|
음식 알레르기 탐구중
우유 1리터에는 30-35g의 단백질이 함유
casein or serum β-lactoglobulin 등 단백질 알레르기 존재함.
약 60%의 CMA는
IgE 매개성
CM에는
최소 20개의 잠재적 알레르기 유발 단백질이 포함
Nutrients. 2021 May; 13(5): 1525.
Published online 2021 Apr 30. doi: 10.3390/nu13051525
PMCID: PMC8147250
PMID: 33946553
Cow’s Milk Protein Allergy as a Model of Food Allergies
Arianna Giannetti,1 Gaia Toschi Vespasiani,2 Giampaolo Ricci,3 Angela Miniaci,1 Emanuela di Palmo,1 and Andrea Pession1,*
Elvira Verduci, Academic Editor, Gian Vincenzo Zuccotti, Academic Editor, and Diego Peroni, Academic Editor
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
Cow’s milk allergy (CMA) is one of the most common food allergies in infants, and its prevalence has increased over recent years. In the present paper, we focus on CMA as a model of food allergies in children. Understanding the diagnostic features of CMA is essential in order to manage patients with this disorder, guide the use of an elimination diet, and find the best moment to start an oral food challenge (OFC) and liberalize the diet. To date, no shared tolerance markers for the diagnosis of food allergy have been identified, and OFC remains the gold standard. Recently, oral immunotherapy (OIT) has emerged as a new therapeutic strategy and has changed the natural history of CMA. Before this, patients had to strictly avoid the food allergen, resulting in a decline in quality of life and subsequent nutritional, social, and psychological impairments. Thanks to the introduction of OIT, the passive approach involving rigid exclusion has changed to a proactive one. Both the heterogeneity in the diagnostic process among the studies and the variability of OIT data limit the comprehension of the real epidemiology of CMA, and, consequentially, its natural history. Therefore, well-planned randomized controlled trials are needed to standardize CMA diagnosis, prevention, and treatment strategies.
우유 알레르기(CMA)는
유아에게 가장 흔한 식품 알레르기 중 하나로,
최근 몇 년 동안 유병률이 증가하고 있습니다.
본 백서에서는
어린이 식품 알레르기의 한 모델로서
CMA에 초점을 맞춥니다.
이 질환을 가진 환자를 관리하고,
제거 식단의 사용을 안내하며,
구강 음식 챌린지(OFC)를 시작하고
식단을 자유화할 수 있는 최적의 시기를 찾기 위해서는
CMA의 진단적 특징을 이해하는 것이 필수적입니다.
현재까지
식품 알레르기 진단을 위한 공유된 내성 마커는 확인되지 않았으며,
OFC가 여전히 표준으로 사용되고 있습니다.
최근에는
경구 면역 요법(OIT)이 새로운 치료 전략으로 등장하여
CMA의 자연사를 바꾸어 놓았습니다.
그 전에는
환자가 음식 알레르겐을 철저히 피해야 했기 때문에
삶의 질이 떨어지고 영양, 사회적, 심리적 장애가 발생했습니다.
OIT의 도입으로
엄격한 배제와 관련된 수동적인 접근 방식이
능동적인 접근 방식으로 바뀌었습니다.
연구 간 진단 과정의 이질성과
OIT 데이터의 가변성은
CMA의 실제 역학에 대한 이해를 제한하고
결과적으로 그 자연사에 대한 이해를 제한합니다.
따라서
CMA 진단, 예방 및 치료 전략을 표준화하기 위해서는
잘 계획된 무작위 대조 시험이 필요합니다.
Keywords: cow’s milk allergy, oral food challenge, oral immunotherapy, diet, skin prick test, serum-specific IgE, breastfeeding
1. Introduction
The prevalence of food allergies (FAs) and especially cow’s milk allergy (CMA, currently one of the most common FAs among children [1,2]) has increased in recent decades.
CMA is defined as a reproducible adverse reaction to one or more cow’s milk (CM) protein (usually casein or serum β-lactoglobulin) [3]. The underlying immunological mechanism, presentation times, and organs involved differentiate CMA from other adverse reactions to CM such as lactose intolerance [4].
CMA, like all FAs, can be divided into two main categories according to the type of immunological mechanism underlying it: immunoglobulin (Ig)E-mediated or non-IgE mediated [5] (Figure 1). IgE-mediated reactions are the most common. On the other hand, there are non-IgE mediated reactions that can arise from other cellular processes involving eosinophils or T-cells.
최근 수십 년 동안
식품 알레르기,
특히 우유 알레르기(CMA, 현재 어린이에게 가장 흔한 식품 알레르기 중 하나[1,2])의
유병률이 증가했습니다.
CMA는
하나 이상의 우유(CM) 단백질(보통 카제인 또는 혈청 β-락토글로불린)에 대한
재현 가능한 이상 반응으로 정의됩니다[3].
근본적인 면역학적 메커니즘,
발현 시간,
관련 기관에 따라
CMA는 유당 불내증과 같은 CM에 대한 다른 이상 반응과 구별됩니다[4].
CMA는
모든 FA와 마찬가지로
면역학적 기전의 유형에 따라
면역글로불린(Ig)E 매개 또는
비-IgE 매개[5]의 두 가지 주요 범주로 나눌 수 있습니다(그림 1).
IgE 매개 반응이 가장 흔합니다.
반면에
호산구 또는 T세포와 관련된
다른 세포 과정에서 발생할 수 있는
비 IgE 매개 반응도 있습니다.
Clinical presentation of IgE and non IgE CMA.
CMA usually occurs in the first 2 years of life and especially within the first year, unlike other allergies, such as peanut, tree nuts, fish and shellfish allergies which may develop later in childhood or adulthood. Most allergies (including CM allergies) resolve spontaneously during childhood or adolescence, whereas peanut and tree nut allergies are more likely to persist into adulthood [6,7].
땅콩, 견과류, 생선 및 조개류 알레르기와 같은
다른 알레르기와 달리
CMA는 보통 생후 2년, 특히 첫해에 발생하며,
어린 시절이나 성인기에 발생할 수 있는 다른 알레르기와는 달리
생후 1년 이내에 발생합니다.
대부분의 알레르기(CM 알레르기 포함)는
어린 시절이나 청소년기에 자연적으로 해결되지만
땅콩 및 견과류 알레르기는 성인기까지 지속될 가능성이 더 높습니다[6,7].
2. Cow’s Milk Composition
CM contains from 30 to 35 g of protein per liter and many proteins, which are all potential allergens [8].
Through the acidification of raw skim milk to pH 4.6 at 20 °C it is possible to obtain two different fractions: the coagulum, containing the casein proteins which account for 80% of the fraction, and the lactoserum (whey proteins), representing 20% of the total milk proteins [9]. These proteins can also be divided into soluble and insoluble proteins [10].
The major milk allergens are soluble proteins, named whey proteins, which represent approximately 20% of total proteins [11]. Allergens present in the serum fraction include α-lactalbumin (Bos d 4) and β-lactoglobulin (Bos d 5), which are the most abundant, and immunoglobulins (Bos d 7), serum albumin (BSA, Bos d 6), and traces of lactoferrin, lysozyme, proteose-peptone, and transferrin [9]. In particular lactoferrin, lactoperoxidase, and lysozyme are important antimicrobial agents, while lactoferrin, β-lactoglobulin, and α-lactalbumin are important tumor suppressors [12].
The remaining 80% is represented by insoluble proteins known as caseins (known as Bos d 8). Total caseins can be divided into four proteins, representing different percentages of the whole fraction: αS1-casein, which is the most important (Bos d 9, 32%), as well as αS2-casein (Bos d 10, 10%), β-casein (Bos d 11, 28%), and κ-casein (Bos d 12, 10%). The main role of caseins relates to their mineral binding and carrier capacity, specifically for calcium and phosphorus [12].
CMAs are most frequently caused by whey proteins, but they can also be promoted by caseins [13]. As a matter of fact, most patients are sensitized to casein (Bos d 8), β-lactoglobulin (Bos d 5), and α-lactalbumin (Bos d 4), which are the major milk allergens. There are only a few studies that describe allergies to minor serum proteins such as immunoglobulin, bovine serum albumin, or lactoferrin [14].
CM contains at least 20 potentially allergenic proteins [15]. Most children with milk-allergy are sensitized to more than one allergen, with a greater variability of symptoms.
CM에는
리터당 30~35g의 단백질과 많은 단백질이 포함되어 있으며,
이는 모두 잠재적인 알레르기 유발 물질입니다 [8].
20°C에서 탈지분유를 pH 4.6으로 산성화하면
분획의 80%를 차지하는
카제인 단백질이 포함된 응집체와
전체 우유 단백질의 20%를 차지하는 락토세럼(유청 단백질)의
두 가지 분획을 얻을 수 있습니다 [9].
이러한
단백질은
수용성 단백질과
불용성 단백질로 나눌 수도 있습니다[10].
주요 우유 알레르겐은
유청 단백질이라고 하는 수용성 단백질로
전체 단백질의 약 20%를 차지합니다[11].
혈청 분획에 존재하는 알레르겐으로는
α-락트알부민(Bos d 4)과
β-락토글로불린(Bos d 5)이 가장 많고
면역글로불린(Bos d 7),
혈청 알부민(BSA, Bos d 6),
미량의 락토페린, 라이소자임, 프로테오즈 펩톤 및 트랜스페린 등이 있습니다 [9].
특히
락토페린, 락토페록시다아제, 리소자임은 중요한 항균제이며,
락토페린, β-락토글로불린, α-락트알부민은 중요한 종양 억제제입니다[12].
나머지 80%는
카제인(Bos d 8로 알려진)으로
알려진 불용성 단백질이 차지합니다.
총 카세인은
전체 분획의 다른 비율을 나타내는
네 가지 단백질로 나눌 수 있습니다:
가장 중요한
αS1-카세인(Bos d 9, 32%)과
αS2-카세인(Bos d 10, 10%),
β-카세인(Bos d 11, 28%),
κ-카세인(Bos d 12, 10%)입니다.
카제인의 주요 역할은
특히 칼슘과 인에 대한
미네랄 결합 및 운반 능력과 관련이 있습니다 [12].
CMA는
유청 단백질에 의해 가장 자주 발생하지만
카제인에 의해서도 촉진될 수 있습니다 [13].
실제로 대부분의 환자는
주요 우유 알레르겐인
카제인(Bos d 8),
β-락토글로불린(Bos d 5), α
-락트알부민(Bos d 4)에 민감하게 반응합니다.
면역글로불린,
소 혈청 알부민 또는
락토페린과 같은 소량의 혈청 단백질에 대한 알레르기를 설명하는 연구는 거의 없습니다[14].
CM에는
최소 20개의 잠재적 알레르기 유발 단백질이 포함되어 있습니다[15].
우유 알레르기가 있는 대부분의 어린이는
한 가지 이상의 알레르겐에 민감하게 반응하며
증상의 변동성이 더 큽니다.
Table 1 provides a short synthesis of cow’s milk allergens and their characteristics.
Table 1
Main characteristics of CM allergens, adapted from Hochwallner [8].
Allergen NameProteinConcentration (g/L)Size (kDa)Prevalence (% of Patients)Allergenic Activity (% of Patients)
Whey (20%) (5 g/L) | Bos d 4 | α–Lactalbumin | 1–1.5 | 14.2 | 0–67 | 12 |
Bos d 5 | β–Lactoglobulin | 3–4 | 18.3 | 13–62 | 19 | |
Bos d 6 | Bovine serum albumin | 0.1–0.4 | 66.3 | 0–76 | 1 | |
Bos d 7 | Immunoglobulins | 0.6–1 | 160 | 12–36 | ||
Lactoferrin | 0.09 | 80 | 0–35 | 3 | ||
Whole casein (80%) (30 g/L) | Bos d 9 | αS1–casein | 12–15 | 23.6 | 65–100 | 26 |
Bos d 10 | αS2–casein | 3–4 | 25.2 | |||
Bos d 11 | β–casein | 9–11 | 24 | 35–44 | 35 | |
Bos d 12 | k–casein | 3–4 | 19 | 35–41 | 26 |
3. Subtypes of Immune-Mediated Reactions to CM
CMAs have a range of clinical manifestations, with variable intensity. Moreover, clinical features can differ from “immediate” to “delayed” reactions, and this reflects the different pathogenesis (Figure 1).
Approximately 60% of CMA are IgE-mediated, although estimates change according to the study population and age [1].
The remaining 40% is divided into non IgE-mediated and mixed forms. The latter have different underlying mechanisms, presentations, and implications, which complicate the attempts to estimate the prevalence of CMA.
Non IgE-mediated CMAs are caused by less clear immune mechanisms. In this case, clinical findings are deferred and may occur 48 h or days after CM ingestion. Moreover, there are no specific symptoms or biomarkers that can guide the diagnosis, making it difficult to reach a conclusion. Typical non-IgE-mediated forms of CMA include CM enteropathy, food protein-induced proctitis/proctocolitis (FPIAP), food protein-induced enterocolitis syndrome (FPIES), and Heiner syndrome (pulmonary hemosiderosis) [1].
There are also mixed forms of CMA (both IgE- and non-IgE-mediated) that may have either humoral and/or cell-mediated mechanisms and may present with acute and/or chronic symptoms. These include atopic dermatitis, allergic eosinophilic esophagitis, and eosinophilic gastritis [1].
CMA는
다양한 강도의 다양한 임상 증상을 보입니다.
또한 임상적 특징은
"즉각적" 반응에서
"지연된" 반응까지 다를 수 있으며,
이는 다양한 발병 기전을 반영합니다(그림 1).
연구 집단과 연령에 따라 추정치는 달라지지만,
약 60%의 CMA는
IgE 매개성입니다[1].
나머지 40%는
비 IgE 매개형과 혼합형으로 나뉩니다.
후자는
근본적인 메커니즘,
증상 및 시사점이 다르기 때문에
CMA의 유병률을 추정하는 시도가 복잡해집니다.
비 IgE 매개 CMA는
덜 명확한 면역 메커니즘으로 인해 발생합니다.
이 경우 임상 소견이 지연되며
CM 섭취 후 48시간 또는
며칠 후에 발생할 수 있습니다.
또한 진단을 안내할 수 있는
특정 증상이나 바이오마커가 없기 때문에
결론을 내리기가 어렵습니다.
대표적인
비-IgE 매개 형태의 CMA에는
CM 장병증, 식품 단
백질 유발 직장염/직장염(FPIAP),
식품 단백질 유발 장염 증후군(FPIES),
하이너 증후군(폐혈증) 등이 있습니다[1].
또한 체액성 및/또는
세포 매개 메커니즘을 가질 수 있으며
급성 및/또는 만성 증상을 나타낼 수 있는
혼합 형태의 CMA(IgE 매개 및 비-IgE 매개 모두)도 있습니다.
여기에는
아토피성 피부염,
알레르기성 호산구성 식도염,
호산구성 위염이 포함됩니다[1].
4. Prevalence of CMA
Before 1950, CMA was rarely diagnosed. Since 1970, significantly varying estimates of the incidence have been reported (ranging from 1.8% to 7.5%), reflecting the differences in diagnostic criteria and study design [16].
As a matter of fact, the prevalence estimates of CMA are affected by many factors. There is a marked heterogeneity in the prevalence of FA in the majority of papers. This could be the result of misleading differences in study design or methodology (including use of different definitions of CMA), or differences between populations and geographic areas [17].
Alongside the IgE, non-IgE, and mixed forms, there are also non-immune mediated reactions (i.e., intolerance), which are sometimes misclassified.
Another confounding factor while assessing prevalence is that many studies come from self-reports, with the consequent limitations linked to the subjective nature of the data [17]. Actually, the majority of studies on the epidemiology or natural history of FA have limitations. A precise evaluation requires a prospective ascertainment with a confirmatory oral food challenge (OFC) at predetermined intervals over time. For these reasons, studies such as these are rarely conducted due to their intrinsically reduced feasibility and ethical issues [17].
Therefore, determining an accurate diagnosis of CMA is fundamental. The process begins with an allergy-focused history that will guide all further investigations. In case that personal history is suggestive of allergy, a skin prick test (SPT) or specific IgE (sIgE) blood assay should be performed.
Evidence of sensitization (positive SPT or sIgE) with a suggestive history is usually sufficient to confirm the diagnosis, although OFC remains the gold standard [18].
It is important to emphasize that sensitization, i.e., raised sIgE directed against a specific antigen or positive SPT, in the absence of a supporting clinical history, is common in the general population but insufficient for a diagnosis of CMA. If diagnostic uncertainty remains even after a focused history and SPT/sIgE, an OFC is recommended to confirm diagnosis [18].
Other issues that may affect the estimates are the study design (prospective cohort vs cross-sectional), study population (demographic factors, geography, genetic/environmental factors), and natural history (incomplete identification of resolved cases) [1].
Despite these limitations during the assessment, a large number of studies in the United States and worldwide have attempted to estimate the prevalence of CMA [1].
An important contribution to prevalence studies was made by a meta-analysis performed by Rona et al., who analyzed publications from 1990 to 2005 and included only original studies (a total of 51 papers were considered appropriate for inclusion). The prevalence of self-reported FA was very high compared to that obtained using objective measures. Self-reported prevalence of CMA varied from 1.2% to 17%. The prevalence of CMA using SPT alone and sIgE alone, instead, was from 0.2% to 2.5% and from 2% to 9%, respectively. Studies using symptoms and sensitization (SPT ≥ 3 mm or sIgE > 0.35 kU/L) ranged from 0% to 2% prevalence, and those relying on OFC from 0% to 3% [19].
Another important meta-analysis and systematic review of CMA prevalence in Europe was performed by Nwaru et al., who analyzed publications from 2000 to 2012 (including 42 papers) [20]. The prevalence of self-reported CMA was 2.3% (95% CI 2.1–2.5), greater than that using SPT alone (0.3%, 95% CI 0.03–0.6) and sIgE alone (4.7%, 95% CI 4.2–5.1). The prevalence of CMA diagnosed by OFC was 0.6% (95% CI 0.5–0.8) and that using OFC or reported history of CMA was 1.6% (95% CI 1.2–1.9).
These meta-analyses show that prevalence estimates can be influenced by many factors such as geographic region, source population (high risk of referral bias vs general population), age and participation rates, and limitations of diagnosis [6].
Another important contribution was the EuroPrevall birth cohort study, published in 2015. In this study 12,049 children from nine different countries were enrolled, and 9336 (77.5%) were followed up until the age of 2 years. The authors calculated an overall incidence of challenge-proven CMA of 0.54% (95% CI 0.41–0.70) and showed differences in national incidences ranging from 1% (in the Netherlands and United Kingdom) to <0.3% (in Lithuania, Germany, and Greece). In this unique cohort study, they also showed that affected infants, without detectable specific antibodies to CM, were very likely to tolerate CM 1 year after diagnosis, whereas only half of those with specific antibodies in serum overcame their disease in the same period of time [21].
1950년 이전에는 CMA가 거의 진단되지 않았습니다.
1970년 이후 진단 기준과 연구 설계의 차이를 반영하여
1.8%에서 7.5%까지 상당히 다양한 발병률 추정치가 보고되었습니다[16].
실제로 CMA의 유병률 추정치는
여러 가지 요인에 의해 영향을 받습니다.
대부분의 논문에서
FA의 유병률에는 현저한 이질성이 존재합니다.
이는 연구 설계 또는 방법론의 오해의 소지가 있는 차이(CMA의 다른 정의 사용 포함) 또는
인구와 지역 간의 차이[17]로 인한 결과일 수 있습니다.
IgE, 비 IgE 및 혼합 형태와 함께 비면역 매개 반응(즉, 과민증)도 있는데,
이 또한 때때로 잘못 분류되기도 합니다.
유병률을 평가할 때 또 다른 혼란스러운 요소는
많은 연구가 자가 보고를 통해 이루어지며,
결과적으로 데이터의 주관적인 특성과 관련된 한계가 있다는 것입니다[17].
실제로 FA의 역학 또는 자연사에 관한 대부분의 연구에는 한계가 있습니다. 정확한 평가를 위해서는 일정 기간 동안 미리 정해진 간격으로 확인된 경구 음식 챌린지(OFC)를 통해 전향적으로 확인해야 합니다. 이러한 이유로 이러한 연구는 본질적으로 실현 가능성이 낮고 윤리적 문제로 인해 거의 수행되지 않습니다[17].
따라서
CMA의 정확한 진단을 결정하는 것은
기본입니다.
이 과정은
모든 추가 조사를 안내할
알레르기 중심의 병력 조사로 시작됩니다.
개인 병력에서 알레르기가 의심되는 경우
피부 단자 검사(SPT) 또는
특정 IgE(sIgE) 혈액 검사를 실시해야 합니다.
OFC가 여전히 표준으로 남아 있지만,
일반적으로 의심 병력이 있는 감작의 증거(SPT 또는 sIgE 양성)는 진단을 확인하는 데 충분합니다[18].
감작, 즉 특정 항원에 대한 sIgE 상승 또는 SPT 양성이 뒷받침되는 임상 병력이 없는 경우, 일반 인구에서 감작이 흔하지만 CMA 진단에는 충분하지 않다는 점을 강조하는 것이 중요합니다. 집중적인 병력 및 SPT/sIgE 검사 후에도 진단의 불확실성이 남아 있는 경우, 진단을 확인하기 위해 OFC를 권장합니다[18].
추정치에 영향을 미칠 수 있는 다른 문제로는 연구 설계(전향적 코호트 대 횡단면), 연구 집단(인구통계학적 요인, 지리, 유전적/환경적 요인), 자연력(완치 사례의 불완전한 식별) 등이 있습니다[1].
평가 과정에서 이러한 한계에도 불구하고
미국과 전 세계에서 많은 연구가 CMA의 유병률을
추정하려고 시도했습니다[1].
유병률 연구에 중요한 기여를 한 것은 1990년부터 2005년까지 발표된 논문을 분석하고 독창적인 연구만을 포함한 Rona 등의 메타 분석입니다(총 51개의 논문이 포함하기에 적절한 것으로 간주됨). 자가 보고된 FA의 유병률은 객관적인 측정치를 사용하여 얻은 유병률에 비해 매우 높았습니다. 자가 보고된 CMA의 유병률은 1.2%에서 17%까지 다양했습니다. 반면, SPT만을 사용한 CMA 유병률은 0.2%에서 2.5%, sIgE만을 사용한 유병률은 2%에서 9%로 각각 나타났습니다. 증상과 감작(SPT ≥ 3mm 또는 sIgE > 0.35 kU/L)을 사용한 연구는 유병률이 0%에서 2%, OFC에 의존한 연구는 0%에서 3%로 나타났습니다[19].
유럽에서 CMA 유병률에 대한 또 다른 중요한 메타 분석 및 체계적 검토는 2000년부터 2012년까지의 출판물(42개 논문 포함)을 분석한 Nwaru 등이 수행했습니다[20]. 자가 보고된 CMA의 유병률은 2.3%(95% CI 2.1-2.5)로 SPT 단독(0.3%, 95% CI 0.03-0.6) 및 sIgE 단독(4.7%, 95% CI 4.2-5.1)보다 높았습니다. OFC로 진단된 CMA의 유병률은 0.6%(95% CI 0.5-0.8), OFC를 사용하거나 CMA 병력이 보고된 경우의 유병률은 1.6%(95% CI 1.2-1.9)였습니다.
이러한 메타 분석은 유병률 추정치가 지리적 지역, 출처 인구(일반 인구 대비 의뢰 편향 위험이 높음), 연령 및 참여율, 진단의 한계 등 여러 요인에 의해 영향을 받을 수 있음을 보여줍니다[6].
또 다른 중요한 기여는 2015년에 발표된 EuroPrevall 출생 코호트 연구입니다. 이 연구에는 9개국에서 12,049명의 어린이가 등록되었으며, 9336명(77.5%)이 2세까지 추적 관찰되었습니다. 저자들은 도전성이 입증된 CMA의 전체 발생률을 0.54%(95% CI 0.41-0.70)로 계산했으며, 국가별 발생률은 1%(네덜란드와 영국)에서 0.3% 미만(리투아니아, 독일, 그리스)까지 차이를 보였습니다. 이 독특한 코호트 연구에서 연구진은 또한 CM에 대한 특정 항체가 검출되지 않은 감염 영아는 진단 후 1년이 지나면 CM에 잘 견디는 반면, 혈청에 특정 항체가 있는 영아 중 절반만이 같은 기간에 질병을 극복한 것으로 나타났습니다[21].
5. Diagnosis
Establishing an early and certain diagnosis of CMA is important to initiate the elimination diet in the case the diagnosis is confirmed or to avoid unnecessary dietary restrictions when it is not [22].
The diagnosis of CMA begins from the onset of signs and symptoms of CMA. Diagnosis is based on the combination of clinical history and physical examination, allergy tests such as sIgE and SPT, and, when indicated, OFC.
The first step is to evaluate the family and personal history in order to analyze every sign and symptom of the patient. Successively, it is fundamental to perform a differential diagnosis through laboratory evaluation and physical examination [23].
In addition to physical examination, there are objective assays used routinely in both epidemiological studies and clinical practice to investigate the condition, including sIgE and SPT. Despite the usefulness of sIgE antibodies (for tissue-bound and circulating IgE antibodies), these tests cannot differentiate between sensitization alone and clinical allergy [22]. The union of an evident history of allergic symptoms after CM exposure, associated with evidence of sensitization, certainly helps to make a definite diagnosis.
It has been demonstrated that the greater the food sIgE levels are and the SPT wheal size is, the higher the chances that the patient will manifest adverse reactions during an OFC. Numerous papers have analyzed the possibility of establishing a cutoff for sIgEs and SPTs for CM and its proteins that could predict whether a patient would react to an OFC [24]. Actually, several studies showed that cutoffs can vary with age [25], and many researchers are attempting to recommend diagnostic cutoffs for children [26,27]. However, cutoffs may change among different studies because of the type of allergen used to perform SPTs (commercial extract vs raw milk) or because of the degree of cooking [24].
Methods using sIgE measured [28] with in vitro immunoassays are still commonly referred to as IgE radioallergosorbent tests (RAST), and identify the level of IgE binding to specific proteins. Many studies have proposed a range of predictive cutoff values for the diagnosis of CMA, demonstrating a lack of agreement among different centers (Table 2).
CMA를 조기에 확실하게 진단하는 것은
진단이 확정된 경우
제거 식단을 시작하거나 그렇지 않은 경우
불필요한 식이 제한을 피하는 데 중요합니다[22].
CMA의 진단은
CMA의 징후와 증상이 시작될 때부터 시작됩니다.
진단은
임상 병력 및 신체 검사,
sIgE 및 SPT와 같은 알레르기 검사,
그리고 필요한 경우 OFC의 조합을 기반으로 합니다.
첫 번째 단계는
환자의 모든 징후와 증상을 분석하기 위해
가족력과 개인 병력을 평가하는 것입니다.
이어서 실험실 평가와 신체 검사를 통해 감별 진단을 수행하는 것이 기본입니다[23].
신체 검사 외에도
역학 연구와 임상 진료 모두에서 상태를 조사하기 위해
일상적으로 사용되는 객관적인 분석법이 있는데,
여기에는 sIgE와 SPT가 포함됩니다. (조직 결합 및 순환 IgE 항체의 경우)
sIgE 항체의 유용성에도 불구하고
이러한 검사로는 감작과 임상 알레르기를 구분할 수 없습니다[22].
감작의 증거와 관련된 CM 노출 후 알레르기 증상의 명백한 병력을 결합하면
확실한 진단을 내리는 데 확실히 도움이 됩니다.
식품 sIgE 수치가 높고
SPT 휠 크기가 클수록
환자가 OFC 중에 부작용을 나타낼 가능성이 높다는 것이 입증되었습니다.
수많은 논문에서
환자가 OFC에 반응할지 여부를 예측할 수 있는 CM과
그 단백질에 대한 sIgE 및 SPT의 컷오프 설정 가능성을 분석했습니다[24].
실제로 여러 연구에 따르면 컷오프는 연령에 따라 달라질 수 있으며[25], 많은 연구자들이 어린이를 위한 진단 컷오프를 권장하려고 시도하고 있습니다[26,27]. 그러나 컷오프는 SPT를 수행하는 데 사용되는 알레르겐의 유형(상업용 추출물 대 생우유) 또는 조리 정도에 따라 연구마다 달라질 수 있습니다 [24].
체외 면역 분석으로 측정한 sIgE를 사용하는 방법[28]은 여전히 일반적으로 IgE 방사선 알레르기 흡착 검사(RAST)라고 하며, 특정 단백질에 결합하는 IgE의 수준을 파악합니다. 많은 연구에서 CMA 진단을 위한 다양한 예측 컷오프 값이 제안되었지만, 여러 센터 간에 일치하지 않는 것으로 나타났습니다(표 2).
Table 2
Positive predictive values of 90% and 95% of sIgE levels for a positive challenge.
Author, YearAge90%95%Method
Sampson and Ho, 1997 [29] | 5.2 years | 23 kU/L | 32 kU/L | CAP system FEIA |
Garcia–Ara et al., 2001 [30] | 4.8 months | 2.5 kU/L | 5 kU/L | CAP system FEIA |
Sampson, 2001 [31] | 3.8 years | 15 kU/L | 32 kU/L | CAP system FEIA |
Garcia–Ara et al., 2004 [32] | 13–18 months | 1.5 kU/L | 2.7 kU/L | CAP system FEIA |
19–24 months | 6 kU/L | 9 kU/L | ||
25–36 months | 14 kU/L | 24 kU/L | ||
Celik–Bilgili et al., 2005 [33] | <1 year | 25.8 kU/L | CAP system FEIA | |
Komata et al., 2007 [25] | <1 year | 5.8 kU/L | CAP system FEIA | |
1 year | 38.6 kU/L | |||
2 years | 57.3 kU/L | |||
Martorell et al., 2008 [34] | 12 months | 5.8 kU/L | CAP system FEIA | |
18 months | 9.8 kU/L | |||
24 months | 27.5 kU/L | |||
36 months | 7.4 kU/L | |||
48 months | 5 kU/L | |||
Van der Gutgen et al., 2008 [35] | <2.5 years | 5 kU/L | 7.5 kU/L | CAP system FEIA |
Ott. et al., 2008 [36] | 52.7 kU/L | 66.9 kU/L | CAP system FEIA |
Predictive cutoff values are found to be lower in younger children and increase with age [32], with diagnostic cutoff values remaining valid independently of the total serum IgE [37].
Therefore, it is difficult to assess standardized cutoffs for CM sIgE above which an OFC would not be required. Each patient would consequently need to be evaluated individually.
Traditionally sensitization is defined as the observation of a detectable sIgE level, (often sIgE > 0.35 kU/L but sometimes >0.10 kU/L) [1], although an OFC would be required if the sIgE level is positive but low.
SPTs have been used for decades to demonstrate or to exclude sensitization to allergens, as they are easy to perform, inexpensive, well tolerated, and provide immediately available results [22]. Traditionally, measured sensitization is often defined as a wheal at least 3 mm larger than the negative control [1]. Therefore, many studies aimed to avoid OFC by finding a cutoff of SPT able to predict a positive outcome of OFC [38] (Table 3).
예측 컷오프 값은 어린 소아에서 더 낮고 나이가 들수록 증가하는 것으로 밝혀졌으며[32], 진단 컷오프 값은 총 혈청 IgE와 무관하게 유효합니다[37].
따라서 OFC가 필요하지 않은 CM sIgE에 대한 표준화된 컷오프값을 평가하기는 어렵습니다. 따라서 각 환자를 개별적으로 평가해야 합니다.
전통적으로 민감화는 검출 가능한 sIgE 수치(대개 0.35 kU/L 이상이지만 때로는 0.10 kU/L 이상)의 관찰로 정의되지만[1], sIgE 수치가 양성이지만 낮은 경우 OFC가 필요할 수 있습니다.
SPT는 수행하기 쉽고, 저렴하며, 내약성이 좋고, 즉시 사용 가능한 결과를 제공하기 때문에 알레르겐에 대한 감작을 입증하거나 배제하는 데 수십 년 동안 사용되어 왔습니다[22]. 전통적으로 측정된 감작성은 종종 음성 대조군보다 최소 3mm 이상 큰 두드러기로 정의됩니다[1]. 따라서 많은 연구에서 OFC의 양성 결과를 예측할 수 있는 SPT의 컷오프를 찾아내어 OFC를 피하고자 했습니다[38](표 3).
Table 3
Positive predictive value of 90% and 95% of SPT for a positive challenge.
Author, YearAgeØ SPT 90%Ø SPT 95%Type of Allergen
Eigenmann and Sampson, 1998 [39] | 4.6 years | >5 mm | Glycerinate extract | |
Sporik et al., 2000 [40] | 3 years | >8 mm | Glycerinate extract | |
<2 years | >6 mm | |||
Calvani et al., 2007 [41] | 3.6 years | 15 mm | Fresh milk | |
12 mm | α-Lactalbumin | |||
8 mm | Casein | |||
10 mm | β-lactoglobulin | |||
Calvani et al., 2012 [42] | 3.7 years | 20 mm | Fresh milk | |
10 mm | α-Lactalbumin | |||
7 mm | Casein | |||
8 mm | β-Lactoglobulin | |||
Onesimo et al., 2013 [38] | 2.7 years | 4.9 mm | α-Lactalbumin | |
4.3 mm | Casein | |||
5.6 mm | β-Lactaglobulin | |||
Kido et al., 2016 [43] | 1.4 years | 15 mm | Glycerinate extract |
A recent review by Cuomo et al. [24] reported that none of the cutoffs proposed in the literature could be used to definitively diagnose CMA. However, they found that in children aged <2 years, CMA diagnosis seemed to be highly likely when the sIgE reaction to CM extract was ≥5 kU/L, or when SPTs reactions with a commercial extract were above 6 mm, or when prick-by-prick reactions with fresh CM were above 8 mm [24].
However, if the clinical history is uncertain, SPT wheals measuring between 3 and 5 mm may be clinically irrelevant, and low levels of sIgE may be found in children without clinical CMA [33].
The negative predictive value of SPTs and sIgE is excellent (>95%) for immediate reactions [33]. Therefore, despite negative IgE tests, if there is a strong suspicion of CMA, an OFC is necessary to confirm the absence of a clinical allergy [13].
Despite this, even if OFC still remains the gold standard for CMA diagnosis (particularly the DBPCFC) [1], it is rarely required in clinical practice.
The OFC in CMA is performed by using baked or fresh milk. As baked milk is less allergenic in a context where a positive challenge is unexpected, it may be used initially because reactions are less likely to be severe [22].
OFCs should be performed under medical supervision in a hospital setting with an emergency kit available, especially in case of positive SPT or sIgE to CM and in infants at risk of an immediate reaction [13].
There is a lot of interest among clinicians in identifying markers that can predict the chance of developing tolerance and hence overcoming the allergy. Many studies have showed that IgE levels, expressed either as SPT wheal size or serum sIgE level, could be useful in discriminating between children who remained hypersensitive and those who became tolerant [44,45].The aim of most of these studies was to determine whether the monitoring of food sIgE levels over time could aid in the prediction of when patients would develop clinical tolerance. The likelihood estimates founded in these studies could help clinicians in providing prognostic information and in timing subsequent food challenges, thereby decreasing the number of premature and unnecessary DBPCFC [46].
Even if there is a lack of studies in this regard, some markers that may predict a persistent CMA have been identified over time. This explains the great interest of clinicians in finding a marker.
As a general rule, higher maximum IgE levels are associated with a reduced likelihood of developing tolerance [47].
Expressly regarding CMA, the association between increasing levels and persistence of allergy has been demonstrated, whereas decreasing levels indicate a faster recovery [48]. Low levels of IgG4 to β-lactoglobulin, instead, were found in children who required a longer elimination diet [36].
Vanto et al. [44] found that SPT wheal size <5 mm at diagnosis could be used to correctly identify 83% of individuals who developed tolerance at 4 years, whilst a wheal size ≥5 mm correctly identified 74% with persistent CMA.
These cutoff levels vary from study to study, possibly because of differences between the studied groups.
Garcia-Ara et al. [32] showed that sIgE levels predictive of clinical reactivity increased with age.
Shek and colleagues reported that the rate of reduction in food sIgE levels over time was predictive of the likelihood of developing tolerance in milk allergy. They were able to elaborate estimates of developing tolerance based on the reduction in sIgE levels, with a probability of tolerance of 31% in the case of a decrease by 50% in IgE levels, a probability of 45% in the case of a decrease by 70%, a probability of 66% when the decrease was 90%, and a probability of 94% for a decrease by 95% [46].
The value of sIgE has been analyzed with the aim of providing individuate cutoff levels related to the development of tolerance. Sampson et al. reported a positive predictive value of 95% in children with a median age of 3.8 years and CM-sIgE ≥ 15 kU/L [31]. Yavuz et al. examined sIgE levels which could predict a negative OFC in infants at different ages: by sIgE < 2.8 kU/L for children under 1 year, by 11.1 kU/L for children aged <2 years, and by <13.7 KU/l for children aged <6 years [49].
Cuomo 등[24]의 최근 검토에 따르면 문헌에서 제안된 어떤 컷오프도 CMA를 확실하게 진단하는 데 사용할 수 없다고 보고했습니다. 그러나 2세 미만의 소아에서 CM 추출물에 대한 sIgE 반응이 ≥5 kU/L이거나 상업용 추출물을 사용한 SPT 반응이 6mm 이상이거나 신선한 CM을 사용한 찌르기 반응이 8mm 이상일 때 CMA 진단 가능성이 높은 것으로 나타났습니다[24].
그러나 임상 병력이 불확실한 경우, 3~5mm 사이의 SPT 휠은 임상적으로 관련이 없을 수 있으며, 임상 CMA가 없는 소아에서 낮은 수준의 sIgE가 발견될 수 있습니다 [33].
즉각적인 반응에 대한 SPT 및 sIgE의 음성 예측값은 우수합니다(>95%)[33]. 따라서 IgE 검사 음성에도 불구하고 CMA가 강하게 의심되는 경우 임상 알레르기가 없음을 확인하기 위해 OFC가 필요합니다 [13].
그럼에도 불구하고 OFC가 여전히 CMA 진단의 표준으로 남아 있지만(특히 DBPCFC)[1], 임상에서는 거의 필요하지 않습니다.
CMA의 OFC는 구운 우유 또는 신선한 우유를 사용하여 수행됩니다. 구운 우유는 양성 반응이 예상치 못한 상황에서 알레르기 유발 가능성이 적기 때문에 초기에 사용할 수 있습니다[22].
OFC는 병원 환경에서 의료진의 감독 하에 응급 키트가 준비된 상태에서 실시해야 하며, 특히 SPT 또는 sIgE가 CM에 양성인 경우와 즉각적인 반응의 위험이 있는 영아의 경우 더욱 그렇습니다[13].
임상의들 사이에서는 내성 발생 가능성을 예측하여 알레르기를 극복할 수 있는 마커를 식별하는 데 많은 관심이 있습니다. 많은 연구에 따르면 SPT wheal 크기 또는 혈청 sIgE 수치로 표현되는 IgE 수치는 과민 반응을 유지하는 어린이와 내성이 생긴 어린이를 구별하는 데 유용할 수 있습니다[44,45].이러한 연구의 대부분은 시간 경과에 따른 음식 sIgE 수치 모니터링이 환자가 언제 임상 내성이 생길지 예측하는 데 도움이 될 수 있는지 확인하는 것이 목적이었습니다. 이러한 연구에서 발견한 가능성 추정치는 임상의가 예후 정보를 제공하고 후속 음식 문제를 해결하는 데 도움을 주어 불필요한 조기 DBPCFC의 수를 줄일 수 있습니다[46].
이와 관련된 연구가 부족하지만, 시간이 지남에 따라 지속적인 CMA를 예측할 수 있는 몇 가지 마커가 확인되었습니다. 이는 마커를 찾는 데 대한 임상의의 큰 관심을 설명합니다.
일반적으로 최대 IgE 수치가 높을수록 내성 발생 가능성이 감소합니다[47].
CMA의 경우, 수치가 증가하면 알레르기가 지속되는 반면, 수치가 감소하면 회복이 빨라진다는 연관성이 입증되었습니다 [48]. 대신 β- 락토글로불린의 낮은 수치는 더 긴 제거식이 필요한 어린이에게서 발견되었습니다 [36].
Vanto 등[44]은 진단 시 SPT 휠 크기가 5mm 미만인 경우 4년 후 내성이 발생한 개인의 83%를 정확하게 식별할 수 있는 반면, 휠 크기가 5mm 이상인 경우 74%를 지속성 CMA로 정확하게 식별할 수 있다는 것을 발견했습니다.
이러한 컷오프 수준은 연구 그룹 간의 차이로 인해 연구마다 다릅니다.
Garcia-Ara 등[32]은 임상적 반응성을 예측하는 sIgE 수치가 나이가 들수록 증가한다는 것을 보여주었습니다.
Shek과 동료들은 시간이 지남에 따라 식품 sIgE 수치가 감소하는 속도가 우유 알레르기의 내성 발생 가능성을 예측할 수 있다고 보고했습니다. 그들은 sIgE 수치가 50% 감소한 경우 31%, 70% 감소한 경우 45%, 90% 감소한 경우 66%, 95% 감소한 경우 94%의 확률로 내성 발생 확률을 정교하게 추정할 수 있었습니다[46].
내성 발달과 관련된 개별적인 차단 수준을 제공하기 위해 sIgE의 값을 분석했습니다. 샘슨 등은 중앙 연령이 3.8세이고 CM-sIgE가 15kU/L 이상인 소아에서 95%의 양성 예측 값을 보고했습니다[31]. Yavuz 등은 다양한 연령대의 영아에서 음성 OFC를 예측할 수 있는 sIgE 수치를 조사했습니다: 1세 미만 어린이의 경우 2.8 kU/L 미만, 2세 미만 어린이의 경우 11.1 kU/L 미만, 6세 미만 어린이의 경우 13.7 KU/L 미만 [49].
6. Risk Factors for CMA
The development of all FAs is influenced by genetics, environment, and genome–environment interactions, including epigenetic effects. Numerous risk factors for CMA have been identified or proposed that can contribute to allergy or sensitization.
There are unchangeable risk factors associated with a higher risk of FA, such as sex (male sex in children), race/ethnicity (increased among Asian and black children compared to white children), and family history of atopy [6]. It is generally presumed that atopy in parents increases atopic risk for the developing infant. This latter is one of the strongest risk factors, as occurs in other atopic diseases.
Koplin et al. discovered in a population of one-year-old infants with FA that the risk of FA increased to 40% in patients with one immediate family member with any allergic disease and to 80% in patients with two immediate family members with any allergic disease as compared to children no family history of allergy [50].
Controversy still exists as to whether a family history of atopy is also associated with a higher risk of CMA in infants. Goldberg et al., in a population-based study in 2013 [51], compared the parental atopic status of children with IgE-CMA (n = 66) with a group of healthy infants (n = 156). They reported no significant differences between the two groups and concluded that parental history of atopy alone cannot be used to anticipate which infants are at greater risk of developing IgE-mediated CMA [51].
On the contrary, in a recent paper by Sardecka et al. [52] on 138 infants with CMA and 101 healthy infants without allergy (with CMA confirmed by an elimination test and OFC), it was reported that the incidence of CMA was three times higher in infants with a positive family history for allergy. In this study it was also found that mothers of children with CMA were four times more likely to have a university-level education as compared to mothers of children without allergy [52].
As with all FAs, it is well known that atopic disease in general and particularly atopic dermatitis is an important risk factor for IgE-mediated CMA. This explain why the suspicion of CMA should be stronger in moderate-to-severe atopic dermatitis that starts in the first 6 months of life [53].
Atopic comorbidities such as asthma, especially when inadequately handled, are associated with frequent and severe reactions to milk [54]. Actually, it is still not known whether this is caused by a more severe allergic phenotype or by a barrier function.
Another factor that may have a protective role with respect to food sensitization and allergy later in childhood is increased food diversity in infancy [55]. In fact, Roduit et al. reported that an increased diversity of food within the first year of life might have a protective effect with respect to asthma, FA, and food sensitization [55].
Another risk factor for FA that has been identified is parents’ country of origin. The NHANES study, conducted between 2005 and 2006, compared the risk of food sensitization between US-born children and foreign-born children.
Compared to those born outside the United States, US-born children and adolescents had higher risk of sensitization to any food. Among the foreign-born, those who arrived before 2 years of age had higher odds of food sensitization than those who arrived later [56].
Other potential risk factors that can be examined to reduce/prevent FAs, are: increased hygiene, the influence of the microbiome [57], dietary fat (reduced consumption of omega-3-polyunsaturated fatty acids), reduced consumption of antioxidants, increased use of antacids (reducing digestion of allergens), obesity (being an inflammatory state), and the timing of food introduction in diet (increased risk of delaying oral ingestion of allergens, with environmental exposure, in the absence of oral exposure, leads to sensitization and allergy) [6].
A National Academies of Sciences report (2016) examined many factors and theories suggested to influence the risk of FA [58]. This group examined the “dual allergen exposure hypothesis”, attributed to Gideon Lack, and assessed that there is limited but consistent evidence that an impaired skin barrier plays a role in sensitization as a first step toward FA [6]. This theory suggest that low-dose cutaneous exposure is sensitizing and facilitated by an impaired skin barrier and inflammation. Meanwhile, oral exposure could cause the development of tolerance [6].
Numerous perinatal factors can influence the development of CMA and FAs, but the relationship between them is still controversial [59,60]. Sardecka et al. reported an increased risk of CMA in premature newborns, as previously noted [61], which may result from increased intestinal permeability [52]. The mode of delivery may also influence the development of FAs. The incidence of CMA may be higher in infants born by cesarean section because of the influence on the microbiota and, consequentially, on the immune system. Actually, no relationship between CMA and the type of delivery has ever been observed in studies [52,62].
모든 FA의 발달은 후성유전학적 영향을 포함한 유전, 환경 및 게놈-환경 상호작용의 영향을 받습니다. 알레르기 또는 감작에 기여할 수 있는 수많은 CMA의 위험 요인이 확인되거나 제안되었습니다.
성별(어린이의 경우 남성), 인종/민족(백인 어린이에 비해 아시아 및 흑인 어린이에서 증가), 아토피 가족력[6] 등 FA의 높은 위험과 관련된 변하지 않는 위험 요인이 있습니다. 일반적으로 부모의 아토피가 있는 경우 아기가 아토피에 걸릴 위험이 높아지는 것으로 추정됩니다. 후자는 다른 아토피 질환과 마찬가지로 가장 강력한 위험 요인 중 하나입니다.
Koplin 등은 1세 유아를 대상으로 한 연구에서 알레르기 가족력이 없는 어린이에 비해 직계 가족 중 알레르기 질환이 있는 환자가 한 명 있는 경우 FA의 위험이 40%, 직계 가족 중 알레르기 질환이 있는 환자가 두 명 있는 경우 80%까지 증가한다는 사실을 발견했습니다[50].
아토피 가족력이 유아의 CMA 위험 증가와도 관련이 있는지에 대해서는 여전히 논란이 있습니다. 2013년 인구 기반 연구[51]에서 골드버그 등은 IgE-CMA를 가진 아동(n = 66)의 부모의 아토피 상태를 건강한 유아 그룹(n = 156)과 비교했습니다. 연구진은 두 그룹 간에 유의미한 차이가 없다고 보고했으며, 부모의 아토피 병력만으로는 어떤 영아가 IgE 매개 CMA에 걸릴 위험이 더 높은지 예측할 수 없다고 결론지었습니다 [51].
반대로, 최근 Sardecka 등[52]의 논문에서는 CMA가 있는 138명의 영아와 알레르기가 없는 101명의 건강한 영아(제거 검사 및 OFC로 CMA가 확인됨)를 대상으로 한 연구에서 알레르기 가족력이 있는 영아에서 CMA 발생률이 3배 더 높았다고 보고했습니다. 이 연구에서는 또한 CMA가 있는 아동의 어머니가 알레르기가 없는 아동의 어머니에 비해 대학 수준의 교육을 받았을 가능성이 4배 더 높은 것으로 나타났습니다 [52].
모든 FA와 마찬가지로 일반적으로 아토피 질환, 특히 아토피 피부염이 IgE 매개 CMA의 중요한 위험 인자라는 것은 잘 알려져 있습니다. 이는 생후 6개월에 시작되는 중등도에서 중증의 아토피 피부염에서 CMA를 더 강하게 의심해야 하는 이유를 설명합니다[53].
천식과 같은 아토피 동반 질환, 특히 부적절하게 관리되는 경우 우유에 대한 빈번하고 심각한 반응과 관련이 있습니다 [54]. 실제로 이것이 더 심한 알레르기 표현형에 의한 것인지 아니면 장벽 기능에 의한 것인지는 아직 알려지지 않았습니다.
어린 시절의 음식 감작 및 알레르기와 관련하여 보호 역할을 할 수 있는 또 다른 요인은 유아기의 음식 다양성 증가입니다 [55]. 실제로 Roduit 등은 생후 첫해에 음식의 다양성이 증가하면 천식, FA 및 음식 감작과 관련하여 보호 효과가 있을 수 있다고 보고했습니다[55].
확인된 또 다른 FA의 위험 요소는 부모의 출신 국가입니다. 2005년부터 2006년 사이에 실시된 NHANES 연구에서는 미국에서 태어난 어린이와 외국에서 태어난 어린이 간의 식품 과민증 위험을 비교했습니다.
미국에서 태어난 어린이와 청소년은 외국에서 태어난 어린이와 청소년에 비해 모든 식품에 대한 민감성 위험이 더 높았습니다. 외국 출생자 중에서는 2세 이전에 입국한 아동이 나중에 입국한 아동보다 식품 과민증에 걸릴 확률이 더 높았습니다[56].
FA를 줄이거나 예방하기 위해 조사할 수 있는 다른 잠재적 위험 요인으로는 위생 개선, 미생물 군집의 영향[57], 식이 지방(오메가-3-불포화지방산 섭취 감소), 항산화제 섭취 감소, 제산제 사용 증가(알레르겐의 소화 감소), 비만(염증 상태), 식단에서 음식 도입 시기(환경 노출로 알레르겐의 구강 섭취 지연 위험 증가, 구강 노출이 없는 경우 민감화 및 알레르기 유발)[6] 등이 있습니다[57].
미국 국립과학원 보고서(2016)에서는 FA의 위험에 영향을 미치는 것으로 알려진 여러 요인과 이론을 조사했습니다[58]. 이 그룹은 기드온 랙(Gideon Lack)의 '이중 알레르겐 노출 가설'을 검토한 결과, 피부 장벽 손상이 FA의 첫 단계로서 감작에 영향을 미친다는 제한적이지만 일관된 증거가 있다고 평가했습니다[6]. 이 이론에 따르면 저선량 피부 노출은 피부 장벽 손상과 염증에 의해 감작을 일으키고 촉진됩니다. 한편 경구 노출은 내성을 유발할 수 있습니다 [6].
수많은 주산기 요인이 CMA와 FA의 발달에 영향을 미칠 수 있지만, 이들 간의 관계는 여전히 논란의 여지가 있습니다[59,60]. 앞서 언급한 바와 같이 [61], 미숙아에서 CMA 위험이 증가한다고 보고했는데, 이는 장 투과성 증가로 인해 발생할 수 있습니다 [52]. 분만 방식도 FA의 발생에 영향을 미칠 수 있습니다. 제왕절개로 태어난 신생아의 경우 미생물총과 결과적으로 면역 체계에 영향을 미치기 때문에 CMA 발생률이 더 높을 수 있습니다. 실제로 CMA와 분만 유형 간의 관계는 연구에서 관찰된 적이 없습니다[52,62].
6.1. The Role of Vitamin D
During the last decades, interest in the role of vitamin D in allergic disease has progressively increased. Numerous papers have suggested its possible role as an immune modulator in allergies, especially with respect to lymphocyte activation, antigen receptor function, and signaling pathways [63]. Still, the precise molecular mechanisms involved in vitamin D’s genomic and non-genomic actions remain incompletely defined [64] and not fully understood.
A lack of vitamin D has been associated with an increased risk of FA in many papers [64,65]. Actually, these associations are controversial and need further exploration, as vitamin D sufficiency has also been associated with an increased risk of allergic sensitization.
It is known that populations with lower levels of vitamin D are more susceptible to developing food allergies [66].
An Italian cross-sectional study performed by Lombardi et al. showed that the association between vitamin D levels and allergies was weak, and reported that it was necessary to implement studies involving larger samples to better assess this association [67].
Ecological studies have shown that there is an association between lower sunlight exposure and FA [68].
On the other hand, other papers reported that higher levels of vitamin D could increase the risk of allergic sensitization and FA.
For this reason, the relationship between vitamin D and development of FA is still controversial. Further studies are required to assess the role of vitamin D in the prevention of allergic diseases [68].
지난 수십 년 동안 알레르기 질환에서
비타민 D의 역할에 대한 관심이 점차 증가해 왔습니다.
수많은 논문에서 특히 림
프구 활성화, 항원 수용체 기능 및 신호 경로와 관련하여
알레르기에서 면역 조절제로서의 역할 가능성을 제시했습니다 [63].
하지만
비타민 D의 게놈 및 비게놈 작용에 관여하는
정확한 분자 메커니즘은 아직 불완전하게 정의되어 있으며[64]
완전히 이해되지 않은 상태입니다.
많은 논문에서 비타민 D 부족은
FA의 위험 증가와 관련이 있는 것으로 나타났습니다 [64,65].
사실 이러한 연관성은 논란의 여지가 있으며 비타민 D 부족이 알레르기 감작의 위험 증가와도 관련이 있기 때문에 추가 연구가 필요합니다.
비타민 D 수치가 낮은 인구는
식품 알레르기에 더 취약한 것으로 알려져 있습니다[66].
Lombardi 등이 수행한 이탈리아 횡단면 연구에 따르면
비타민 D 수치와 알레르기 사이의 연관성은 약했으며,
이러한 연관성을 더 잘 평가하기 위해 더 큰 표본을 대상으로 한 연구를 시행할 필요가 있다고 보고했습니다 [67].
생태학적 연구에 따르면
낮은 햇빛 노출과 FA 사이에는 연관성이 있는 것으로 나타났습니다 [68].
반면에 다른 논문에서는 비타민 D 수치가 높을수록
알레르기 감작과 FA의 위험이 높아질 수 있다고 보고했습니다.
이러한 이유로 비타민 D와 FA 발생 사이의 관계는 여전히 논란의 여지가 있습니다. 알레르기 질환 예방에서 비타민 D의 역할을 평가하기 위해서는 추가 연구가 필요합니다 [68].
6.2. The Role of Breastfeeding
It is known that breastfeeding has an important role in the establishment of gut microbiota, nutritional status (with a role in preventing obesity and other nutritional disorders), the immunological system, and neuro-psychomotor development.
Human milk is composed of many molecules with potential immune-modulating roles: antibodies, predominantly secretory immunoglobulin A (s-IgA), cytokines (TGF-β, IL-10, IL-12, thymic stromal lymphopoietin) and chemokines, hormones and growth factors, polyunsaturated fatty acids (PUFAs), glutamine and dietary nucleotides, glycoproteins, oligosaccharides, and microRNA [69,70]. During infancy, it also represents the principal source of protein, fat, calcium, phosphorus, and vitamin B12. For this reason, breastfeeding should not be easily eliminated but encouraged instead [71].
According to the World Health Organization (WHO), breastfeeding is the perfect method of infant feeding; it is recommended exclusively in the first 6 months of life and partially until 2 years of age [72]. Exclusive breastfeeding means that infants should be fed only with breastmilk in the first 6 months of life and receive no other liquid or solids except for vitamins, mineral supplements, or medicines.
The main allergens in CM are casein, α-lactalbumin, and β-lactoglobulin. It is known that casein and α-lactalbumin are natural elements of human milk, while β-lactoglobulin is not present in it [15]. Therefore, the presence of β-lactoglobulin in human milk is caused by maternal ingestion of CM. Actually, it is still not understood whether there is a transfer of proteins such as β-lactoglobulin into breast milk. In any case, it seems that a small fraction of dietary proteins can resist digestion and become eventually allergenic [73].
Current guidelines expressly affirm that in infants with CMA, mothers should be encouraged to continue breastfeeding [69].
As suggested by American Academy of Pediatrics (AAP) and ESPGHAN recommendations, breastfeeding should be continued while solid foods are introduced into the diet [74]. From an allergological standpoint, continuing breastfeeding during solid food introduction and delaying this introduction until at least 17 weeks of age were associated with fewer FAs [75]. Thus, the early introduction of allergenic foods while breastfeeding might be a protective factor against FAs.
As recommended by the AAP, when breastfeeding is not possible or not sufficient, the introduction of CM proteins can be done in the first days or weeks of life through a CM formula [76].
However, the role of early exposure to CM proteins as a risk factor for the development of CMA and FA in general is still not clear. Data regarding a direct relationship between breastfeeding and FA are insufficient [77].
Exclusive breastfeeding for at least 4–6 months was first recommended by the European Section of Pediatrics and the AAP in the early 2000s to prevent FA and CMA in early childhood [78].
In 2008, the AAP affirmed that there was still no convincing evidence that the delayed introduction of allergenic foods beyond 4–6 months had a significant protective effect against the development of allergic disease [78].
A randomized trial study by Saarinen et al. [79] reported that feeding with CM formula in maternity hospitals increased the risk of CMA when compared with feeding with other supplements. However exclusive breastfeeding does not totally eliminate the risk.
Another prospective study on CMA in exclusively breastfed infants by Host et al. [80] underlined that early accidental and occasional exposure to CM proteins may initiate sensitization in predisposed newborns. Subsequent exposure to small amounts of CM proteins in human milk may act as booster doses by eliciting allergic reactions [80].
In a 2018 study, Sardecka et al. [52] found that the risk of CMA in children during the first year of life decreased as a result of a longer period of breastfeeding.
On the contrary, in a prospective large birth cohort study of 13,019 infants, Katz et al. reported that only 0.05% of the newborns who received a regular introduction of CM formula within the first 14 days developed CM-IgE, whereas 1.75% of the infants who started the CM formula between the ages of 105 and 194 days developed CM-IgE [81]. Thus, the authors concluded that early exposure to CM, in addition to breastfeeding, might stimulate tolerance.
Furthermore, a recent case—control study by Onizawa et al. [82] supported the hypothesis that early, regular, and continuous exposure to CM formula, started within the first month of life, can prevent CMA.
Further studies are required in order to confirm the possibility of preventing CMA with regular and early administration of CM formula.
7. Natural History of CMA
This paper focuses on CMA as a model of FAs in children.
The rate of resolution of FAs was reviewed by Savage et al. in 2016 [7]; it was found that some allergies have a high rate of resolution in childhood, such as milk (>50% by age 5–10 years), egg (approximately 50% by age 2–9 years), wheat (50% by age 7 years) and soy (45% by age 6 years) allergies, with complete resolution in adolescence. Others that usually persist include peanut (approximately 20% by age 4 years), tree nut (approximately 10%), fish, and shellfish allergies (further studies are necessary).
The natural history of CMA is unique. Resolution is usually common [1] and this contributes to the complication of prevalence estimates.
Actually, there is some heterogeneity in the estimated rate of resolution: studies show different resolution rates (Table 4). Whereas until now there has been a clearly notable heterogeneity among studies, in a combined analysis of patients with CMA in infancy, by the age of 5, 50% developed tolerance and by early adolescence, 75% developed tolerance [1].
Table 4
Natural history of CMA in different populations and settings, adapted from Mousan et al. [2].
Authors/Year of PublicationNumber of SubjectsPopulation/Study DesignTolerance RateAge of Tolerance(year)
Høst et al., 2002 [86] | 39 (24 IgE-mediated) | General prospective birth cohort | 56% | 1 |
77% | 2 | |||
87% | 3 | |||
92% | 5 | |||
97% | 15 | |||
Vanto et al., 2004 [44] | 162 (95 IgE-mediated) | Referral retrospective | 44% | 2 |
69% | 3 | |||
77% | 4 | |||
Garcia-Ara et al., 2004 [32] | 66 IgE-mediated | Referral retrospective | 68% | 4 |
Saarinen et al., 2005 [85] | 118 (75 IgE-mediated) | General prospective birth cohort | 51% | 2 |
74% | 5 | |||
85% | 8.6 | |||
Skripak et al., 2007 [84] | 807 IgE-mediated | Referral retrospective | 19% | 4 |
42% | 8 | |||
64% | 12 | |||
79% | 16 | |||
Fiocchi et al., 2008 [87] | 112 IgE-mediated | Referral retrospective | 52.7% | 5 |
Martorell et al., 2008 [34] | 170 IgE-mediated | Referral retrospective | 82% | 4 |
Santos et al., 2010 [47] | 139 (66 IgE-mediated) | Referral retrospective | 41% | 2 |
Ahrens et al., 2012 [88] | 52 IgE-mediated | Referral retrospective | 61.5% | 12 |
Elizur et al., 2012 [83] | 54 IgE-mediated | General prospective birth cohort | 57.4% | 2 |
65% | 4 | |||
Wood et al., 2013 [89] | 293 IgE-mediated | Prospective | 53% | 5.5 |
Yavuz et al., 2013 [49] | 148 IgE-mediated | Referral retrospective | 20% | 2 |
34% | 4 | |||
39% | 6 | |||
Schoemaker et al., 2015 [21] | 55 | EuroPrevall, European population-based | 57% | 2 |
Prospective |
A large population cohort study in Israel showed that only 57% of children with CMA resolved their allergy by the age of 4–5, and the majority of these allergies were resolved by age 2 [83].
In contrast, it is important to underline that clinically based studies suggest a poorer prognosis, since they include children who are at higher risk of allergy [17].
Santos et al., in a recent prospective study analyzing Portuguese children with CMA between 1997 and 2006, found that only 41% developed tolerance at the age of 10 [47].
Another important retrospective study of milk allergy by Skripak et al. [84] evidenced that the median age of outgrowing CMA was 10 years. In this case the definition of the development of allergy was having sIgE for milk <3 kUA/L or passing an OFC. Despite important heterogeneity among the studies (CMA diagnosis, study population, clinical features of CMA), it seems that more recent studies have shown less optimistic results, with lower rates of resolution.
It is accepted that 87% of children outgrow CMA by age of 3 [85], but the percentage of patients with persistent allergy has increased, although it was found to vary among publications. This may suggest that the natural history of CMA is changing over time.
Understanding these overall trends and the reasons for the variation has important implications for management and treatment.
8. Factors Associated with the Natural History
Many factors have been associated with the natural history of FA with respect to both the development of tolerance and its persistence. Most of these markers have been studied for CMA.
Early identification of patients in which CMA is likely to persist will provide the clinician with useful insights about when and how to start CM reintroduction [22].
As a general rule, non-IgE-mediated allergy resolves more rapidly than IgE-mediated [85].
First of all, it is known that persistent allergy has been connected with more severe clinical features at presentation. Secondly, persistent FA has been linked with an earlier age at diagnosis [83], the presence of other atopic diseases and their severity (allergic rhinitis, asthma, eczema) [49], the presence of other FAs (most commonly egg allergy [49,59]), and a lower threshold dose to trigger a reaction [7]. In addition, reactivity to baked milk (BM) on first exposure is also associated with the persistence of CMA [90].
The natural history of FA varies substantially, and it is known that the variation of food-sIgE or SPT wheal size in time can predict the probability of resolution and the development of tolerance [48]. Generally speaking, larger wheal size on SPT or higher sIgE levels are associated with persistence of FA [89,91]. These associations are consistent with findings from Kim et al. showing that higher sIgE levels at first reaction were the most significant predictors of persistent CMA [92].
Moreover, a strong relation between the food allergen and the persistence of FA has been demonstrated. Some FAs, such as those to milk and egg, have a high likelihood of resolution, whereas sufferers of other allergies such as those to peanut and tree nuts have lower probability of developing tolerance. To sum up, when approaching FA, the clinician should take into account the type of allergen involved, together with SPT results and sIgE levels. Yearly follow-up with repetition of sIgE should be advisable until complete stabilization, as this has a higher prognostic value in predicting tolerance acquisition and the likelihood of passing an OFC [7,93].
The Role of Baked Milk
The baking process alters protein epitopes which are no longer recognizable by the epitope-specific IgE, leading to decreased allergenicity [1].
Regarding CM, whey proteins such as α-lactalbumin and β-lactoglobulin include conformational epitopes that are heat-labile, whereas casein contains mostly heat-resistant epitopes [94].
As a consequence, BM-driven reactions are indicative of more persistent CMA.
To date, only few papers have compared the development of tolerance to BM as compared to fresh milk, although many retrospective studies have supposed a quicker CMA resolution upon regular ingestion of BM [95].
In a recent study conducted in infants under the age of 2 years, Uncuoglu et al. found that 81% of children with IgE-mediated CMA were baked-milk tolerant [96].
Nowak-Wegrzyn et al., in their study based on 100 children with documented CMA, showed that 75% tolerated BM and were able to include BM products into their diet. After 3 months of BM ingestion, children had significantly smaller SPT wheals as compared to baseline [97].
Kim et al. [92] reported that tolerance to BM products was an advantageous prognostic factor for the development of tolerance to unheated milk. Moreover, the ingestion of BM products seemed to considerably accelerate the development of tolerance as opposed to a strict avoidance diet.
A controlled randomized clinical trial by Esmaeilzadeh et al. further confirmed that regular assumption of BM products accelerated the tolerance to fresh milk [98].
In conclusion, tolerance to BM usually precedes tolerance to fresh milk and represents a reliable predictor for the less severe and persistent CMA phenotype [94].
9. Treatment and Oral Immunotherapy
Since the 1930s, scientific literature on CMA has continuously increased. In recent decades, new diagnostic methods and therapies have been developed [99].
From the beginning, the cornerstone of treatment was represented by an elimination diet with strict avoidance of the offending food and its substitution, when possible, with hydrolyzed formulas [100]. However, despite rigid adherence to diet, CM can be inadvertently ingested through processed foods.
In support of this statement, Alonso et al. followed 80 patients with CMA [101] until the achievement of tolerance or up to the age of 18 years (in the case of other allergic diseases), finding accidental ingestion of milk in at least a third of them [102]. This can lead to a feeling of insecurity in children and their parents, significantly worsening their QoL [103].
Given that the avoidance diet as the preferred approach towards CMA has demonstrated limited efficacy, finding a new targeted therapy is pivotal. In response to this need, a novel treatment known as oral immunotherapy (OIT) has emerged through the last decade, changing the history of CMA and FA in general.
Oral tolerance induction testing was first attempted in laboratory animals in 1909 by Besredka, who demonstrated that oral or rectal administration of CM could protect from clinical manifestations such as anaphylaxis [104].
Before this new treatment, patients had to strictly avoid the food allergen, with the consequent reduction in QoL as well as nutritional, social, and psychologic impairment [105].
Nowadays, OIT is the most promising approach for the management of FA [106]. It consists of repeated administration of increasing amounts of the food allergen until reaching a target dose, in order to provide protection against the clinical features and inflammation [107]. Once the target is achieved, the patient must maintain a regular intake of the allergen to preserve the state of desensitization [108]. In fact, “desensitization” refers to a reversible state in which patients can eat higher doses of the food allergen without symptoms as compared with pre-treatment doses [109]. On the other hand, “tolerance” is the ability to introduce the allergen without any adverse reaction once therapy is completed.
Thus, the aim of OIT is to introduce allergenic food into the normal diet, or, in high-risk patients, to prevent life-threatening conditions after inadvertent ingestion [107]. In those patients, OIT is given at a lower dose in order to avoid severe reactions after accidental exposure [107].
OIT is potentially indicated for children with evidence of IgE-mediated CMA and in whom avoidance diet is ineffective, undesirable, or decreases QoL [110]. According to EAACI Guidelines [110], OIT is recommended for persistent CMA for children from around 4 to 5 years of age in order to increase the threshold for clinical manifestations of allergy. Restricting OIT in this age group can be explained by the fact that achievement of tolerance occurs before school age.
OIT has an immunological role in the modulation of humoral and cellular immunity. In particular, humoral changes such as a decrease in IgE levels and a rise in IgG levels, mainly IgG4, have been described. IgG4 could have an antigen-neutralizing effect and decrease basophil and mast cell activation, with the suppression of IgE production [107]. Moreover, OIT drives a reduction in Th2 cell line and Th2 cytokine expression [95].
OIT can be divided into two different phases. The first is the so-called “induction phase” or “dose escalation phase” where the main target is to achieve the tolerated dose [111]. It starts with a small dose, usually in micrograms of allergenic proteins which do not cause a reaction, and continues until the achievement of a target dose or until symptoms preclude further increments [112]. The allergen dose is augmented once or twice a week until reaching a maintenance dose. There are many protocols differing in the amounts of time required: from flash protocols (one week) to slow protocols (>6 months) [107].
Furthermore, the initial dose needs to be adapted to the patient following a personalized medicine approach. For example, low doses should be used in high-risk patients, while a more rapid introduction of the allergenic food could be performed in low-risk patients [113].
The second phase is a “maintenance phase” characterized by repeated intake of maximum tolerated doses of CM [114].
Whether the induced tolerance by OIT is permanent or transient, the long-term effects are still unclear. In agreement with the most recent available studies, not all the children subjected to OIT are able to introduce normal amounts of CM in their diet. Thus, OIT substantially increases the threshold dose necessary to elicit clinical manifestations, resulting in clinical tolerance in a large number of patients [115]. Permanent oral tolerance is reasonably achievable only in a part of the treated patients [116].
Table 5 summarizes the data from various studies on the efficacy of OIT milk.
Table 5
Efficacy of milk OIT.
Author, YearType of StudyType of MilkPopulation (n)Age (years)Partial ToleranceComplete Tolerance
Meglio P. et al., 2004 [117] | Open-label | Fresh CM | 21 | 6–10 | 14.3% (40–80 mL of CM) | 71.4% (200 mL of CM) |
Narisety SD. et al., 2009 [118] | Open | Fresh CM | 15 | 6–16 | 33% (16 g of CM proteins) | |
Goldberg M. et al., 2015 [119] | Open | Baked CM | 14 | 6.5–12.7 | 21% (1.3 g of CM proteins) | |
Takahashi M. et al. 2016 [120] | Open | Microwave heated CM | 31 | 5–17 | 45.2% (200 mL of CM) | |
Ebrahimi M. et al.2017 [121] | Open | Fresh CM | 14 | 3.5–7 | 92.9% (200 to 250 mL of CM) | |
Skripak et al., 2008 [122] | Randomized, double-blind, placebo-controlled | Fresh CM | 13 | 6–17 | 30.8% (500 mg of CM proteins) | |
Longo G. et al., 2008 [123] | Randomized open-label | Fresh CM | 30 | 5–17 | 54% (5–150 mL of CM) | 36% (> 150 mL of CM) |
Pajno GB. et al., 2010 [124] | Randomized, placebo controlled | Fresh CM | 15 | 4–10 | 67% (200 mL ofCM) | |
Martorell A. et al., 2011 [125] | Randomized, placebo controlled | Fresh CM | 30 | 2–3 | 90% (200 mL of CM) | |
Amat F. et al.2017 [126] | Randomized | Baked CMFresh CM | 43 | 3–10 | 26.8% (0.27–2.5 g of CM proteins) | 36.6% (2.72 g of CM proteins) |
Maeda M, et al., 2020 [127] | Randomized controlled | Fresh CM | 28 | 3–12 | 50% (100 mL of CM) | |
Mota I. et al., 2018 [128] | Prospective | Fresh CM | 42 | 2–18 | 92% (200 mL of CM) | |
Berti I. et al., 2019 [129] | Prospective | Fresh CM | 73 | 3–11 | 97% (150 mL of CM) | |
De Schryver S. et al., 2019 [130] | Prospective, randomized-controlled | Fresh CM | 41 | 6–18 | 73.2% (200 mL of CM) | |
Efron A. et al.,2018 [131] | Retrospective, case-control | Fresh CM | 43 | 1–4 | 86% (250 mL of CM) | |
Kauppila T.K. et al., 2019 [132] | Retrospective | Fresh CM | 296 | 5–17 | 56% (200 mL of CM) | |
Demir E. et al., 2020 [133] | Retrospective, cohort study | Fresh CM | 47 | 3–13 | 89.3% (200 mL of CM) | |
Gruzelle V. et al., 2020 [134] | Retrospective | Baked CM | 64 | 2–16 | 42.2% (254 mL of CM) |
To date, only few randomized studies have compared the efficacy of immunotherapy to elimination diet, underlining the need for further research with more homogeneous and wider populations.
In this regard, Staden et al. [112] described a population of 47 children with DBPCFC-confirmed CMA, randomly assigned either to OIT or elimination diet. The patients were clinically evaluated at baseline and after a period of 21 months, with repetition of an OFC to assess the persistence of tolerance. At the follow-up OFC, 36% and 35% of the patients in the OIT group and in the control group, respectively, achieved complete tolerance. Although similar results were observed, if we include children who achieved partial tolerance (patients who needed a regular intake of the allergen to maintain tolerance), the efficacy rate of OIT increased to 64% [112]. OIT resulted superior to the elimination diet, with an increased threshold dose for allergic reactions and a reduced burden of severe reactions following accidental ingestion of CM. In a randomized study by Morisset et al. [135], 60 infants with CMA were randomized into an OIT group and a control group treated with elimination diet group. OIT was proposed for those who did not react to the OFC (60 mL of milk). In this study, the rate of spontaneous recovery after 6 months in the control group (60%) resulted considerably lower as compared with that of the OIT group (88.9%). In addition, patients treated with OIT showed lower reactivity in terms of SPT size and lower sIgE levels [135], in accordance with the results of other studies [136].
A recent review with a meta-analysis on OIT in CMA by Martorell Calatayud et al. reported that rates of desensitization after OIT ranged from 36% to 77%, with an estimated tolerance close to 30% [28]. They concluded that this new strategy was an effective and reasonably safe alternative to the avoidance diet. Moreover, their study showed that significantly more patients achieved tolerance with OIT than with the elimination diet [28].
Although many studies highlighted the benefits of OIT, there is still a lack of well-conducted studies concerning the risk of side effects of this novel therapeutic approach.
Since several studies have reported side effect rates of 50–60% [117,136], increasing with exercise and the pollen season, continuous medical supervision during OIT is still mandatory. During OIT mild, localized, and self-limiting side effects usually occur, including oral itching and rhino-conjunctivitis. Symptoms that can lead to the discontinuation of OIT occur in just a small percentage of cases, and include abdominal pain (the most common), wheezing, laryngeal spasms, vomiting, and urticaria [137]. In fact, OIT is usually associated with a modest increase in risks of systemic side effects and a substantial increase in minor local adverse reaction [138]. Among various studies, anaphylactic reactions and the resulting intramuscular administration of epinephrine have been reported in 6.7% to 30.8% of all patients subjected to OIT [28].
The risk–benefit ratio of OIT is still debated. While the efficacy of this approach has been well studied, the evaluation of an effective improvement in the QoL of the patient remains limited to small or uncontrolled studies [139]. In fact, only few studies evaluate children’s perceptions of improved of their QoL as compared to perceptions by parents. A recent paper [139] described how OIT could improve the QoL of (both partially and totally desensitized) food-allergic children and their parents, through the Food Allergy Quality of Life Questionnaire—Child Form (FAQLQ-CF) and the FAQLQ—Parent Form (FAQLQ-PF), respectively. These results were concordant with those of Carraro et al., who gave the same questionnaire to parents of patients with CMA and found a substantial increase in all the investigated areas of QoL (emotional impact, food anxiety, and social and dietary limitations) in children with CMA [140].
Conversely, in 2021 Kauppila et al. reported that the Health-Related Quality of Life (HRQoL) among OIT patients did not differ significantly from that of the age- and gender-standardized general population [141].
In conclusion, OIT is an effective strategy for treating CMA which needs to be performed under the cautious supervision of an experienced specialist. The children who can obtain the greatest benefit from this therapy are those with high sIgE levels and high risk of life-threatening conditions such as anaphylaxis. For these patients, OIT should be considered as a possibility to avoid severe reactions and improve quality of life. However, OIT should be considered as an individualized treatment, and each step needs to be adapted to the specific patient [107].
10. Conclusions
CMA represents a model of FAs, since it is the most common and most studied FA in early life. For this reason, clearly understanding its epidemiology, diagnostic criteria, and appropriate treatment can guide the clinician and provide useful insights to better comprehend all other allergies. Ensuring proper diagnosis and prognosis and identifying the possibility of allergy resolution are therefore key components of management.
Thus far there are still no shared tolerance markers for the diagnosis of CMA and FAs in general. Although the negative predictive value of SPT and sIgE is excellent, the OFC, particularly DBPCFC, remains the gold standard for diagnosis. The heterogeneity of diagnostic tools used in literature further limits a reliable estimate of CMA epidemiology and consequentially of its natural history. Appropriately diagnosing CMA is therefore pivotal in understanding its natural history and avoiding unnecessary strict diets that may lead to nutritional deficiencies. In fact, milk is the most important element in children’s diets, providing the necessary intake of fats, proteins, calcium, phosphorus, and vitamin B12. Furthermore, the elimination diet is known to be possibly linked to an increased risk of severe reaction after the inadvertent ingestion of the allergen.
In the last decade there have been many changes in the approach to CMA, which has become proactive. OIT can indeed lead to a change in the natural history of this disease, accelerating tolerance acquisition and the likelihood of passing an OFC.
Therefore, further larger, well-designed, randomized, placebo-controlled trials are necessary to find new diagnosis, prevention, and treatment strategies.
Author Contributions
Conceptualization: A.G., G.T.V. and G.R.; Resources: A.G., G.T.V., A.M. and E.d.P.; Methodology: A.G., G.R. and A.P.; Writing—Original Draft Preparation: A.G., G.T.V., A.M., and E.d.P.; Writing—Review and Editing: A.G., G.T.V., G.R., and A.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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