Efficacy and safety of hydrolyzed rice-protein formulas for the treatment of cow's milk protein allergy

Foods for special medical purposes (FSMPs) with a protein fraction made of hydrolyzed rice protein (HRPs) have been on the market in Europe since the 2000s for the treatment of cow's milk protein allergy (CMPA). HRP formulas (HRPFs) are proposed as a plant-based alternative to cow's milk protein-based extensively hydrolyzed formulas (CMP-eHF) beside the soy protein formulas whose use in CMPA is controversial. HRPFs do not contain phytoestrogens and are derived from non-genetically modified rice. HRPFs are strictly plant-based apart from the addition of vitamin D₃ (cholecalciferol). As the amino acid content of rice proteins differs from that of human milk proteins, the protein quality of these formulas is improved by supplementation with free lysine, threonine, and tryptophan. The consumption of HRPFs has risen: for example, in France HRPFs account for 4.9% in volume of all formulas for children aged 0–3 years. Several studies have shown the adequacy of HRPFs in treating CMPA. They ensure satisfactory growth from the 1st weeks of life for infants and toddlers, both in healthy children and in those with CMPA. HRPFs can be used to treat children with CMPA either straightaway or in second intention in cases of poor tolerance to CMP-eHF for organoleptic reasons or for lack of efficacy. In France, the cost of HRPFs is close to that of regular infant or follow-on formulas.     

婴儿牛奶蛋白过敏的危险因素：多中心调查分析

目的 通过多中心临床研究了解婴儿牛奶蛋白过敏（CMPA）发生的危险因素。方法 以2016年6月至2017年5月于深圳市6家医院儿科门诊就诊的1 829例1~12月龄婴儿为调查对象,通过问卷调查,筛选CMPA可疑病例,然后进行食物回避激发试验以确诊CMPA。采用多因素logistic回归分析调查婴儿CMPA发生的危险因素。结果 1 829例患儿中,82例确诊为CMPA（4.48%）。多因素logistic回归分析显示,母亲食物过敏（OR=4.91,95% CI：2.24~10.76）、母亲孕期使用抗生素（OR=3.18,95% CI：1.32~7.65）、开始添加辅食月龄小于 < 4个月（OR=3.55,95% CI：1.52~8.27）是CMPA的独立危险因素（P < 0.05）,而纯母乳喂养（OR=0.21,95% CI：0.08~0.58）和 > 6个月添加辅食（OR=0.38,95% CI：0.17~0.86）是CMPA的保护因素（P < 0.05）。结论 小于4月龄添加辅食、母亲食物过敏、母孕期使用抗生素是婴儿CMPA发生的危险因素。     

Family history of atopy in infants with cow's milk protein allergy: A French population-based study

ObjectivesThis French multicenter, cross-sectional, observational study aimed to describe the family history of atopy in infants with cow's milk protein allergy (CMPA), and the related diagnostic approaches used by specialists in a real-life ambulatory setting.Patients and methodsIn total, 1674 infants with suspected CMPA [median age 4.5 months (range: 0.1–18.0), males 54%] were enrolled in the study by 466 private physicians (pediatricians: 97%). Family history of atopy was defined as a known history of atopy in at least one first- (father, mother, and/or sibling) and/or second-degree relative (grandparents, uncles, and aunts), as reported by parents to physicians.ResultsAtopy in a first-degree relative was more common among infants with documented or high probability of CMPA (in 84% and 80% of cases, respectively, vs. the other subgroups, P = 0.005). Most infants experienced digestive (92%) and skin (61%) symptoms suggestive of CMPA. Delayed reactions were reported in 64% of infants. According to a post-classification based on the results of previous diagnostic tests and procedures, 1133 infants (68%) had highly probable (52%) or documented CMPA (16%). In these infants, a history of atopy was reported in first- and/or second-degree relative(s) in 86% of cases (81% in first-degree relatives). Whatever the family history of atopy, the characteristics of the infants were similar, except for fewer pets in the case of negative family atopy (14% vs. 25%, P < 0.001). Atopy in a parent was more frequent in infants who presented with the first signs suggestive of CMPA within the first 6 months of life vs. those with later first symptoms (75% vs. 65%, P = 0.063).ConclusionThis French study confirms the high rate of family history of atopy in first-degree relatives of infants with probable or documented CMPA.     

Cow's milk allergy: color Doppler ultrasound findings in infants with hematochezia

Objectiveultrasound (US) has been an important diagnostic tool to identify several causes of gastrointestinal bleeding. Infants with cow's milk allergy (CMA) may present hematochezia and the confirmation of the diagnosis can be difficult. The aim of this study is to describe grayscale and color Doppler ultrasound findings in patients with CMA.Methodswe retrospectively studied 13 infants with CMA. All infants presented severe hematochezia and abdominal pain. All underwent an US study with the diagnosis of allergic colitis. This diagnosis was based on clinical findings, recovery after infant or mother exclusion diets in the case of exclusive breastfeeding and positive oral challenge test.Resultsthe mean age ranged from 1 to 6 months (mean = 3.53). Seven out of 13 infants (53.8%) had grayscale and color Doppler sonographic repeated after exclusion diet. Twelve out of 13 (92,3%) showed abnormalities at US and CDUS at beginning. The positive findings suggesting colitis were thickened bowel walls and increased vascularity, especially in the descending and sigmoid colon. Colonoscopy and histopathological findings were compatible with allergic colitis. After a diet change the 13 infants recovered and their oral challenge tests were positive.ConclusionDoppler US may be very useful in diagnosing secondary colitis, such as CMA, and to exclude several other abdominal diseases that can emulate this disease.     

广西地区小婴儿牛奶蛋白过敏的临床特征与相关因素分析

目的：探讨广西地区≤3月龄婴儿牛奶蛋白过敏(cow＇s milk protein allergy,CMPA)的临床症状与相关因素,提高 CMPA 的诊断与防治水平。方法纳入2012年7月1日至2014年12月30日,广西壮族自治区妇幼保健院儿科门诊首诊及外周医院转诊疑似 CMPA 的就诊患儿,设计观察量表,由中、高级儿科医生分选并确诊病例,门诊及电话随访,完成资料收集。结果共纳入137例患儿,过敏组51例,对照组(排除病例)86例,过敏组与对照组共有的症状包括腹泻、便秘、血便、腹痛、胃食管反流(gastroesophageal reflux,GER)、消化不良、厌食拒食、喂养困难等。过敏组与对照组喂养方式(即母乳喂养、混合喂养、人工喂养)、不当添加辅食、新生儿期间长期使用抗生素、父母过敏体质等11项指标差异无统计学意义(P ﹥0.05)。两组间就诊时有胃食管反流[20例(39.2%)vs.7例(8.1%)]、新生儿期间接触牛奶成分配方奶[51例(100%)vs.71例(82.6%)]、喂养不耐受(含 GER)[17例(33.3%)vs.11例(12.8%)]、肠道感染[8例(15.7%)vs.4例(4.7%)]、输血及使用血制品[12例(23.5%)vs.11例(12.8%)]5项指标差异有统计学意义(χ2＝19.538、P ＝0.000,χ2＝9.989、P ＝0.002,χ2＝8.308、P ＝0.004,χ2＝4.691、P ＝0.030,χ2＝5.198、P ＝0.023)。结论≤3月龄婴儿 CMPA 以腹泻、血便、GER 等消化系统症状为主要表现,新生儿时期接触牛奶成分配方奶具有重要触发作用。     

血清IgE测定对牛奶过敏婴儿的临床意义

目的 探讨牛奶蛋白特异性IgE(sIgE)对牛奶蛋白过敏症(CMPA)患儿的临床意义。方法 依据sIgE 检测结果将96 例CMPA 患儿分为IgE⁺ 组(n=26)与IgE^- 组(n=70), 对比分析两组患儿的临床特点;予食物回避和使用深度水解蛋白粉或氨基酸粉干预16 周后, 比较两组患儿的干预效果。结果 CMPA 患儿血清IgE 阳性率为27%。IgE⁺ 组的首次发病年龄低于IgE^- 组(P<0.05);过敏性家族史和呼吸道症状发生率高于IgE^- 组(P<0.05);重度CMPA、消化道症状、体重低下、生长迟缓、贫血和低蛋白血症发生率低于IgE^- 组(P<0.05)。IgE⁺ 组患儿主要临床症状表现为红斑、荨麻疹、呕吐、流涕、咳嗽、喘息和阵发性哭闹, 发生率高于IgE^- 组(P<0.05);IgE^- 组患儿主要临床症状表现为湿疹、便秘和腹泻, 发生率高于IgE⁺ 组(P<0.05)。干预16 周后, 两组间各临床症状缓解率均在80％以上, 且两组间各临床症状缓解率比较差异均无统计学意义(P>0.05)。结论 CMPA患儿血清IgE 阳性率不高。IgE^- 组临床症状更不典型, 多为非过敏性临床表现。早期食物回避和使用深度水解蛋白粉或氨基酸粉干预对IgE⁺ 和IgE^- 患儿均能获益。     

Accuracy of serum IgE concentrations and papule diameter in the diagnosis of cow's milk allergy

Objective

To compare serum concentrations of specific IgE and mean papule diameters induced in the immediate skin reactivity test with cow's milk and its fractions with results of the oral challenge test, and to establish cutoff points capable of predicting clinical reactivity to cow's milk in patients treated at a referral service.

不同孕期母亲免疫水平对婴儿牛奶蛋白过敏的影响

目的 探讨不同孕期母亲Th1/Th2免疫水平与婴儿牛奶蛋白过敏（CMPA）之间的关联。方法 选取2016年7月至2018年12月于山东省潍坊市益都中心医院及青州市中医院就诊的单胎健康孕妇及其子代为研究对象。检测母亲孕中期、孕后期的白细胞介素（IL）-2、干扰素-γ（IFN-γ）、IL-4和IL-10水平,并分别于出生后1年内进行CMPA问卷调查,对临床怀疑CMPA的婴儿进行食物回避及牛奶口服激发试验,将符合CMPA的48例婴儿纳入CMPA组,其余977例正常婴儿纳入对照组。对CMPA婴儿进行单因素分析,并采用泊松回归分析不同孕期母亲各Th1/Th2型细胞因子水平与CMPA之间的关联。结果 CMPA的检出率为4.68%,临床表现包括消化系统症状、皮肤表现、呼吸系统症状及其他表现。单因素分析结果显示,CMPA组母亲食物过敏、母亲过敏性疾病史的发生率均明显高于对照组（P < 0.05）,母乳喂养率明显低于对照组（P < 0.05）。CMPA组的母亲IL-2（孕中期和孕后期）、IFN-γ（孕后期）较对照组明显降低（P < 0.05）。母亲孕后期低IFN-γ及孕中期、孕后期低IL-2与婴儿CMPA存在显著关联（P < 0.05）;校正母乳喂养、母亲食物过敏及母亲过敏性疾病史等因子后发现,母亲孕后期低IL-2、低IFN-γ与婴儿CMPA仍存在显著关联（P < 0.05）。结论 孕后期母体的Th1型细胞因子水平下降,可能会导致胎儿的免疫改变,从而增加其子代出生后罹患CMPA的风险。     

FokI rs2228570和TMPRSS6 rs855791多态性与儿童牛奶蛋白过敏的相关性

目的 探讨维生素D受体（VDR）基因FokI rs2228570及TMPRSS6 rs855791基因多态性与儿童牛奶蛋白过敏（CMPA）的关系。方法 应用实时荧光定量PCR检测100例CMPA儿童及100例健康儿童（对照组） VDR基因FokI rs2228570和TMPRSS6 rs855791单核苷酸多态性。使用多因素logistic回归模型评估CMPA发生的危险因素。结果 CMPA组与对照组TMPRSS6 rs855791基因型CC、CT、TT分布频率差异有统计学意义（P=0.008）,CMPA组的TT基因型占优势。多因素logistic回归分析提示rs855791 TT基因型的儿童发生CMPA的风险增加（OR=3.473,P=0.011）。而VDR基因FokI rs2228570基因型分布在两组儿童间的差异无统计学意义（P=0.686）。结论 TMPRSS6 rs855791多态性与儿童CMPA的发生有关联,TT基因型可能为儿童CMPA的易感基因型,而VDR基因FokI rs2228570多态性与儿童CMPA无关联。     

Serum immunoglobulin E,IgA, and IgG antibodies to different cow's milk proteins in children with cow's milk allergy: Association with prognosis and clinical manifestations

Diverse pathogenic mechanisms elicit different clinical manifestations in cow's milk allergy (CMA). Our aim was to determine the concentration of serum immunoglobulin levels to different cow's milk proteins in patients with CMA and to determine how these values were related to clinical symptoms and prognosis. Fifty children (mean age 10.9 months, range: 1–34 months) with previously confirmed CMA were enrolled in this study. All had various clinical manifestations of CMA, including gastrointestinal, skin, and respiratory symptoms. At the diagnosis of CMA the serum total and the milk‐specific immunoglobulin (Ig)E values were measured by enzyme immunoassay and fluoroimmunoassay, respectively, while the relative levels of serum IgA and IgG antibodies against different cow's milk proteins were determined by a sensitive enzyme‐linked immunosorbent assay (ELISA). The results were compared to those of 30 non‐atopic age‐matched control children. On average, after 9.2 months (range 2–31 months) on a milk‐free diet, a repeated challenge was performed in 38 children. At the re‐challenge, 12 patients had clinical symptoms while the remaining 26 children were symptom‐free. The IgG antibody level to bovine serum albumin (BSA) was significantly lower in the patients than in the controls (median: 0.36 vs. 2.94, p < 0.01). There was a close correlation among all individual IgA and IgG antibodies to different cow's milk proteins. The anti‐α‐casein IgG level (of 2.10) in children with a positive reaction at the re‐challenge was significantly higher than in those with a negative reaction (0.89) (p < 0.05). The total IgE serum concentration was also significantly higher in those who had symptoms at the re‐challenge compared to those who did not have any reaction at this time (22.9 vs. 6.8 kU/l, geometric mean, p < 0.02). There was no association between the clinical manifestations and the IgG and IgA antibody levels to the cow's milk proteins studied, except for the anti‐BSA IgA level, which was higher in patients with gastrointestinal symptoms. The serum total IgE and anti‐α‐casein IgG levels could have prognostic values; their increase at the beginning of the disease may indicate the development of tolerance to cow's milk only at a later age and after a longer duration of CMA. However, as there is considerable overlap among the values observed in different groups of patients, there is a limitation of these tests for predicting the prognosis.     

婴幼儿牛奶蛋白过敏对罗马Ⅳ标准功能性胃肠病诊断的影响

目的 探讨婴幼儿牛奶蛋白过敏（CMPA）对罗马Ⅳ标准功能性胃肠病（FGID）诊断的影响。方法 选取84例1月龄至3岁的CMPA患儿作为病例组,84例健康体检确诊无CMPA的婴幼儿作为对照组。由儿科消化专科医生使用罗马Ⅳ标准FGID诊断问卷询问两组婴幼儿的父母,评估临床症状,进行FGID诊断。结果 病例组家族过敏史发生率明显高于对照组（P < 0.05）。84例病例组中,38例（45%）符合罗马Ⅳ版诊断FGID的标准;而84例对照组中,13例（15%）符合罗马Ⅳ版诊断FGID的标准（P < 0.05）。根据FGID罗马Ⅳ标准,婴儿反流、功能性腹泻、婴儿排便困难、功能性便秘等胃肠病,病例组的诊断率均高于对照组（P < 0.05）。对对照组中诊断为FGID的患儿进行FGID常规治疗,病例组中诊断为FGID的患儿除常规治疗外,进行了牛奶蛋白回避治疗。治疗3个月后,病例组的症状缓解率显著高于对照组（P < 0.05）。结论 在婴幼儿中,CMPA对罗马Ⅳ标准FGID的诊断有重要影响,诊断FGID时应该考虑CMPA的可能。