies, and other baked goods. A probabilistic risk assessment model was developed to estimate potential risks. Milk occurrence and contamination levels were reported in a previous article from our group. Dose-response curves for milk were constructed using values (n=1078) from published double-blind placebo-controlled food challenges. Canadian consumption data was extracted from a national survey, and a homemade survey involving food-allergic Canadians. Milk eliciting doses (ED) were 0.23 (ED01), 1.34 (ED05), 3.42 (ED10), and 16.3 (ED25) mg of milk protein (Log-Normal distribution). Average exposures, per eating occasion, were 24mg (dark chocolate), 3.9mg (baked goods), and 0.20mg (cookies) of milk proteins. The estimated risk of having a milk-induced allergic reaction by consuming foods with PAL for milk was higher for dark chocolate (16%; 15,881/100,000) than baked goods (3.8%; 3,802/100,000) or cookies (0.6%; 646/100,000) in milk-allergic Canadians. Dark chocolate, cookies, and baked goods with PAL for milk, should be avoided by milk-allergic Canadians (consuming or not products with PAL) to prevent allergic reactions.
... As reviewed above, a diagnosis of FA on the basis of the parent's history is inaccurate in a sizeable proportion of cases. 23 An accurate history is important in order to ascertain the delay in timing of ingestion and the onset of symptoms, the type of symptoms, the food allergens likely to be causing the problem, and the risk of atopy. Although essential for planning the necessary clinical evaluation and investigations, the clinical history alone corresponds to a positive double-blind placebo-controlled challenge in about 30-40% of cases. ...
... Hence, there is a need for reliable diagnostic tests for FA. 23 IgE-mediated food allergy is by far the most studied type of disease; there is good general knowledge of the mechanisms, reliable diagnostic tools, but no proactive treatment. Skin testing or the detection of circulating allergen-specific IgE antibodies is an accurate diagnostic tool for patients with IgE-mediated milk allergy. ...
... Skin testing or the detection of circulating allergen-specific IgE antibodies is an accurate diagnostic tool for patients with IgE-mediated milk allergy. 23,24 Although false positives are problematic in children with atopic dermatitis, false negative skin prick tests are 22 In addition, the test results may also remain positive some time after clinical reactivity has resolved. In general, studies show that strongly positive skin tests, confirmed by allergen-specific serum IgE assays, have a positive predictive value of 95% in infants with IgE-mediated FA. 6,25 The radioallergosorbent (RAST) test and similar semi-quantitative in vitro assays that provide evidence of IgE-mediated food-allergy are being replaced by more quantitative measurements of food specific IgE antibodies. ...
OBJETIVOS: Apresentar uma revisão atualizada e crítica sobre alergias alimentares, focando principalmente em tratamento e prevenção. FONTES DOS DADOS: Revisão da literatura publicada obtida através do banco de dados MEDLINE, sendo selecionados os mais atuais e representativos do tema (2000-2006). A pesquisa incluiu os sites da European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) e American Academy of Pediatrics (AAP). SÍNTESE DOS DADOS: A prevalência de doenças alérgicas tem aumentado nas últimas décadas e alergia alimentar parece fazer parte desse aumento. Alergia alimentar é muito mais comum em pediatria e apresenta impacto médico, financeiro e social significativos em crianças menores e suas famílias. Tratamento e prevenção da alergia alimentar são desafios maiores do ponto de vista da saúde pública e para as comunidades médica e científica. Há muita informação incorreta e condutas médicas discutíveis nessa área. Apresentamos e discutimos as recomendações publicadas pelos Comitês de Nutrição da ESPGHAN juntamente com a Sociedade Européia Pediátrica de Alergologia e Imunologia Clínica (ESPACI) e AAP. CONCLUSÃO: Excesso de diagnósticos de alergia alimentar é bastante prevalente. Há necessidade de uniformização de definições e procedimentos diagnósticos. O objetivo primário do manejo deve ser o de instituir medidas efetivas de prevenção das alergias alimentares. Há necessidade de métodos precisos para confirmar ou excluir o diagnóstico. Os pacientes necessitam tratamento apropriado através da eliminação de alimentos que causam sintomas, ao mesmo tempo evitando os efeitos adversos nutricionais e o custo de dietas inadequadas.OBJECTIVE: To present an up-to-date and critical review regarding food allergies, focusing mainly on treatment and prevention. SOURCES: Review of published literature searched on MEDLINE database; those data which were the most up-to-date and representative were selected (2000-2006). The search included the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the American Academy of Pediatrics (AAP). SUMMARY OF THE FINDINGS: The prevalence of allergic diseases has increased over the last decades, and food allergy seems to be part of this increase. Food allergy is much more common in pediatrics and has a significant medical, financial and social impact on young children and their families. Treatment and prevention of food allergy is a major challenge for public health, scientific and medical communities. There is a lot of misinformation and the medical management of this condition is still discussable. We present and discuss the guidelines regarding criteria for the prevention of food allergy and atopic diseases published by the Nutrition Committees of ESPGHAN jointly with the European Society for Pediatric Allergy and Clinical Immunology (ESPACI) and AAP. CONCLUSION: The overdiagnosis of food allergy is quite prevalent. There is a need for standardization of definitions and diagnostic procedures. The primary goal of therapy should be to first establish effective means of preventing food allergies. There is a need for accurate diagnostic methods to confirm or rule out the diagnosis. Patients need appropriate treatment by eliminating foods that cause symptoms, while avoiding the nutritional side effects and the cost of inappropriate diets.
... The result is a cumulative distribution of the MEDs in which the probability (between 0 and 100%) of the allergic response is presented that occurs at a certain dose (amount of protein intake) less than or equal to this certain dose. For comparison, data from the literature [5,222324 were fitted using the same method. In determining the individual MED, we used the discrete dose at which the symptoms occur instead of the cumulative dose for several reasons. ...
... Besides acute reactions, we also studied late reactions which typically develop within 24 to 72 hours after ingesting CMP. When late reactions are described in the literature, they form a substantial part of the positive test results, ranging from 20% to 60% [22,26]. When only acute reactions are included, as in the study by Schade et al. [25], a much lower incidence of CMA is found than mentioned in the literature. ...
... However studies that are developed to determine MEDs often only describe the lowest MED within the population encountered, whereas a distribution of MEDs within that population is not established [31] . Flinterman et al. [5], Baehler et al. [22], Caminiti et al. [23] and Patriarca et al. [24] however, do represent data in their studies describing allergic reactions to CMP which can be used for determining the cumulative distribution of MEDs in their population.Table 5 Information on the populations represented inFigure 1 Study[24] Tertiary referral centre Children with CMA from the outpatient clinic offered an oral desensitization. ...
Background
Children with cow’s milk allergy (CMA) need a cow’s milk protein (CMP) free diet to prevent allergic reactions. For this, reliable allergy-information on the label of food products is essential to avoid products containing the allergen. On the other hand, both overzealous labeling and misdiagnosis that result in unnecessary elimination diets, can lead to potentially hazardous health situations. Our objective was to evaluate if excluding CMA by double-blind placebo-controlled food challenge (DBPCFC) prevents unnecessary elimination diets in the long term. Secondly, to determine the minimum eliciting dose (MED) for an acute allergic reaction to CMP in DBPCFC positive children.
Methods
All children with suspected CMA under our care (Oct’05 - Jun’09) were prospectively enrolled in a DBPCFC. Placebo and verum feedings were administered on two randomly assigned separate days. The MED was determined by noting the ‘lowest observed adverse effect level’ (LOAEL) in DBPCFC-positive children. Based on the outcomes of the DBPCFC a dietary advice was given. Parents were contacted by phone several months later about the diet of their child.
Results
116 children were available for analysis. In 76 children CMA was rejected. In 60 of them CMP was successfully reintroduced, in 2 the parents refused introduction, in another 3 the parents stopped reintroduction. In 9 children CMA symptoms reappeared. In 40 children CMA was confirmed. Infants aged ≤ 12 months in our study group have a higher cumulative distribution of MED than older children.
Conclusions
Excluding CMA by DBPCFC successfully stopped unnecessary elimination diets in the long term in most children. The MEDs form potential useful information for offering dietary advice to patients and their caretakers.
... The reaction time at CM challenge varies: 2 clinically distinct groups of patients, immediate and delayed reactors, have been discerned (Dannaeus and Johansson 1979, Ford et al. 1983, Isolauri and Turjanmaa 1996. However, the time limit between the 2 groups is not exactly defined: some authors have used 1 h (Dannaeus and Johansson 1979, Ford et al. 1983, Tainio and Savilahti 1990, others 2 h (Räsänen et al. 1992, Baehler et al. 1996 or 8 h (Høst and Halken 1990). In one study, all the positive responses occurring within 2 h after the last (4 th ) dose were considered to be immediate reactions (Vanto et al. 1999). ...
... However, the percentage of patients reacting within 1 h at challenge has varied from 25% to 74% (Goldman et al. 1963, Dannaeus and Johansson 1979, Jakobsson and Lindberg 1979, Ford et al. 1983, Hill et al. 1986, Tainio and Savilahti 1990. In studies using other limits for reaction types, 40% to 57% of patients have been classified as immediate reactors (Høst and Halken 1990, Baehler et al. 1996, Isolauri and Turjanmaa 1996, Vanto et al. 1999. ...
... Of the cutaneous symptoms, urticaria and/or exanthema are reported in 11-35% of patients (Goldman et al. 1963, Jakobsson and Lindberg 1979, Ford et al. 1983, Hill et al. 1986, Høst and Halken 1990, Tainio and Savilahti 1990, Baehler et al. 1996, angioedema in 12-28% (Ford et al. 1983, Baehler et al. 1996 and atopic dermatitis in 17-67% of patients (Goldman et al. 1963, Gerrard et al. 1973, Jakobsson and Lindberg 1979, Ford et al. 1983, Hill et al. 1986, Ventura and Greco 1988, Høst and Halken 1990, Baehler et al. 1996. Urticaria, exanthema and angioedema usually appear within minutes after ingestion of a provoking dose of CM, whereas the emergence of symptoms of atopic dermatitis, such as erythema, pruritus, oedema, papules, oozing, crusting and excoriation vary from hours to days (Hill et al. 1986, Stalder and Taïeb 1993, Bock and Sampson 1994, Isolauri and Turjanmaa 1996. ...
Diss. -- Helsingin yliopisto.
... The underlying interplay between CMA and AD in infant and children populations has been widely researched for many years. In 1996, Baehler et al. demonstrated, through a double-blind placebocontrolled food challenge (DBPCFC) method, the distinct differences between type I and type IV hypersensitivity reactions in infants and young children with CMA [23]. The oral food challenge (OFC) test, specifically the double-blind placebo-controlled food challenge (DBPCFC) test, is the gold standard for diagnosing a food allergy [18][19][20][21][22]. ...
... The oral food challenge (OFC) test, specifically the double-blind placebo-controlled food challenge (DBPCFC) test, is the gold standard for diagnosing a food allergy [18][19][20][21][22]. By conducting a DBPCFC test, the study found that dermatological symptoms of urticaria, erythematous rash, and angioedema were noted primarily in the immediate hypersensitivity reaction group (62.5% of participants with CMA), whereas gastrointestinal symptoms were noted in the delayed-type hypersensitivity group (28.8% of participants with CMA) [23]. However, more recent studies have shown dermatological manifestations occurring within both mechanisms [24]. ...
Of the many symptoms associated with cow's milk allergy (CMA), many populations face the burden of the appearance or worsening of atopic dermatitis (AD) when consuming milk products. Due to the prevalence and possible severity of symptoms, it is important to understand the underlying immune mechanisms involved in such reactions. Hypersensitivity reactions are exaggerated immune responses to often benign antigens, many times resulting in a cascade of pro-inflammatory processes. Of the four major types, type I and IV are of most relevance when considering atopic dermatitis worsened by cow's milk. Considered a "true allergy," type I (immediate) hypersensitivity reactions occur within hours after secondary exposure to an allergen and are primarily driven by antibodies and humoral immune responses. On the contrary, type IV (delayed) hypersensitivity reactions are driven by cell-mediated responses involving T-cell activation. Due to the array of symptoms induced by these complex reactions, it is imperative to diagnose early and treat appropriately. In this literature review, we aim to highlight the primary underlying immune contributors to hypersensitivity reactions, discuss AD as a manifestation of hypersensitivity reactions to cow's milk, and consider current and future treatment options for combatting hypersensitivities manifesting as AD.
... Exclusive breastfeeding at three months and its association 134 with sensitisation to the predefined food allergens and FHS Table 4.14 Any breastfeeding at six months and its association with 134 sensitisation to the predefined food allergens and FHS Table 4. 15 Any breastfeeding at nine months and its association with 134 sensitisation to the predefined food allergens and FHS Table 4. 16 Any breastfeeding at 12 months and its association with 135 sensitisation to the predefined food allergens and FHS Table 4.17 "Ever" breastfed and its association with sensitisation to 135 ...
... Also, apart from one study (Zuberbier et al. 2004), the majority of research papers do not mention whether the DBPCFCs have been tested for blindness (Baehler et al. 1996 can have different effects on the allergenicity of food proteins. Any form of processing used for preparing the challenge food could therefore potentially influence the challenge outcome. ...
p> Introduction: It is unclear at present which type of food challenge (open vs. double blind) is best suited for the diagnosis of food hypersensitivity (FHS) in children.
This research aimed to assess 1) what is the best approach for the diagnosis of FHS; 2) how maternal dietary and infant feeding and weaning practices influence the development of FHS; 3) the role of a personal or family history of atopy in dietary practices.
Methods: A birth cohort of children born during 2001 - 2002 was recruited at the ante-natal clinic and followed prospectively for two years. In addition, three sets of school cohorts were approached to participate in the study. To address the first aim, all cohorts were utilised and the use of open food challenges (OFC) and double blind placebo controlled food challenges (DBPCFC) were assessed in the diagnosis of FHS. To address the second aim the birth cohort was used. A food frequency questionnaire (FFQ) was developed and validated to obtain the information on the maternal diet. Standardised questionnaires were developed and used prospectively to assess feeding and weaning practices and their influence on the infant’s FHS. To address the third aim the family history of atopy was obtained during recruitment of the birth cohort.
Results: We found that the positive predictive value of the one-day OFC challenges was higher than the one-week OFC. The data therefore suggest that OFC may be suitable for diagnosing immediate (objective) symptoms, whereas a DBPCFC may be needed for the diagnosis of delayed (subjective) symptoms.
Fruit and vegetable intake during pregnancy, food avoidance during lactation and weaning age of the infant affected the development of FHS.
A family history of atopy positively affected exclusive breast feeding at three months and delayed introduction of peanuts into the infant’s diet by six months. </p
... Metod¹ diagnostyczn¹ decyduj¹c¹ o w³aciwym rozpoznaniu, weryfikuj¹c¹ wszystkie wy¿ej wymienione etapy postêpowania diagnostycznego, jest doustna próba prowokacji pokarmowej. Próba ta ma najwa¿niejsze znaczenie w wykazaniu zwi¹zku miêdzy spo¿yciem pokarmu a objawami klinicznymi, niezale¿nie od mechanizmów patogenetycznych prowadz¹cych do ich wyst¹pienia [33,34,35,36]. Wykonanie jej metod¹ podwójnie lepej próby kontrolowanej placebo pozwala wykluczyae udzia³ czynników psychogennych, których udzia³ w poczuciu choroby jest niepodwa¿alny, o czym wiadcz¹ liczne badania [18,19,20,33]. ...
... Brak kontaktu testowanego pokarmu z b³on¹ luzo-w¹ jamy ustnej czyni tê postaae nieprzydatn¹ w diagnostyce zespo³u oral allergy syndrom [37]. Postaae p³ynna za bardziej skrupulatnie kontroluje iloae podanego pokarmu (szybsze wch³anianie) i wyst¹pienie objawów niepo-¿¹danych, pozwala unikn¹ae podania dodatkowej dawki alergenu przed ujawnieniem siê pierwszych symptomów choroby [36]. Ma³a iloae pokarmu natywnego, jak¹ mo-¿emy ukryae w pod³o¿u p³ynnym jest zazwyczaj niewystar-czaj¹ca do wywo³ania objawów klinicznych. ...
... It is therefore clear, that the golden standard to diagnose CMA is by means of a double-blind, placebo-controlled milk challenge, to prevent false-positive results 7,8,10 . The principles on which blinded milk challenges should be based are widely accepted 10,11 , and several protocols have been described 9,[12][13][14] . Performing doubleblind challenges, however, can be very time-consuming and labor-intensive, and most described protocols are therefore limited to use in research-settings. ...
... It has been suggested that patients with CMA can also have isolated 'late' or 'delayed-type' reactions 2 . These are allergic reactions who are said to arise only after more than 24 hours intake of cow's milk 13,14 . This does not concern acute, life-threatening symptoms, but comprises a negative influence of milk-ingestion on chronic conditions such as infantile colic or atopic dermatitis, in the absence of acute reactions. ...
ABSTRACT The golden standard to diagnose,clinical significant cow’s milk allergy (CMA) is bymeans,of a milk-provocation using a placebo-controlled protocol with blinded patients and observers. In most pediatric settings however, provocations are usually performed using open challenges, because this is less time-demanding and labor- intensive. We have therefore designed a protocol for a double-blind, placebo- controlled cow’s milk challenge ,(DBPCCMC) that can be used ,to diagnose immediate-type allergic reactions to milk in a normal pediatric clinical setting. Our experience with this protocol in 154 children referred to our ,pediatric outpatient clinic over a two-year period, showed that it is possible to perform blinded- challenges routinely in the diagnostic work-up of children with suspicion of CMA. The protocol that we describe, provides a safe and efficient method to accurately diagnose,immediate-type allergic reactions in infants ,and ,children. As it ,is generally accepted that DBPCCMCs are superior to open challenges because of the significant improved value, and parental acceptance of the diagnosis, we propose that DBPCCMCs should be implemented into routine pediatric practice, to prevent inaccurate diagnosis and unnecessary elimination diets.
... Seventeen studies were identified representing 1045 positive FCs (98% in children) (Table E5, available in this article's Online Repository at www.jaci-inpractice.org). 27,30,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] At meta-analysis, the estimated rate of anaphylaxis in those individuals reacting with objective symptoms to ED 05 levels of exposure was 4.9% (95% CI: 2.1%-11%) ( Figure E5, available in this article's Online Repository at www.jaci-inpractice.org). Two studies also reported the occurrence of subjective symptoms to low-level exposures. ...
Regional and national legislation mandates the disclosure of “priority” allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen (“may contain”) labels (PAL) which are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and non-uniformity in the use of PAL by food businesses. One potential solution would be to establish internationally-agreed “reference doses”, below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at low-level allergen exposure.
... Despite the likelihood of an overlap of clinical symptoms in IgE-mediated and non-IgE-mediated type immune reactions and combinations of immediate and delayed reactions to the same allergen in the same patient, a detailed history and appropriate laboratory studies indicate the correct diagnosis in most cases (14,28,48). Distinguishing between the mechanisms of immune reactions is important, as IgE-mediated CMPA is associated with a higher risk of multiple food allergies and atopic conditions, such as asthma, later in life (18,28,49). ...
This review addresses the current strategies of inducing tolerance development in infant and childhood cow's milk protein allergy (CMPA). The change in prevention strategies for CMPA has been emphasized based on the lack of evidence to support the efficacy of food allergen avoidance in infancy and the concept of the dual-allergen-exposure hypothesis, which suggests that allergen exposure through the skin leads to sensitization, whereas early oral consumption of allergenic food protein induces oral tolerance. The new approach is based on the likelihood of early introduction of allergenic foods to the infant's diet to reduce the development of food allergies through oral tolerance induction. The latest treatment guidelines recommend the continuation of breast feeding and the elimination of cow's milk and products from the maternal diet in exclusively breast-fed infants with CMPA, the use of an extensively hydrolyzed infant formula (eHF) with proven efficacy in CMPA as the first elimination diet in formula-fed infants with CMPA and the use of amino acid-based formula (AAF) in severe cases, such as anaphylaxis, enteropathy, eosinophilic esophagitis, and food protein-induced enterocolitis syndrome (FPIES), as well as cases of multiple system involvement, multiple food allergies, and intolerance to extensively hydrolyzed formula (eHF). In conclusion, this paper presents the current knowledge on tolerance development in infants and children with CMPA to increase the awareness of the clinicians concerning the new approaches in CMPA treatment Tolerance development is considered a relatively new concept in CMPA, inducing a shift in interventions in CMPA from a passive (avoidance of responsible allergen) toward a proactive (tolerance induction) strategy.
... Immunotoxicity from exposure to cow's milk is one of the most common causes of food allergies, affecting roughly 3% of the population, and involves both immediate type (immunoglobulin [Ig] E-dependent) and delayed type (IgEindependent) sensitivity reactions. Accordingly, hypersensitivity to milk proteins can present as a complex of symptoms including dermatitis, urticaria, gastrointestinal indications, airway reactivity, and anaphylactic shock (1)(2)(3). Although milk contains more than 40 distinct proteins, those of primary clinical significance are casein and b-lactoglobulin (BLG), the major component of milk whey (7). ...
Allergies to cow's milk are very common and can present as life-threatening anaphylaxis. Consequently, food labeling legislation mandates that foods containing milk residues, including casein and/or β-lactoglobulin, provide an indication of such on the product label. Because contamination with either component independent of the other can occur during food manufacturing, effective allergen management measures for containment of milk residues necessitates the use of dual screening methods. To assist the food industry in improving food safety practices, we have developed a rapid lateral flow immunoassay test kit that reliably reports both residues down to 0.01 μg per swab and 0.1 ppm of protein for foods. The assay utilizes both sandwich and competitive format test lines and is specific for bovine milk residues. Selectivity testing using a panel of matrices with potentially interfering substances, including commonly used sanitizing agents, indicated reduction in the limit of detection by one-to fourfold. With food, residues were easily detected in all cow's milk–based foods tested, but goat and sheep milk residues were not detected. Specificity analysis revealed no cross-reactivity with common commodities, with the exception of kidney beans when present at high concentrations (> 1%). The development of a highly sensitive and rapid test method capable of detecting trace amounts of casein and/or β-lactoglobulin should aid food manufacturers and regulatory agencies in monitoring for milk allergens in environmental and food samples.
... Only 1 study [37] examines objective measurements (nasal eosinophilia and nasal airway patency) in young children with allergic rhinitis (AR) and nonallergic rhinitis, finding them useful for distinguishing the 2 phenotypes. Very few studies appraise methods for defining the phenotypes of urticaria and anaphylaxis [38][39][40] . ...
Background:
During the last decades, a large number of phenotypes and disease classifications of allergic diseases have been proposed. Despite the heterogeneity across studies, no systematic review has been conducted on phenotype classification and the criteria that define allergic diseases. We aimed to identify clinically expressed, population-based phenotypes of allergic diseases and their interrelationships, to explore disease heterogeneity and to evaluate the measurements employed in disease diagnosis.
Methods:
We conducted a search of MEDLINE up to December 2012, to identify relevant original studies published in the English language that examine at least one objective of this systematic review in subjects aged 0-18 years. The screening of titles and abstracts and the extraction of data were conducted independently by two reviewers.
Results:
From a total of 13,767 citations, 197 studies met the criteria for inclusion, with 54% being cohort studies. Allergic diseases were studied as a single entity in 55% (109/197) of the studies or in the context of multimorbidity in 45%. Asthma accounted for 81.7% of the studies examining single diseases. Overall, up to 33 different phenotypes of allergic disease were reported. Transient early, late-onset and persistent wheeze were the most frequently reported phenotypes. Most studies (78%) used questionnaires. The skin-prick test was the preferred measurement of sensitization (64%). Spirometry and bronchial hyperresponsiveness were assessed in one third of the studies, peak flow rate in 8.6% and disease severity in 35%.
Conclusions:
Studies reporting phenotypes of allergic diseases in children are highly heterogeneous and often lack objective phenotypical measures. A concerted effort to standardize methods and terminology is necessary.
... For those that did not, protein levels were calculated based on the protein content levels used by Taylor et al. (2002) or on those listed by the USDA National Nutrient Database for Standard Reference (USDA, 2011). For those publications that only presented cumulative eliciting dose values, the dosing scheme provided in the paper was used to derive the discrete MEDs, assuming that all patients followed the published dosing scheme (Astier et al., 2006;Baehler et al., 1996;Grimshaw et al., 2003;Vlieg-Boerstra et al., 2008;Wainstein et al., 2010). If cumulative doses were reported but no dosing scheme was given in the publication, the most-likely dosing scheme was inferred from the pattern of cumulative doses reported and the description in the text, and this inferred scheme was used to calculate the discrete MEDs (Bock et al., 1978;Glaumann et al., 2012;May, 1976). ...
Food allergy is a public health concern, affecting up to 6% of children and 2% of adults. The severity of allergic reactions can range from mild to potentially life-threatening. In addition, the minimum amount of protein needed to provoke an allergic reaction in an individual patient (the minimal eliciting dose, MED) ranges from a few micrograms to several grams. To determine whether a retrospective analysis of published data from oral food challenges could be used to assess the potential relationship between MEDs and reaction severities at the MEDs, a three class (mild, moderate, severe) reaction grading system was developed by integrating previously published reaction grading systems. MEDs and symptoms were collected from food challenge studies and each reaction was graded using the integrated grading system. Peanut allergic patients who experienced severe reactions had significantly higher MEDs and threshold distribution doses than those who experienced mild and moderate reactions. No significant differences in threshold distributions according to the severity grading were found for milk, egg and soy. The relationship between threshold dose distribution and reaction severity based on these grading criteria differed between peanut and other allergens, and severe reactions occurred in some patients at low MEDs for all of these food allergens.
Copyright © 2015. Published by Elsevier Ltd.
... A proteína do leite de vaca (LV) apresenta potencial alergênico alto e é considerada o mais frequente componente dietético causador de alergia alimentar (1) . O diagnóstico da alergia à proteína do leite de vaca (APLV) baseia-se nas manifestações clínicas, na resposta à dieta de exclusão e posterior teste de desencadeamento duplo-cego controlado por placebo (padrão-ouro) (2) . No entanto, devido às suas dificuldades práticas, rotineiramente faz-se a opção pelo teste de provocação aberto (3)(4)(5) . ...
To determine clinical and follow up characteristics of children enrolled in a program to supply formulas for cow's milk allergy.
descriptive study of a convenience sample composed of 214 children up to three years old, with clinical diagnosis of cow's milk allergy and/or standardized oral challenge, referred to the Program of Formulas for Cow's Milk Allergy at a Pediatric University Hospital, in Natal, Rio Grande do Norte, Brazil (2007/2009). Clinical-epidemiological data and formula indication (soy, protein hydrolysates or aminoacid formula) were assessed at the first consultation. Clinical response and nutritional evolution (Anthro-OMS2006) were observed after three months. Chi-square and paired t-test were used, being p<0.05 significant.
At the first consultation, mean age was 9.0±6.9 months. Digestive manifestations occurred in 81.8%; cutaneous ones, in 36.9% and respiratory ones in 23.8%. BMI Z-score <-2.0 standard deviations (SD) was found in 17.9% of children with isolated digestive symptoms, in 41.7% of those using cow's milk and in 8.7% of those using other formulas (p<0.01). The following formulas were used: soy in 61.2%, protein hydrolysates in 35.4% and aminoacids in 3.3%. Mean BMI Z-scores at initial consultation and after three months were, respectively: -0.24±1.47SD and 0.00±1.26SD (p=0.251), with soy formula, and -0.70±1.51SD and -0.14±1.36SD (p=0.322) with protein hydrolysates formula.
Digestive manifestations of cow's milk allergy were preponderant, and lead to greater nutritional impairment. The use of replacement formulas (isolated soy protein and protein hydrolysates) was important to maintain the nutritional status.
A syndrome of chronic diarrhea, vomiting, and failure to thrive was described 35 years ago. The syndrome was caused by damage in the jejunum after ingestion of cow's milk. Symptoms appeared in young infants shortly after introduction of cow's milk formula. Patients had moderate steatorrhea, decreased absorption of D‐xylose, and, often, iron‐deficiency anemia and hypoproteinemia. They had strong IgA and IgG antibodies to cow's milk. IgE antibodies to cow's milk were negative, as a rule. Indicators of cell‐mediated immune reaction to cow's milk proteins were often positive. Patients were tolerant to cow's milk by the age of 3 years. Malabsorption was due to damage to the jejunal mucosa: Varying villus atrophy was associated with inflammation in surface epithelium and lamina propria. The epithelial cell renewal rate increased. Surface epithelial cells decreased in height, with short, furry microvilli and large aggregates of lysozymes. The number of intraepithelial lymphocytes was markedly increased, but normalized during cow's milk elimination. Most of these lymphocytes had α/β T‐cell receptors, and many were cytotoxic. Some specimens had an increase in γ/δ T‐cell receptor‐bearing cells. In the lamina propria, CD4+ cells predominated, and some of them were activated. IgA‐ and IgM‐containing cells were markedly increased during cow's milk exposure, but IgE cells were not abnormal. The density of eosinophils was moderately increased. Secretion of interferon‐γ by cells isolated from patients' intestines was markedly increased. Morphologic and immunologic findings suggest that T‐cell‐mediated reaction to proteins in cow's milk is present in the small intestines of patients with this syndrome and causes this enteropathy.
Background
Dientamoeba fragilis is a rare cause of chronic infectious diarrhea and colitis in children.
Methods
Review of the clinical manifestations, diagnostic methods, and clinical course of D. fragilis infection in our hospital.
Results
Eleven pediatric patients are discussed, seven of whom had a history of recent travel. Clinical manifestations of infectious diarrhea included anorexia, intermittent vomiting, abdominal pain, and diarrhea, ranging from 1 to 100 weeks in duration. Peripheral eosinophilia was present in seven patients. One patient with well‐documented bovine protein allergy had intermittent episodes of diarrhea and abdominal pain, despite an appropriate elimination diet. Eosinophilic colitis documented by colonoscopy, was due to D. fragilis . Metronidazole was effective in treating five patients, and iodoquinol was effective in treating four others.
Conclusions
D. fragilis should be included in the differential diagnosis of chronic diarrhea and eosinophilic colitis. The identification of this pathogen requires clinical awareness of epidemiologic risk factors and presenting complaints, as well as the laboratory staining procedures essential to its proper identification.
Background:
Cow's milk (CM) is an increasingly common cause of severe allergic reactions, but there is uncertainty with respect to severity of reactions at low-level CM exposure, as well as the reproducibility of reaction thresholds.
Objective:
We undertook an individual participant data (IPD) meta-analysis of studies reporting double-blind, placebo-controlled food challenges in CM to determine the rate of anaphylaxis to low-level exposures and the reproducibility of reaction thresholds.
Methods:
We performed a systematic review and IPD meta-analysis of studies reporting relevant data. Authors were contacted to provide additional data and/or clarification as needed. Risk of bias was assessed using the National Institute for Clinical Excellence methodologic checklists.
Results:
Thirty-four studies were included, representing data from over 1000 participants. The cumulative ED01 and ED05 (cumulative doses causing objective symptoms in 1% and 5% of the at-risk allergic population) were 0.3 (95% confidence interval [CI], 0.2-0.5) and 2.9 (95% CI, 1.6-5.4) mg, respectively. At meta-analysis, 4.8% (95% CI, 2.0-10.9) and 4.8% (95% CI, 0.7-27.1) of individuals reacting to ≤5 mg and ≤0.5 mg of CM protein had anaphylaxis (minimal heterogeneity, I2 = 0%). Then 110 individuals underwent repeat double-blind, placebo-controlled food challenges; the intraindividual variation in reaction threshold was limited to a ½-log change in 80% (95% CI, 65-89) of participants. Two individuals initially tolerated 5 mg CM protein but then reacted to this dose at a subsequent challenge, although neither had anaphylaxis.
Conclusions:
About 5% of CM-allergic individuals reacting to ED01 or ED05 exposure might have anaphylaxis to that dose. This equates to 5 and 24 anaphylaxis events per 10,000 patients exposed to an ED01 or ED05 dose, respectively, in the broader CM-allergic population. Most of these anaphylactic reactions would be mild and respond to a single dose of epinephrine.
A number of studies have reported comorbidity of food allergies with various neuropsychiatric disorders, such as anxiety, depression, attention-deficit hyperactivity disorder, and autism. However, inconsistent results across clinical studies have left the association between food allergy and behavioral disorders inconclusive. We postulated that the heterogeneities in genetic background among allergic cohorts affect symptom presentation and severity of food allergy, introducing bias in patient selection criteria toward individuals with overt physical reactions. To understand the influence of genetic background on food allergy symptoms and behavioral changes beyond anaphylaxis, we generated mouse models with mild cow’s milk allergy by sensitizing male and female C57BL/6J and BALB/cJ mice to a bovine whey protein, β-lactoglobulin (BLG; Bos d 5). We compared strain- and sex-dependent differences in their immediate physical reactions to BLG challenge as well as anxiety-like behavior one day after the challenge. While reactions to the allergen challenge were either absent or mild for all groups, a greater number of BLG-sensitized BALB/cJ mice presented visible symptoms and hypothermia compared to C57BL/6J mice. Interestingly, male mice of both strains displayed anxiety-like behavior on an elevated zero maze without exhibiting cognitive impairment with the cross maze test. Further characterization of plasma cytokines/chemokines and fecal microbiota also differentiated strain- and sex-dependent effects of BLG sensitization on immune-mediator levels and bacterial populations, respectively. These results demonstrated that the genetic variables in mouse models of milk allergy influenced immediate physical reactions to the allergen, manifestation of anxiety-like behavior, levels of immune responses, and population shift in gut microbiota. Thus, stratification of allergic cohorts by their symptom presentations and severity may strengthen the link between food allergy and behavioral disorders and identify a population(s) with specific genetic background that have increased susceptibility to allergy-associated behavioral disorders.
Food allergy and allergen management are important global public health issues. In 2011, the first iteration of our allergen threshold database (ATDB) was established based on individual NOAELs and LOAELs from oral food challenge in roughly 1750 allergic individuals. Population minimal eliciting dose (EDp) distributions based on this dataset were published for 11 allergenic foods in 2014. Systematic data collection has continued (2011–2018) and the dataset now contains over 3400 data points. The current study provides new and updated EDp values for 14 allergenic foods and incorporates a newly developed Stacked Model Averaging statistical method for interval-censored data. ED01 and ED05 values, the doses at which 1%, and respectively 5%, of the respective allergic population would be predicted to experience any objective allergic reaction were determined. The 14 allergenic foods were cashew, celery, egg, fish, hazelnut, lupine, milk, mustard, peanut, sesame, shrimp (for crustacean shellfish), soy, walnut, and wheat. Updated ED01 estimates ranged between 0.03 mg for walnut protein and 26.2 mg for shrimp protein. ED05 estimates ranged between 0.4 mg for mustard protein and 280 mg for shrimp protein. The ED01 and ED05 values presented here are valuable in the risk assessment and subsequent risk management of allergenic foods.
Background
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects both patients and their families. Current therapies often alleviate symptoms but do not prevent or eradicate the disease.
Objectives
Our objective was to determine whether pancreatic enzyme supplementation is an effective and safe treatment in refractory pediatric AD associated with food allergies.
Methods
We conducted an open-label pilot study using a case–control design. Patients with severe AD and known food allergies refractory to conventional therapies and exclusion diets were recruited and treated for 6 weeks with oral supplementation of pancreatic enzymes. The primary endpoint was the severity of AD, using the Scoring Atopic Dermatitis (SCORAD) index. Secondary measures included markers of intestinal permeability (urinary sucrose and lactulose/mannitol excretion).
Results
A total of 11 patients met all eligibility criteria and completed the trial. Significant improvement in AD was observed after 6 weeks of pancreatic enzyme supplementation (SCORAD index 52.3 ± 5.5 vs. 34.6 ± 7.6; p = 0.0008). Beneficial effect was observed in 9 of 11 patients, without adverse events. Fractional urinary sucrose excretion improved to a level comparable to that of age-matched controls (p < 0.05). However, urinary lactulose:mannitol ratios remained abnormally high compared with those of controls (p = 0.01).
Conclusions
Pancreatic enzyme supplementation was associated with improved AD and gastroduodenal permeability. Additional randomized placebo-controlled studies are required before this treatment can be recommended in this clinical setting.
Food allergy (FA) was born as cow’s milk (CM) allergy (CMA). Only humans began and continue to use milk of other animals to nurse offspring, although Hippocrates recorded gastric upset and hives due to CM and proposed dietetic measures. The use of animal milk to feed children began spreading around the mid-eighteenth century, with a preference for ass or goat’s milk rather than for CM [249]. In parallel, the consequent decline in breast feeding became evident from the fifteenth to nineteenth centuries: perhaps “nine months of blood, nine months of milk” [95] were too heavy. Subsequent discoveries in the fields of microbiology and medicine provided a more thorough basis for development of substitutes for breast milk (BM). Comparisons against the advisers of bottle feeding were requested, with unhappy results [95] and also differences in mortality among the BM-fed infants compared to non-BM-fed infants were worthlessly pointed out [249]. Even if at the start of the 20th century the first cases of anaphylaxis [436], one of which was fatal [161], and of CMA [196] were documented in the German literature, artificial feeding increased like an avalanche in the 20th century [249].
ABSTRACT
Cow milk protein allergy (CMPA) occurs when the body’s immune system reacts in an abnormal way to the protein found in milk products and it is one of the common causes of adverse food reaction during infancy and early childhood. Incidence is higher in non-breast fed babies than breast fed. Recent demographic and health survey from Pakistan reported rate of exclusive breastfeeding and non-exclusively breastfed is 38% and 67% respectively. CMPA is the common problem in our country and there is no published literature regarding incidence, clinical presentation and management of this disease. This review paper after briefly discussing the epidemiology, patho-physiology and clinical presentation of CMPA provides practical evidence based guidelines on the management of infants and children suffering from CMPA in Pakistan.
Key words: CMPA, Management guidelines, Pakistan.
Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced enteropathies are non-IgE-mediated gastrointestinal food allergic disorders that typically affect infants and resolve by 3 years of age. While these syndromes are distinct entities, each is characterized by typical clinical features and causative foods. These disorders are immune-mediated, and T lymphocytes appear to play a central role in the disease process; however, the full nature of the underlying immune deregulation has yet to be elucidated. In this chapter, we review the clinical aspects of these syndromes, including their prevalence, presentation, causative foods, and natural history, and examine what is known of their pathophysiology, concentrating on FPIES.
Threshold doses, also known as minimal eliciting doses, exist, below which food-allergic patients will not react adversely to an allergenic food. Considerable variation exists with respect to threshold doses for individuals with specific food allergies. As an example, the individual threshold doses for peanut can range from 0.1 mg up to 2.5 g of peanut protein. The clinical determination of threshold doses is best done through double-blind placebo-controlled food challenges. Ideally, such challenges should start at rather low doses to identify patients with the highest sensitivity to the specific allergenic food. The adoption of population thresholds that would protect the vast majority of individuals with specific food allergies by public health agencies would provide the food industry with a sounder basis for labeling and especially advisory labeling. Improved knowledge of individual threshold doses can provide guidance to patients in the successful implementation of avoidance diets.
Los fenómenos alérgicos han aumentado en todo el mundo, incluyendo cuadros provocados por alimentos y aditivos. La alergia alimentaria es altamente prevalente en los primeros años de vida, su persistencia parece ser más frecuente que lo que se pensaba y puede ser causa de cuadros inmunes graves. La literatura en el tema es abundante y la información publicada disímil, lo que hace necesario seguir criterios estrictos para evaluar la calidad de la información publicada. Hasta que no contemos en el país con estudios locales sólidos que respalden Guías de Diagnóstico y Tratamiento, es recomendable que estos pacientes sean manejados por especialistas. En este artículo se revisa y discuten aspectos relacionados con la definición, epidemiología, principales alérgenos, tipos de reacciones inmunes asociadas a los cuadros alérgicos, diagnóstico y tratamiento de las alergias alimentarias.
In 2011, an expert panel was assembled to establish appropriate Reference Doses for allergenic food residues as a part of the VITAL (Voluntary Incidental Trace Allergen Labeling) program of The Allergen Bureau of Australia & New Zealand (ABA). These Reference Doses would guide advisory labeling decisions for use on food labels. Individual NOAELs and LOAELs were obtained from clinical challenges of food-allergic subjects. Statistical dose-distribution models (log-normal, log–logistic, Weibull) were applied to the individual NOAELs and LOAELs for each allergenic food. The Reference Doses, in terms of mg of total protein from the allergenic food, were based upon either the ED01 (for peanut, cow’s milk), the 95% lower confidence interval of the ED05 (for wheat, soybean, cashew, shrimp, sesame seed, mustard, and lupine), or both (egg, hazelnut) using all appropriate statistical dose-distribution models. Reference Doses were established for 11 allergenic foods ranging from 0.03 mg for egg protein to 10 mg for shrimp protein. Reference Doses were not established for fish or celery due to poor model fits with existing data. Reference Doses were not established for other tree nuts beyond hazelnut and cashew because of the absence of data on NOAELs and LOAELs from individual subjects.
There has been a dramatic proliferation of precautionary labeling by manufacturers to mitigate the perceived risk from low-level contamination from allergens in food. This has resulted in a significant reduction in choice of potentially safe foods for allergic consumers.
We aimed to establish reference doses for 11 commonly allergenic foods to guide a rational approach by manufacturers based on all publically available valid oral food challenge data.
Reference doses were developed from statistical dose-distribution modeling of individual thresholds of patients in a dataset of more than 55 studies of clinical oral food challenges. Sufficient valid data were available for peanut, milk, egg, and hazelnut to allow assessment of the representativeness of the data used.
The data were not significantly affected by the heterogeneity of the study methodology, including little effect of age on results for those foods for which sufficient numbers of adult challenge data were available (peanut and hazelnut). Thus by combining data from all studies, the eliciting dose for an allergic reaction in 1% of the population estimated for the following were 0.2 mg of protein for peanut, 0.1 mg for cow's milk, 0.3 mg for egg, and 0.1 mg for hazelnut.
These reference doses will form the basis of the revised Voluntary Incidental Trace Allergen Labeling (VITAL) 2.0 thresholds now recommended in Australia. These new levels will enable manufacturers to apply credible precautionary labeling and provide increased consumer confidence in their validity and reliability, as well as improving consumer safety.
Strictly speaking, allergy to cow’s milk should only be diagnosed if reproducible abnormal reactions are observed and are confirmed by specific reactions in immunological tests. In practice, diagnosis is usually based on reactions following the consumption of cow’s milk, with or without immunological confirmation. It would be logical to describe cases with immunological confirmation as allergy, and those without as intolerance to cow’s milk. However, the possibility of cow’s milk intolerance progressing to become an allergy blurs this distinction. As for many other childhood allergies, the number of cases of cow’s milk allergy diagnosed is clearly increasing. Before 1950, cow’s milk allergy was considered to be very rare. In developed regions, cow’s milk allergy is now suspected to affect at least 10% of infants, and has been confirmed in more than 5% of children. An estimated 0.4–0.5% of cases occur in children who were entirely breastfed before weaning. We began by studying replacement foods, providing efficient supplementation on the elimination of cow’s milk from the diet. We are currently studying the mechanisms of cow’s milk allergy, which often begins when the child is very young, possibly even during the gestation period in some cases.
SECTION 1: INTRODUCTION: Allergy and clinical immunology societies have issued guidance for the management of food allergy.1,2 Guidelines are now regarded as translational research instruments, designed to provide cutting-edge benchmarks for good practice and bedside evidence for clinicians to use in an interactive learning context with their national or international scientific communities. In the management of cow's milk allergy (CMA), both diagnosis and treatment would benefit from a reappraisal of the more recent literature, for “current” guidelines summarize the achievements of the preceding decade, deal mainly with prevention,3–6 do not always agree on recommendations and date back to the turn of the century.7,8 In 2008, the World Allergy Organization (WAO) Special Committee on Food Allergy identified CMA as an area in need of a rationale-based approach, informed by the consensus reached through an expert review of the available clinical evidence, to make inroads against a burdensome, world-wide public health problem. It is in this context that the WAO Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines was planned to provide physicians everywhere with a management tool to deal with CMA from suspicion to treatment. Targeted (and tapped for their expertise), both on the DRACMA panel or as nonsitting reviewers, were allergists, pediatricians (allergists and generalists), gastroenterologists, dermatologists, epidemiologists, methodologists, dieticians, food chemists, and representatives of allergic patient organizations. Ultimately, DRACMA is dedicated to our patients, especially the younger ones, whose burden of issues we hope to relieve through an ongoing and collective effort of more interactive debate and integrated learning.
Definitions: Adverse reactions after the ingestion of cow's milk can occur at any age from birth and even among infants fed exclusively at the breast, but not all such reactions are of an allergic nature. A revision of the allergy nomenclature was issued in Europe in 20019 and was later endorsed by the WAO10 under the overarching definition of “milk hypersensitivity,” to cover nonallergic hypersensitivity (traditionally termed “cow's milk intolerance”) and allergic milk hypersensitivity (or “cow's milk allergy”). The latter definition requires the activation of an underlying immune mechanism to fit. In DRACMA, the term “allergy” will abide by the WAO definition (“allergy is a hypersensitivity reaction initiated by specific immunologic mechanisms”). In most children with CMA, the condition can be immunoglobulin E (IgE)-mediated and is thought to manifest as a phenotypical expression of atopy, together with (or in the absence of) atopic eczema, allergic rhinitis and/or asthma. A subset of patients, however, have non-IgE mediated (probably cell-mediated) allergy and present mainly with gastro-intestinal symptoms in reaction to the ingestion of cow's milk.
REFERENCES, SECTION 1:
1. American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006;96(Suppl 2):S1–S68.
2. Mukoyama T, Nishima S, Arita M, Ito S, Urisu A, et al. Guidelines for diagnosis and management of pediatric food allergy in Japan. Allergol Int. 2007;56:349–361.
3. Prescott SL. The Australasian Society of Clinical Immunology and Allergy position statement: Summary of allergy prevention in children. Med J Aust. 2005;182:464–467.
4. Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, et al. Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15:291–307.
5. Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, et al. Dietary prevention of allergic diseases in infants and small children. Part I: immunologic background and criteria for hypoallergenicity. Pediatr Allergy Immunol. 2004;15:103–11.
6. Muraro A, Dreborg S, Halken S, Høst A, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part II. Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases. Pediatr Allergy Immunol. 2004;15:196–205.
7. Høst A, Koletzko B, Dreborg S, Muraro A, Wahn U, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80–84.
8. American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulae. Pediatrics. 2000;106:346–349.
9. Johansson SG, Hourihane JO, Bousquet J. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56:813–824.
10. Johansson SG, Bieber T, Dahl R. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, 2003. J Allergy Clin Immunol. 2004;113:832–836.
IntroductionImportant factors concerning food hypersensitivity reactionsNatural history of food allergyPrevention of food allergyDietary manipulation for food hypersensitivitiesDietary management of food hypersensitivitiesDiscussion of specific symptomsNovel approaches in food hypersensitivityProblems with dietary treatment in food hypersensitivityAcknowledgementsReferencesFurther readingUseful addresses
Although apparently easy, the diagnosis of cow's milk allergy is still complicated by the distinction between true allergy confirmed by immunological criteria and intolerance, in which these criteria are absent. Simple or double-blind challenge tests can confirm the diagnosis, but must be very prolonged in order to have an absolute value. The proteins responsible have been known for a long time, but current progress concerns the allergenic epitopes. The cellular and tissue phenomena responsible for the clinical manifestations have been identified on mononuclear cells and on the intestinal mucosa or skin. The mechanisms of natural tolerance are discussed, particularly the role of CD8 cells. Lastly, in the fortunately fairly rare cases in which this tolerance does not develop naturally, tolerance induction methods can be performed in hospital.
The diagnosis of food allergy is based on double-blind placebo controlled food challenges. A review of the literature describes the indications of these tests, once the proof of sensitization has been made by prick-tests and RAST or epicutaneous reactions. The required elements prior to oral challenges, the contraindications, the preparation and monitoring of patients, the equipment and personnel in charge of DBPCFC and the medical responsibility are reviewed. Technical aspects of food preparation include the storage, the choice of the nature of foods to be tested, and the vehicles; the procedures of incrementation of doses are detailed, as well as the issues concerning the minimal starting dose and final dose. Symptoms and delays of onset, pitfalls and failures are analysed. Finally, the tendency to lighten procedures in favour of simple blind oral challenges is discussed.
Hypersensitivity to cow milk proteins is one of the main food allergies and affects mostly but not exclusively infants, while it may also persist through adulthood and can be very severe. Different clinical symptoms of milk allergy have been established. The diagnosis of milk allergy differs widely due to the multiplicity and degrees of symptoms, and can be achieved by skin or blood tests. Cow milk contains more than 20 proteins (allergens), that can cause allergic reactions. Casein fractions and -lactoglobulin are the most common cow milk allergens. Human milk is free of -lg, similar to camel milk. On the contrary, -lg is a major whey protein in cow, buffalo, sheep, goat, mare and donkey milk. Caseins in milk of the different species differ in fraction number, amino acid composition, and their peptide mappings. -Casein is the major fraction in goat casein, which is similar to human casein and different from cow casein. The peptide mappings of goat -la and -lg are completely different from those of cow milk. Different procedures can reduce the allergenicity of cow milk proteins by heat or enzymatic treatment to some degree. Allergies to milk proteins of non-bovine mammals have also been documented due to cross-reactivity between cow milk proteins and their counterpart in other species, and even between goat and sheep caseins. Genetic polymorphisms of milk proteins play an important role in eliciting different degrees of allergic reactions. Goat milk lacking -s1-casein, which is the main casein in cow milk, is less allergenic than goat milk with -s2-casein, which is more typical for many goat breeds. Several studies have reported real and dramatic benefits from using goat, camel, mare or even soy milk as alternatives in cases of cow milk allergy and they can be considered hypoallergenic. However, therapeutic benefits vary with the degree of severity of the allergy and may be only around 60% of all cases, since other studies revealed allergenicity to occur also for any of those other milks. © 2006 Published by Elsevier B.V.
Allergische Erkrankungen nehmen bei Kindern seit Jahren zu, und die Kuhmilchallergie ist eine der frhesten Manifestationen des so genannten allergic march. Pathogenetisch unterscheidet man prinzipiell IgE- und nicht-IgE-mediierte allergische Reaktionen: Erstere fhren eher zu klinischen Sofortreaktionen und knnen labordiagnostisch nachgewiesen werden (Hautpricktest, spezifischer Antikrpernachweis), Letztere manifestieren sich verzgerter, und konklusive Labortests fehlen. Auch die eosinophilen gastrointestinalen Erkrankungen knnen durch Kuhmilchproteine getriggert sein. An Organsystemen sind v.a. der Gastrointestinaltrakt sowie die Haut und der Respirationstrakt betroffen, seltener werden anaphylaktische Reaktionen beobachtet. Therapeutisch erfolgt eine ditetische Exklusion von Kuhmilchprotein, meist im 1. Lebensjahr, bzw. bis zum klinischen Nachweis der Toleranzentwicklung, die in der Regel bis zum vollendeten 3. Lebensjahr erfolgt.Allergies in childhood are increasing steadily, and cows milk allergy often represents the beginning of the so-called allergic march. To date, the two best understood pathomechanisms allow a distinction between IgE-mediated and non-IgE-mediated allergic reactions: IgE-mediated reactions lead mostly to clinical reactions of quick onset that can be proven by laboratory tests (skin prick, positive specific antibodies). Non-IgE-mediated reactions have a more delayed clinical manifestation, and conclusive laboratory tests are lacking. Also, eosinophilic gastrointestinal disorders may be triggered by cows milk proteins. The main organ systems involved are the gastrointestinal tract, the skin, and the respiratory tract. Anaphylactic reactions are possible, but rarer. Treatment consists of dietary exclusion of cows milk proteins for at least the 1st year of life or until tolerance has been proven clinically, which is usually the case by the end of the 3rd year.
Food allergy or hypersensitivity is defined as an adverse reaction to food protein which is immune mediated. These disorders are most prevalent in infancy and early childhood. Immediate IgE mediated reactions after ingestion of the offending food are frequently evident by the history of exposure, corroborated by positive skin prick-tests or specific IgE antibodies in serum demonstrating the immunologic abnormality. Immediate reactions can be confirmed by double-blind food challenges. However, patients with food hypersensitivity may present with a variety of symptoms and signs including growth delay, diarrhea, vomiting, protein-losing enteropathy, hematochezia or a shock-like picture, without evidence of IgE mediated immune mechanisms. The immunologic abnormality is more likely cell-mediated and depends on demonstration of inflammation in tissue, often characterized by increased eosinophils. Signs, symptoms and inflammation will improve when the offending antigen is removed, and will return upon subsequent re-introduction, often after several hours or days. As part of the spectrum of gastrointestinal disease related to food allergy there exists eosinophilic gastroenteropathy (EGE) where tissue eosinophilia exists without any demonstrable food hypersensitivity. These << idiopathic >> EGE represent a distinct group of disorders of unknown etiology with activation of eosinophils in the gastrointestinal tract leading to signs and symptoms. Dietary manipulation is frequently unsuccessful, therefore pharmacologic treatment is indicated. This review will outline the clinical spectrum and approach to diagnosis and management of food hypersensitivity disorders and EGE.
Equine milk has important nutritional and therapeutic properties that can benefit the diet of the elderly, convalescent or newborn. The protein content of equine milk is lower than that of bovine milk but similar to that of human milk. In this review qualitative and quantitative differences between the caseins and whey proteins of equine, bovine and human milk are discussed. Important biological and functional properties of specific proteins are reviewed and their significance in human nutrition considered. As well as characterizing equine milk proteins in the context of human nutrition and allergology, the potential industrial exploitation of equine milk is explored. Cross-reactivity of proteins from different species is discussed in relation to the treatment of cows’ milk protein allergy. While there is some scientific basis for the special nutritional and health-beneficial properties of equine milk based on its protein composition and similarity to human milk, further research is required to fully exploit its potential in human nutrition.
There is a perception that asthmatic symptoms may be worsoned by ingestion of certain foods. This study aimed to investigate whether ingestion of cow's milk or egg might induce respiratory symptoms in asthmatic children. Fifty asthmatic children aged 1.5 to 6 years old, with positive Immulite Food Panel FP5 test results were included in the study. Fifty healthy children within the same age group were accepted as control group. Total serum IgE levels were measured and skin prick tests for food allergens including milk and egg were performed. All of the subjects underwent oral, double-blind, placebo-controlled challenge with fresh egg and cow's milk powder. Two medical histories were confirmed by double-blind, placebo-controlled challenge in 9 patients (22.2%). Skin prick tests were positive in 9 patients (18%) with milk and 18 patients (36%) with egg antigen. Two children experienced wheezing, one after ingesting milk and the other after egg challenge (4%). In the control group no positive reactions were seen with egg or milk challenges. Our findings confirm that food allergy can elicit asthma in children, but its incidence is low, even with major allergens such as egg and milk. History, specific IgE determinations and skin prick tests are not reliable in diagnosing food reactions. Since any diet can cause rapid deficiencies in infancy, diet restrictions must not be applied, without performing double-blind, placebo-controlled challenge.
To provide a practical, evidence-based approach to the diagnosis and management of milk protein allergy in infants.
MEDLINE was searched from 1950 to March 2008 using the MeSH heading milk-hypersensitivity. Additional sources were derived from reviews found with the initial search strategy. Evidence was levels I, II, and III.
Milk protein allergy is a recognized problem in the first year of life; cow's milk protein allergy is the most common such allergy. Diagnosis is suspected on history alone, with laboratory evaluations playing a supporting role. Confirmation requires elimination and reintroduction of the suspected allergen. Management includes diet modification for nursing mothers and hydrolyzed formulas for formula-fed infants. Assessing the underlying immunopathology can aid in determining prognosis.
The therapeutic model presented allows rapid assessment of the presence of allergy, timely management, and surveillance for recurrence of symptoms. Breastfeeding can be continued with attentive diet modification by motivated mothers.
Data on the frequency of resolution of anaphylaxis to foods are not available, but such resolution is generally assumed to be rare.
To determine whether the frequency of negative challenge tests in children with a history of anaphylaxis to foods is frequent enough to warrant challenge testing to re-evaluate the diagnosis of anaphylaxis, and to document the safety of this procedure.
All children (n=441) who underwent a double-blind, placebo-controlled food challenge (DBPCFC) between January 2003 and March 2007 were screened for symptoms of anaphylaxis to food by history. Anaphylaxis was defined as symptoms and signs of cardiovascular instability, occurring within 2 h after ingestion of the suspected food.
Twenty-one children were enrolled (median age 6.1 years, range 0.8-14.4). The median time interval between the most recent anaphylactic reaction and the DBPCFC was 4.25 years, range 0.3-12.8. Twenty-one DBPCFCs were performed in 21 children. Eighteen of 21 children were sensitized to the food in question. Six DBPCFCs were negative (29%): three for cows milk, one for egg, one for peanut, and one for wheat. In the positive DBPCFCs, no severe reactions occurred, and epinephrine administration was not required.
This is the first study using DBPCFCs in a consecutive series of children with a history of anaphylaxis to foods, and no indications in dietary history that the food allergy had been resolved. Our study shows that in such children having specific IgE levels below established cut-off levels reported in other studies predicting positive challenge outcomes, re-evaluation of clinical reactivity to food by DBPCFC should be considered, even when there are no indications in history that anaphylaxis has resolved. DBPCFCs can be performed safely in these children, although there is a potential risk for severe reactions.
Dientamoeba fragilis is a rare cause of chronic infectious diarrhea and colitis in children.
Review of the clinical manifestations, diagnostic methods, and clinical course of D. fragilis infection in our hospital.
Eleven pediatric patients are discussed, seven of whom had a history of recent travel. Clinical manifestations of infectious diarrhea included anorexia, intermittent vomiting, abdominal pain, and diarrhea, ranging from 1 to 100 weeks in duration. Peripheral eosinophilia was present in seven patients. One patient with well-documented bovine protein allergy had intermittent episodes of diarrhea and abdominal pain, despite an appropriate elimination diet. Eosinophilic colitis documented by colonoscopy, was due to D. fragilis. Metronidazole was effective in treating five patients, and iodoquinol was effective in treating four others.
D. fragilis should be included in the differential diagnosis of chronic diarrhea and eosinophilic colitis. The identification of this pathogen requires clinical awareness of epidemiologic risk factors and presenting complaints, as well as the laboratory staining procedures essential to its proper identification.
Owing to poor reliability of laboratory tests, diagnosis of food allergy is based on clinical response to double-blind placebo-controlled food challenge. The aim of the present study was to assess the value of duodenal IgE-positive cells in the diagnosis of food allergy. Thirty-one children with a history of possible food allergy underwent duodenal biopsies, skin prick tests, and measurement of serum IgE antibodies, and were put on an elimination diet followed by food challenge. Open food challenges were performed in patients under 12 mo of age, and double-blind placebo-controlled challenges were for suspected foods. On the basis of clinical food hypersensitivity, patients were divided into two groups. Group 1 consisted of 13 children with food allergy. Thirteen of 20 positive provocations elicited reactions within 12 h from the end of the challenge, seven later. Group 2 was the control group and included 18 patients with negative food challenges. The number of IgE-positive cells in biopsy specimens was significantly more elevated in group 1 with respect to group 2 (153.24 +/- 83.13 versus 18.4 +/- 18.9; p < 0.01). Total serum IgE levels were elevated compared with that of the control group (p < 0.01) and correlated with the number of IgE-positive cells (p < 0.001, r = 0.62). Enhanced IgE-containing cells were found in all delayed reactors, but about one-third had negative skin prick tests or specific serum IgE antibodies to the offending foods. Our results showed that systemic reactions to foods are associated with an IgE-mediated response in the duodenal mucosa. Larger studies would be required to assess the predictive value of an increased number of IgE-positive cells in the diagnosis of allergy to food, especially in children with delayed reactions.
Little is known about late phase clinical reactions during oral food challenges and the value of specific IgE in terms of sensitivity and specificity.
We therefore analysed retrospectively the clinical outcome of 387 oral provocations during double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis.
Eighty-seven (81%) children showed a positive clinical reaction to at least one challenge. The vast majority of children (94%) showed clinical symptoms to one or two allergens. One hundred and thirty-one of 259 (51%) of verum challenges and 1/128 (0.8%) placebo challenge were assessed as positive. Oral provocations with hen's egg showed the highest percentage of positive reactions (70%). Sensitivity of specific IgE to the four allergens tested was 90%, specificity 30%. Sensitivity of the parental history as a predictive factor was 48%, specificity 72%. Ninety-two of 131 (70%) children with positive verum provocations showed early reactions, 33 (25%) late and six (5%) combined early and late reactions. In 84/131 (64%) positive provocations one organ system was involved, while in 44 (34%) provocations two and in three (2%) challenges three organ systems were involved. Skin reactions were the most frequent clinical manifestation leading to positive reactions followed by gastro-intestinal and respiratory symptoms. There was no correlation between titration dose and specific IgE. The subgroup of non-sensitized children did not differ in terms of sex, age or titration dose from the total study population.
Double-blind, placebo-controlled oral food challenges are helpful in distinguishing children with clinically manifested symptoms from those with food sensitization. Accurately identifying children with a clinical relevant food allergy may help to prescribe specific diets on a scientific basis, avoiding dietary limitations which may be unnecessary or even harmful.
We evaluated the value of the patch test, skin prick test, and milk‐specific IgE by CAP RAST in 301 infants with suspected hypersensitivity to cow's milk. The patch test was carried out with milk powder, and the skin prick test with cow's milk‐based formula. Hypersensitivity to cow's milk was determined with double‐blind, placebo‐controlled challenge. An immediate reaction to cow's milk challenge was observed in 100 infants (33%), a delayed reaction in 76 (25%), and a negative result in 125 (42%). Skin prick test wheals were significantly greater in infants with immediate reactions than in infants with delayed or negative reactions. Milk‐specific IgE was correlated with the skin prick test (r=0.78, Pn=268) but did not contribute to further discrimination of immediate reactions from delayed or negative reactions compared to skin prick test alone. In our study population, the skin prick test (diameter ≥3 mm) showed a specificity and sensitivity of 91% and 69%; the results for milk‐specific IgE (≥0.7 kU/l) were 88% and 58%, respectively. The patch test did not distinguish subjects with immediate or delayed reactions from those with negative reactions.
A safe, simplified, and rapid method for detection of allergen has been developed. Serotonin, a chemical mediator secreted during an allergic reaction, was used as a marker in electrochemical detection. A 20-microL drop of whole blood was used for the electrochemical detection of allergen using an array microelectrode. When cyclic voltammetry was carried out on whole blood samples containing 1 microg/mL serotonin, an anodic peak current appeared at around 350 mV versus a silver/silver chloride electrode using a Nafion-coated array microelectrode. Allergen was selectively detected using whole blood samples by applying a constant potential of 350 mV after 40 min incubation with addition of allergen. The results obtained by the electrochemical detection method correlated well with the diagnosis obtained from the amount of IgE antibody.
In a study of the manifestations of cow milk allergy in 100 young children (mean age 16 months), 30 items of historical data and information relating to the effects of a standardized milk challenge were entered into a computer data base. Three clusters of patients were derived using a K-means algorithm. In group 1 were 27 patients with predominantly urticarial and angioedematous eruptions, which developed within 45 minutes of ingesting cow milk. They had positive skin test reactions to milk and elevated total and milk specific IgE serum antibody levels. In group 2, 53 patients had pallor, vomiting, or diarrhea between 45 minutes and 20 hours after milk ingestion. These children were relatively IgA deficient. The 20 patients in group 3 had eczematous or bronchitic or diarrheal symptoms; in 17 symptoms developed more than 20 hours after commencing milk ingestion. Of the patients in group 3, only those with eczema had a positive skin test reaction and elevated IgE antibodies to milk. The patients in group 3 were the most difficult to identify clinically; they had a history of chronic ill health, and symptoms developed many hours or days after commencing milk ingestion in the challenge situation. In view of the heterogeneous clinical and immunologic findings in our patients, it is unlikely that a single laboratory test will identify cow milk allergy in all susceptible patients.
The clinical and laboratory features of 68 children with food intolerance or food allergy are reviewed. Young children were affected the most with 79% first experiencing symptoms before age 1 year. Forty-eight (70%) children presented with gastrointestinal symptoms (vomiting, diarrhoea, colic, abdominal pain, failure to thrive), 16 (24%) children with skin manifestations (eczema, urticaria, angioneurotic oedema, other rashes), and 4 (6%) children with wheeze. Twenty-one children had failed to thrive before diagnosis. A single food (most commonly cows' milk) was concerned in 28 (41%) cases. Forty (59%) children had multiple food intolerance or allergy; eggs, cows' milk, and wheat were the most common. Diagnosis was based on observing the effect of food withdrawal and of subsequent rechallenge. In many children food withdrawal will mean the use of an elimination diet which requires careful supervision by a dietician. Laboratory investigations were often unhelpful in suggesting or confirming the diagnosis.
A cohort of 1749 newborns from the municipality of Odense born during 1985 at the University Hospital were followed prospectively for the development of IgE-mediated and non-igE-mediated cow milk allergy (CMA) during their first year. The diagnosis of CMA was based on the results of strict elimination/milk challenge procedures in a hospital setting, and continued clinical sensitivity to cow milk (CM) was assessed by rechallenging every 6–12 months until the age of3 years. Further, in infants with CMA, the Clinical course of adverse reactions to other foods and the development of allergy to inhalant allergens In 3 years were investigated. Of 117 (6.7 %) with symptoms suggestive of CMA, the diagnosis of CMA was proven m 39 infants (2.2%), 64% showed cutaneous symptoms. 59% gastrointestinal symptoms, and 33% had respiratory symptoms. 92% had two or more symptoms and 72 % symptoms from 2 organ systems. Based on a positive skin prick test ( 2 +) and/or AL-RAST class 2 to CM 16 infants at the time of diagnosis, and at reinvestigation at 1 year, a further five infants giving a total of 21, were classified as having IgE-mediated CMA, 19 infants showed “immediate reactions to CM (within 1 h after intake of 2.3 g milk protein) and 20 infants were “late reactors”, No significant correlation between IgE-mediated CMA and “immediate reactions” to CM was demonstrated, The overall prognosis of CMA was good with a total recovery of 22/39 (56%) at 1 year. 30/39 (77%) at 2 years, and 34/39 (87%) at 3 years. Adverse reactions to other foods, particularly egg, citrus, tomato, developed in a total of 21/39 (54%) with the maximum point prevalence of 15/39 (38%) at 18 months, and 9/39 (23%) were still intolerant to other foods at 36 months. Inhalant allergy before 3 years developed in 11/39 (28%), particularly against dog and cat to which the infants had been exposed. Infants with CMA and early IgE, sensitization to CM had an increased risk of persisting CMA (24%) development of persistent adverse reactions to other foods (38%), particularly egg white (29%), and finally, inhalant allergy (48%) before 3 years of age.
Clinical and laboratory observations were made with 38 children afflicted with chronic severe asthma (reversible obstructive airway disease) in which hypersensitivity to food was incriminated in the histories. Symptoms were evoked in double-blind food challenges in only 11/38 children and 14/70 challenges, and were characteristic of immediate-type hypersensitivity and were chiefly gastrointestinal, even though asthma was the common presenting complaint. There were no delayed reactions. Peanut was responsible for 8 reactions, egg for 5, and cow's milk for 1. The feature that most successfully identified those having positive reactions in challenges was a significant wheal reaction in a skin test by puncture technique using a verified extract of 1:20 W/V concentration. No subject with clinically significant, symptomatic hypersensitivity to food had a negative puncture test, and puncture tests were positive in only 10/56 instances of negative reactions in food challenges. Laboratory observations included release of histamine and enzymes from leukocytes and the levels of neutrophil enzymes in serum before and after food provocation tests. While these determinations were of interest with respect to the immunochemical basis of reactions to foods, they did not prove useful for practical clinical diagnosis. The outstanding laboratory findings was the occurrence of "spontaneous" release of 25% to 100% of the histamine from leukocytes in all cases proved clinically hypersensitive by food challenges, which suggests that this may be an indicator of immediate-type hypersensitivity to food. From the findings in the study, a general approach to food hypersensitivity was developed in which the immunologic components coupled with quantitative concentration-response relationships serve to render comprehensible the distinction between asymptomatic (immunologic) hypersensitivity and symptomatic (clinical) hypersensitivity.
47 infants with cow's milk sensitivity were followed for a period varying between 6 months to 4 years (mean 28 months). The age at onset of symptoms varied between 14 days to 20 months. The clinical course was studied in relation to reaginic allergy by use of serum IgE, skin prick test and RAST. Infants with an immediate onset of symptoms from the gastrointestinal tract and the skin after cow's milk intake were discerned as a distinct entity having a high frequency of atopy in the family, positive skin tests and positive RASTs to milk (71%). Cases with delayed reactions to cow's milk seldom had a positive RAST or skin test. Most infants of both groups showed an increasing tolerance to milk. In RAST positive infants the RAST-titers increased significantly after onset of symptoms. After having reached a peak the titers subclined in several cases. The titers did not reflect the degree of milk sensitivity during the follow-up period. However, infants who developed high titers seemed to develop tolerance more slowly than infants with low titers.
To evaluate the role of specific antibody response to milk proteins in patients with milk-protein intolerance, allergen-specific IGE, IgG, and IgG4 to these proteins were measured by ELISA. Bovine casein, gamma globulin (GG), beta-lactoglobulin, and lactalbumin were the milk proteins used. Antibody production to these proteins were analyzed in 18 patients who underwent milk-protein challenges (eight positive and 10 negative) and in five normal children used in the analysis. ELISA results for specific IgE, IgG, and IgG4 to these specific proteins demonstrated no statistically different response to the four milk proteins among the three patient groups by multivariate analysis. When the specific antibody results from the positive challenge group, the negative challenge group, and the normal group were combined, the IgE and IgG4 to GG and the IgG to casein were significantly higher (p less than 0.01) than the corresponding specific antibody to the other proteins tested. The IgG or IgG4 to GG would differentiate the positive from the negative challenge group (p less than 0.05) but were not significantly different from the normal control group. Contrary to previously published studies, these results indicate IgG specific for the milk proteins are not increased in patients with milk-protein intolerance. The data also support the concept that IgE and IgG4 are not elevated in these patients. Therefore, there appears to be no pathogenic role for these specific immunoglobulins in milk-protein intolerance.
For 16 years the double-blind, placebo-controlled food challenge (DBPCFC) has been used at the National Jewish Center for Immunology and Respiratory Medicine to determine whether adverse reactions to foods do occur in children. The objective of these studies was to explore these reproducible adverse reactions and to characterize them. Although skin testing was performed on all subjects, a history of an adverse reaction to food and to subsequent DBPCFC were the only criteria for entry into this study. Of 480 children studied, 185 (39%) have had positive DBPCFC results. In these 480 children, 245 (24%) of 1014 DBPCFCs showed positive results. Egg, peanut, and cow milk accounted for 73% of the positive DBPCFC reactions, but many foods produced reactions. Skin test results were positive in most children with a positive DBPCFC reaction, but the large number of patients with asymptomatic hypersensitivity limited the accuracy of a positive skin test result alone as a predictor of clinical symptoms during food ingestion. Evaluation of results in this large number of children for a prolonged period revealed reproducible patterns of symptoms, timing, and incriminated foods. Placebo reactions were rare. The procedure was safe. Twelve youngsters with a negative DBPCFC result subsequently had positive reactions to open challenges when large amounts of the challenge food were used. In each of these cases the reactions were limited to areas of direct contact with the food or could be explained by the larger amount of food ingested during the open challenge. Multiple food hypersensitivity has been a rare finding. The DBPCFC should be the "gold standard" for both research and clinical diagnostic evaluations until it is superseded by methods that have yet to be developed.
A cohort of 1749 newborns from the municipality of Odense born during 1985 at the University Hospital were followed prospectively for the development of IgE-mediated and non-IgE-mediated cow milk allergy (CMA) during their first year. The diagnosis of CMA was based on the results of strict elimination/milk challenge procedures in a hospital setting, and continued clinical sensitivity to cow milk (CM) was assessed by rechallenging every 6-12 months until the age of 3 years. Further, in infants with CMA, the clinical course of adverse reactions to other foods and the development of allergy to inhalant allergens by 3 years were investigated. Of 117 (6.7%) with symptoms suggestive of CMA, the diagnosis of CMA was proven in 39 infants (2.2%). 64% showed cutaneous symptoms, 59% gastrointestinal symptoms, and 33% had respiratory symptoms. 92% had two or more symptoms and 72% symptoms from greater than or equal to 2 organ systems. Based on a positive skin prick test (greater than or equal to 2+) and/or AL-RAST class greater than or equal to 2 to CM 16 infants at the time of diagnosis, and at reinvestigation at 1 year, a further five infants giving a total of 21, were classified as having IgE-mediated CMA, 19 infants showed "immediate reactions" to CM (within 1 h after intake of 2.3 g milk protein) and 20 infants were "late reactors". No significant correlation between IgE-mediated CMA and "immediate reactions" to CM was demonstrated. The overall prognosis of CMA was good with a total recovery of 22/39 (56%) at 1 year, 30/39 (77%) at 2 years, and 34/39 (87%) at 3 years. Adverse reactions to other foods, particularly egg, citrus, tomato, developed in a total of 21/39 (54%) with the maximum point prevalence of 15/39 (38%) at 18 months, and 9/39 (23%) were still intolerant to other foods at 36 months. Inhalant allergy before 3 years developed in 11/39 (28%), particularly against dog and cat to which the infants had been exposed. Infants with CMA and early IgE sensitization to CM had an increased risk of persisting CMA (24%), development of persistent adverse reactions to other foods (38%), particularly egg white (29%), and finally, inhalant allergy (48%) before 3 years of age.
Patients with hypersensitivity to food documented by a double-blind, placebo-controlled oral food challenge have been reported to have a high rate of release of histamine from basophils in vitro. To determine whether patients with atopic dermatitis and food hypersensitivity had similar high rates of spontaneous histamine release in vitro, whether dietary elimination of relevant food antigens affected this release, and whether a cytokine, histamine-releasing factor, could account for it, we evaluated 63 patients with atopic dermatitis and food hypersensitivity (38 of whom had eliminated the offending foods from their diets), 20 patients with atopic dermatitis without food hypersensitivity, and 18 normal volunteers. Patients with atopic dermatitis and food hypersensitivity were found to have higher rates of spontaneous release of histamine from basophils than controls (mean +/- SE, 35.1 +/- 3.9 percent vs. 2.3 +/- 0.2 percent; P less than 0.001). Those who had eliminated the offending food allergen from the diet for an extended period had a significantly lower rate of histamine release (3.7 +/- 0.5 percent; P less than 0.001). In patients with atopic dermatitis without food hypersensitivity, the rate (1.8 +/- 0.2 percent) did not differ from that in normal controls. Mononuclear cells from persons with food allergies spontaneously produced a histamine-releasing factor in vitro that provoked the release of histamine from the basophils of other food-sensitive persons, but not from those of normal controls. Patients who adhered to a restricted diet had a decline in the rate of spontaneous generation of the factor by their mononuclear cells. The histamine-releasing factor was found to activate basophils through surface-bound IgE. We conclude that in patients with food hypersensitivity, exposure to the relevant antigens produces a cytokine (histamine-releasing factor) that interacts with IgE bound to the surface of basophils, causing them to release histamine.
There is now enough experience with the use of double-blind, placebo-controlled, food challenge (DBPCFC) to recommend its use as an office procedure for most patients complaining of adverse reactions to foods. This manual discusses the practical methods required for the allergist to undertake DBPCFC in the office. Thorough histories supplemented by food allergen skin testing are used to design a DBPCFC that carefully attempts to reproduce the history of food-induced symptoms described by the patient. Precautions that must be taken are delineated before challenge, as is treatment that may be required if a reaction occurs. For those foods to which challenges are positive, longitudinal evaluation with repeated challenge at appropriate intervals help to determine whether or not the problem will resolve over a period of time.
In a study of cows' milk allergy (CMA) in infancy, 135 consecutive challenges were performed on children with a good clinical history of the disorder. Of these, only half of the patients were shown to have the disease. Highly atopic patients responded rapidly to small volumes of milk with acute urticaria, wheezing, stridor and eczema, whereas patients who were relatively non-atopic developed symptoms of eczema, bronchitis and wheezing over several hours or days. In a statistical evaluation of the diagnostic value of skin tests and RAST it was shown for the extracts used in this investigation, and for the population studied, all patients with SPT greater than or equal to 4 had CMA. The results highlight the potential diagnostic value of SPT in the identification of children with some forms of CMA if standardized cows' milk allergen extracts can be prepared.
Forty-six patients with atopic dermatitis ranging from mild to severe were evaluated for food hypersensitivity with double-blind placebo-controlled food challenges. Twenty-eight (61%) patients had a positive prick skin reaction to one of the foods tested. Sixty-five food challenges were performed; 27 (42%) were interpreted as positive in 15 (33%) patients. Egg, milk, and peanut accounted for 78% of the positive reactions. As in previous studies, patients developed skin (96%), respiratory (52%), or gastrointestinal (30%) symptoms during the challenge. These studies indicate that children who have atopic dermatitis unresponsive to routine therapy or who continue to need daily treatment after several months would benefit from evaluation for food hypersensitivity.
To examine the natural history of adverse reactions to foods, 480 children were followed prospectively from birth to their third birthdays. Foods thought to be causing symptoms were evaluated by elimination of suspected foods, open challenges, and double-blind food challenges. Foods producing symptoms were reintroduced into the diet at 1- to 3-month intervals until the symptoms no longer occurred. Of the 480 children completing the study, 28% were thought to have symptoms produced during food ingestion, but in only 8% were these reactions reproduced (excluding fruit and fruit juices). During the first year of life 80% of the initial complaints occurred. The most striking finding was the brief duration during which reactions could be reproduced. The majority of foods were replaced in the diet within 9 months of their incrimination. A long list of foods was reported to produce many symptoms, but only a few foods reproducibly evoked gastrointestinal and skin symptoms, with respiratory symptoms being infrequent. Of great interest was that 75 children were reported to react to fruit or fruit juice, and 56 of these children had reproducible symptoms. This study has found that most food reactions occur during the first year of life, but rechallenge at regular intervals has shown that the food can be reintroduced into the diet by the third year without risk. Almost all reactions that were reproduced appear to be non-immunoglobulin E mediated.
One hundred thirteen patients with severe atopic dermatitis were evaluated for food hypersensitivity with double-blind placebo-controlled oral food challenges. Sixty-three (56%) children experienced 101 positive food challenges; skin symptoms developed in 85 (84%) challenges, gastrointestinal symptoms in 53 (52%), and respiratory symptoms in 32 (32%). Egg, peanut, and milk accounted for 72% of the hypersensitivity reactions induced. History and laboratory data were of marginal value in predicting which patients were likely to have food allergy. When patients were given appropriate restrictive diets based on oral food challenge results, approximately 40% of the 40 patients re-evaluated lost their hypersensitivity after 1 or 2 years, and most showed significant improvement in their clinical course compared with patients in whom no food allergy was documented. These studies demonstrate that food hypersensitivity plays a pathogenic role in some children with atopic dermatitis and that appropriate diagnosis and exclusionary diets can lead to significant improvement in their skin symptoms.
To review the pathogenesis, symptoms, and treatment of gastrointestinal disorders linked to immunopathologic reactions associated with the ingestion of food antigens in infancy and childhood.
A computerized MEDLINE search was performed for the following topics: allergic colitis, allergic proctitis, eosinophilic gastroenteritis, eosinophilic colitis, cow milk intolerance, protein losing enteropathy, and malabsorption. This search was restricted to the English language and human subjects. Articles published between 1960 and 1993 were included as references. The textbooks which were used as references include: (1) Walker WA, et al, eds. Pediatric gastrointestinal disease; pathophysiology, diagnosis, management, Philadelphia: BC Decker, 1991; (2) Wyllie R, et al, eds. Pediatric gastrointestinal disease; pathophysiology, diagnosis, management, Philadelphia: WB Saunders, 1993; (3) Targan SR, et al, eds. Immunology & immunopathology of liver and gastrointestinal tract. Igaku-Shoin, 1991; (4) Goldman H, et al, eds. Pathology of the gastrointestinal tract. Philadelphia: WB Saunders, 1992.
The symptoms of allergic gastroenteropathy may be those of classic allergic reactions or present as symptom complexes that may include diarrhea, malabsorption, and protein-losing enteropathy. The immunopathogenesis of allergic gastroenteropathy is complex and is still not clearly understood. As our understanding of the gastrointestinal mucosal system evolves, we should be able to manage and care for the infants and children who suffer from this group of disorders better.
This article discusses the current understanding of the mechanisms of food hypersensitivity and presents a practical approach to the condition. Skin testing is a useful technique if properly applied and interpreted; however, double-blind placebo-controlled food challenge is the standard for accurate diagnosis against which all other tests should be compared. Treatment still consists of avoidance of the offending food allergens; however, most children lose their reactivity, and thus regular challenges are important.