Development of a low allergenic product for patients with milk allergy and assessment of its specific IgE reactivity.

BACKGROUND: Milk oral immunotherapy is the riskiest and most unpredictable form of oral immunotherapy. We aimed to produce a low allergenic product than conventional once baked-cake/muffin, to develop indirect in-house ELISA to check the tolerance status with milk products and evaluate IgE reactivity of patients' sera via western blotting (WB) and indirect in-house ELISA. METHOD: A low allergenic product named biscotti-twice baked-cake was developed, and the total protein concentration was determined. The protein content was studied by SDS-PAGE and proteomics. Milk-specific IgE (sIgE) binding assays were performed by WB and indirect in-house ELISA by using patients' sera. RESULTS: Casein band intensity was observed to be lower in the biscotti-twice baked-cake than in the once baked-cake (p = .014). Proteomics analysis and αS1-casein measurement showed that the lowest intensity of casein was found in biscotti. The low binding capacity of milk sIgE to biscotti compared with once baked-cake was shown by WB (p = .0012) and by indirect in-house ELISA (p = .0001). In the ROC analysis, the area under the curve (AUC) of the in-house ELISA IgE was comparable with Uni-CAP milk and casein sIgE. The AUC of the in-house ELISA IgE for cake (0.96) and biscotti (1) was slightly better than Uni-CAP milk sIgE (0.94; 0.97) and casein sIgE (0.96; 0.97), respectively. CONCLUSION: The low allergenicity of the newly developed low allergenic product "biscotti-twice baked-cake" has been demonstrated by in vitro experiments. Biscotti could be a safe treatment option than once baked-cake/muffin in patients who are reactive to once baked-milk products.

Out-of-pocket expenses and parent reported quality of life in children with cow's milk protein allergy in Bogotá, Colombia.

OBJECTIVE: To identify the out-of-pocket expenses and parent-reported quality of life (QoL) of children with a diagnosis of cow's milk protein allergy between the ages of 0 and 5 using the Food Allergy Quality of Life Questionnaire - Parent Form. METHODS: A cross-sectional study was conducted in two tertiary care centers in Bogotá. Demographic, medical information, and QoL scores were collected by parental interview. We carried out a cost-of-illness analysis based on self-reported out-of-pocket expenses attributed to the treatment as a whole and the family's monthly income. Exploratory analyses used the QoL scores and the percentage of out-of-pocket expenses attributable to treatment as outcomes. RESULTS: 122 families were analyzed. Median subject age was 17 months (Q1-Q3: 11-26.75 months) and female subjects made up 71% of the sample. The median QoL score was 3.21 points (Q1-Q3: 2.43-4.34) and only differed by age groups and personal history of other food allergies. The median out-of-pocket treatment related costs was 300,000 Colombian pesos (COP) (Q1-Q3: 280,000-340,000 COP). About 17% of the families had to pay over 15% of their monthly income to purchase food and dietary products. Out-of-pocket treatment related costs differed depending on whether the treatment included formulas (Mann-Whitney test p < 0.001). Out-of-pocket treatment expenses were uncorrelated with the QoL scores. CONCLUSION: Food allergy related QoL scores were not associated with out-of-pocket expenses as a whole or as a fraction of monthly income but were higher in children with additional food allergies and in older age groups, suggesting a lower QoL.

Assessment of infant outgrowth of cow's milk allergy in relation to the faecal microbiome and metaproteome.

Previous studies provide evidence for an association between modifications of the gut microbiota in early life and the development of food allergies. We studied the faecal microbiota composition (16S rRNA gene amplicon sequencing) and faecal microbiome functionality (metaproteomics) in a cohort of 40 infants diagnosed with cow's milk allergy (CMA) when entering the study. Some of the infants showed outgrowth of CMA after 12 months, while others did not. Faecal microbiota composition of infants was analysed directly after CMA diagnosis (baseline) as well as 6 and 12 months after entering the study. The aim was to gain insight on gut microbiome parameters in relation to outgrowth of CMA. The results of this study show that microbiome differences related to outgrowth of CMA can be mainly identified at the taxonomic level of the 16S rRNA gene, and to a lesser extent at the protein-based microbial taxonomy and functional protein level. At the 16S rRNA gene level outgrowth of CMA is characterized by lower relative abundance of Lachnospiraceae at baseline and lower Bacteroidaceae at visit 12 months.

Longitudinal assessment of early growth in children with IgE- and non-IgE-mediated food allergy in a healthy infant cohort.

BACKGROUND: There are conflicting associations reported between food allergies (FAs) and poor growth, with some indication that children with multiple FAs are at highest risk. OBJECTIVE: We analyzed longitudinal weight-for-length (WFL) trajectories from our healthy cohort to evaluate growth in children with IgE-mediated FAs and food protein-induced allergic proctocolitis (FPIAP), a non-IgE-mediated FA. METHODS: Our observational cohort of 903 healthy newborn infants was prospectively enrolled to evaluate the development of FAs. Longitudinal mixed effects modeling was used to compare differences in WFL among children with IgE-FA and FPIAP, compared with unaffected children, through age 2. RESULTS: Among the 804 participants who met inclusion criteria, FPIAP cases had significantly lower WFL than unaffected controls during active disease, which resolved by 1 year of age. In contrast, children with IgE-FA had significantly lower WFL than unaffected controls after 1 year. We also found that children with IgE-FA to cow's milk had significantly lower WFL over the first 2 years of age. Children with multiple IgE-FAs had markedly lower WFL over the first 2 years of age. CONCLUSION: Children with FPIAP have impaired growth during active disease in the first year of age which resolves, whereas children with IgE-FA, particularly those with multiple IgE-FA, have impaired growth more prominently after the first year of age. It may be appropriate to focus nutritional assessment and interventions accordingly during these higher risk periods in these patient populations.

Pilot Study of the Applicability, Usability, and Accuracy of the Nutricate© Online Application, a New Dietary Intake Assessment Tool for Managing Infant Cow's Milk Allergy.

BACKGROUND/OBJECTIVES: The mainstay treatment of cow's milk allergy (CMA) is to remove cow's milk proteins from children's dietary intake. In this context, dietary intake of children with CMA should be particularly checked and monitored. The objective of this study was to assess the applicability, usability, and accuracy of a new dietary intake (DI) assessment online tool (Nutricate© online application) for managing CMA in children. SUBJECTS/METHODS: This study used a pre-existing database of DI from the Nutricate© online application. DIs from 30 CMA children were used to compare micro/macronutrients (energy, protein, calcium, and iron intakes) calculated by Nutricate© and NutriLog© as the reference method. Comparisons were performed using the Pearson correlation analysis and the Bland-Altman plot. The Nutricate© tool usability was assessed via a System Usability Scale questionnaire (SUSq). RESULTS: Correlation coefficient between the levels of micro/macronutrients obtained by Nutrilog© and Nutricate© software were highly significant (p = 0.0001) and were well-correlated (R coefficient > 0.6), indicating a very good concordance between the two methods. This observation was reinforced by the Bland-Altman plot, indicating the absence of proportional or fixed bias for energy, protein, calcium, and iron intakes. The mean SUSq score obtained was 81 ± 14, which is considered to be an excellent score. CONCLUSIONS: Nutricate© online application is a reliable method to assess micro/macronutrient (energy, protein, calcium, and iron intakes) intake in CMA children. Applicability and usability of this new dietary intake assessment online tool is excellent.

Assessment of intracellular zinc levels in infants with food protein-induced allergic proctocolitis.

BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is characterized by bloody stools in well-appearing infants. Zinc is a micronutrient that plays a crucial role in immune modulation and is essential for cellular function during immune response. Although there are studies on the assessment of intracellular zinc levels in allergic diseases, no data is available on erythrocyte zinc levels of patients with FPIAP. OBJECTIVE: This study aimed to assess the erythrocyte zinc levels of children with allergic proctocolitis and compare zinc levels with clinical and demographic characteristics. METHODS: This was a case-control study that prospectively compared 50 patients with FPIAP and 50 healthy children without malnutrition. The erythrocyte zinc levels of children were determined using atomic absorption spectrophotometry. RESULTS: Fifty patients with FPIAP, including 28 (51%) girls, with median age of 7.1 ± 2.9 (3-14) months and 50 healthy children, including 26 (53.1%) girls, with median age of 7.7 ± 2.8 (3-13) months were included in the study. Seventy percent (n = 35) of the patients with FPIAP started to have symptoms while they were exclusively breastfeeding. Offending allergen foods were cow's milk (78%), egg (40%), sesame (10%), hazelnut (8%), almond (6%), beef (6%), and peanuts (6%, n = 3). Intracellular (erythrocyte) zinc levels in patients with FPIAP were lower than in the healthy control group (495.5 ± 134 µg/dL, 567.3 ± 154.4 µg/dL, respectively, P = 0.01). Patients with FPIAP aged younger than 6 months had lower intracellular zinc levels compared with those aged above 6 months (457 ± 137 µg/dL; 548 ± 112 µg/dL, respectively, P = 0.01). There was no relationship between zinc levels and time of symptom onset, presence of concomitant disease, being allergic to multiple foods, and family history of atopy (P > 0.05). CONCLUSIONS: FPIAP is a food allergy with limited information on its pathogenesis. Considering the beneficial effects on gastrointestinal system epithelia, zinc may be involved in the pathogenesis of FPIAP. Future comprehensive prospective research on this subject is of importance.

Informing Risk Management for Patients With Cow's Milk Allergy Based on Threshold Dose Distributions Using Low-Dose Food Challenges.

BACKGROUND: The safe consumption of foods depends on their allergen content in relation to patients' lowest observed adverse effect level (LOAEL) and no observed adverse effect level (NOAEL), as well as other factors. In the case of milk, data on LOAEL and NOAEL are limited and conflicting. OBJECTIVE: To determine the threshold dose distribution and the lowest individual eliciting dose (ED) for milk in a large group of milk-allergic patients METHODS: Individuals with confirmed cow's milk allergy who underwent a diagnostic or pre-oral immunotherapy open milk oral food challenge at the Institute of Allergy, Immunology, and Pediatric Pulmonology at Shamir Medical Center between 2010 and 2015 were included. A subgroup of patients with severe milk allergy underwent a modified challenge with a 90- to 120-minute interval after a starting dose of 0.3 mg cow's milk protein. RESULTS: A total of 866 participants (193 with diagnostic challenges and 673 with pre-oral immunotherapy challenges) were included in the study. The discrete ED01 and ED05, or values derived in which 1% or 5% of the respective allergic population would be predicted to experience an allergic reaction, were 1.1 to 1.9 and 4.7 to 5.6 mg milk protein, respectively, and values for cumulative doses for ED01 and ED05 were 0.9 to 1.8 and 5.2 to 6.2 mg milk protein, respectively. No patients, including the most severely milk-allergic individuals who underwent the modified challenge, reacted to the first 0.3 mg protein dose. CONCLUSION: This report provides valuable information about milk NOAELs, LOAELs, and EDs that might assist regulators in decisions about food labeling in general, and milk in particular.

Cow's Milk-related Symptom Score for cow's milk allergy assessment: a meta-analysis for test accuracy.

BACKGROUND: We aimed to assess the ability of Cow's Milk-related Symptom Score (CoMiss) in screening cow's milk protein allergy (CMPA) and assess validation of its sensitivity and specificity. METHODS: We searched the PubMed, WOS, Embase, and Ovid databases using broad terms and keywords for the concepts of the symptom-based score (CoMiss) and cow's milk allergy. We performed the meta-analyses using a meta-package of R software and Meta-DiSc software. RESULTS: Fourteen studies were included with a total of 1238 children. At cut-off value 12, CoMiss had a pooled sensitivity of 0.64 and a pooled specificity of 0.75. The PLR and NLR were 3.05 and 0.5, respectively. The AUC value of the sROC curve was 0.7866. CoMiss showed a significant difference in CMPA patients at baseline and after milk elimination for 2-4 weeks (MD, 7.18), as well as between the CMPA-positive group compared with the CMPA-negative group, however, the statistical significancy was obtained after leave study of Selbuz et al. out of the analysis (MD, 4.61). CONCLUSIONS: CoMiss may be a promising symptom score in the Awareness of the symptoms related to cow's milk allergy and a useful tool in monitoring the response to a cow's milk-free diet. IMPACT: Cow's milk protein allergy (CMPA) is the most frequent food allergy in children under the age of 3 years. Cow's Milk-related Symptom Score (CoMiss) is a clinical scoring system to assist primary healthcare providers in early detection of CMPA We performed a meta-analysis of CoMiss test accuracy. Our findings reflect that CoMiss may be a promising symptom score in CMPA awareness and a useful tool in monitoring the response to a cow's milk-free diet.

Potential allergenicity and hydrolysis assessment of bovine casein and ß-casein by treatment with lactic acid bacteria.

Casein is one of the main allergens in cow's milk, accounting for 80% of cow's milk proteins. The ability of hydrolyzing proteins by bacteria is also different. In this study, the capacity of lactic acid bacteria to hydrolyze casein or ß-casein and the IgG/IgE-binding capacity of hydrolysates were evaluated. The intensity of casein and ß-casein degradation was analyzed by SDS-PAGE and RP-HPLC. The hydrolysates were tested for their capacity to inhibit IgG and IgE binding by ELISA. The peptides in the hydrolysate were also analyzed by LC-MS/MS. In these strains, Lactobacillus rhamnosus (CICC No. 22175) had the strongest hydrolysis of casein and ß-casein. The hydrolysate of Lactobacillus rhamnosus (CICC No. 22175) showed the lowest antigenicity and potential allergenicity. It also hydrolyzed major allergen IgE epitopes and preserved T cell epitopes. Thereore Lactobacillus rhamnosus (CICC No. 22175) could be used for developing hypoallergenic dairy products and the development of tolerance. PRACTICAL APPLICATIONS: By the study, it obtained that a strain of Lactobacillus rhamnosus could effectively degrade casein and reduced the potential allergenicity of casein. At the same time, some major allergic epitopes were hydrolyzed and T cell epitopes were preserved. Therefore, it is very valuable for the application and development of lactic acid bacteria. The hydrolysate can also be used in a new hypoallergenic dairy formula with specific health benefits and promoting oral tolerance.

Updated full range of Eliciting Dose values for Cow's milk for use in food allergen risk assessment.

Access to Eliciting Doses (ED) for allergens enables advanced food allergen risk assessment. Previously, the full ED range for 14 allergenic foods, including milk, and recommendations for their use were provided (Houben et al., 2020). Additional food challenge studies with cow's milk-allergic patients added 247 data points to the original dataset. Using the Stacked Model Averaging statistical method for interval-censored data on the 697 individual NOAELs and LOAELs for milk generated an updated full ED distribution. The ED01 and ED05, the doses at which 1% and 5% of the milk-allergic population would be predicted to experience any objective allergic reaction, were 0.3 and 3.2 mg milk protein for the discrete and 0.4 mg and 4.3 mg milk protein for the cumulative dose distribution, respectively. These values are slightly higher but remain within the 95% confidence interval of previously published EDs. We recommend using the updated EDs for future characterization of risks of exposure of milk-allergic individuals to milk protein. This paper contributes to the discussion on the Reference Dose for milk in the recent Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens. It will also benefit harmonization of food allergen risk assessment and risk management globally.

Hypoallergenicity assessment of an extensively hydrolyzed whey-protein formula in cow's milk allergic infants.

BACKGROUND: Extensively hydrolyzed formulas are recommended for the dietary management of infants with cow's milk allergy (CMA). OBJECTIVES: Hypoallergenicity, growth, and gastrointestinal (GI) tolerability of a new extensively hydrolyzed whey-protein formula (eHWF) in CMA children were assessed. METHODS: In this prospective, randomized, international, multi-center study (Trial NL3889), 34 children with confirmed CMA (74% IgE-mediated) underwent a double-blind, placebo-controlled food challenge (DBPCFC) with an eHWF developed with non-porcine enzymes, supplemented with prebiotic short-chain galacto- and long-chain fructo-oligosaccharides (0.8 g/L, ratio 9:1), arachidonic acid (0.35/100 g), and docosahexaenoic acid (0.35/100 g). If tolerant to the eHWF, children participated in a 7-day open food challenge with this eHWF. Anthropometrics and GI tolerability were assessed in an optional 16-weeks follow-up. RESULTS: Of the 34 children who started the DBPCFC with the eHWF, 25 subjects (19 boys, mean age: 61 weeks, 18 with IgE-mediated CMA) completed the DBPCFC and 7-day open challenge without major protocol deviations and tested negative at both challenges. One child experienced a late moderate eczematous allergic reaction in the optional follow-up period, indicating the need for close monitoring of subjects starting new formula. Weight and length gain followed the World Health Organization growth curves. Changes in frequency and consistency of stools upon test formula intake were transient. CONCLUSIONS: The newly developed eHWF is a suitable option in CMA treatment as all subjects tolerated the product. This result is in line with the international criteria for hypoallergenicity (American Academy of Pediatrics) that state that more than 90% of CMA children must tolerate the formula. Use of the formula is also associated with normal growth curves and GI tolerability. TRIAL REGISTRATION: Trial NL3889, https://www.trialregister.nl/trial/3889.

Teste de provocação oral para alergia à proteína do leite de vaca / Oral challenge test for protein allergy cow milk

INTRODUÇÃO: A APLV é caracterizada pela reação do sistema imunológico às proteínas do leite, principalmente à caseína (proteína do coalho) e às proteínas do soro do leite (alfa-lactoalbumina e beta-lactoglobulina). Os sintomas, em geral, se desenvolvem após a introdução do leite de vaca (LV), fórmulas alimentares ou alimentos à base de LV (por exemplo, mingau de aveia ou leite com outros tipos de engrossantes ou farinhas). Embora crianças em aleitamento materno exclusivo possam entrar em contato com a proteína do LV pelo leite materno, uma vez que a mulher que amamenta consuma LV e seus derivados, um pequeno número destas crianças reagem à essa proteína e desenvolvem APLV. O diagnóstico da APLV é realizado a partir da ocorrência de história clínica sugestiva da APLV, desaparecimento dos sintomas em 1 a 30 dias após exclusão da proteína do leite de vaca (fase de exclusão) da dieta e reaparecimento dos sintomas após reapresentação da proteína do leite de vaca, por meio do teste de provocação oral (TPO). O TPO consiste na oferta progressiva do alimento suspeito e/ou placebo, em intervalos regulares, sob supervisão médica para monitoramento de possíveis reações clínicas, após um período de exclusão dietética necessário para resolução dos sintomas clínicos. TECNOLOGIA: Teste de provocação oral (TPO). PERGUNTA: Qual a acurácia do TPO para diagnóstico de APLV em comparação com os testes diagnósticos disponíveis no SUS? TPO é custo-efetivo e economicamente viável na perspectiva do SUS? EVIDÊNCIAS CLÍNICAS: Em todos os trabalhos apresentados, o TPO, quer seja o aberto ou duplo-cego, é visto, com unanimidade, como o método padrão-ouro dentro do processo de diagnóstico da APLV, mesmo não tendo sido investigado como objeto de estudo em nenhum dos trabalhos incluídos. As evidências que comparam as outras tecnologias incorporadas ao TPO (utilizado como teste de referência), mostram a relação de acurácia e segurança com recomendação baixa ou muito baixa. AVALIAÇÃO ECONÔMICA: Através de simulação computacional por modelo híbrido de árvore de decisão e estados de Markov, foi avaliada a relação de custo-efetividade do TPO em comparação com os testes disponíveis pelo SUS (pesquisa de Imunoglobulina E e teste cutâneo de leitura imediata) como teste diagnóstico para APLV e posterior monitoramento da tolerância adquirida, em crianças até 24 meses. Em ambos os casos, o TPO se mostrou dominante, ou seja, proporciona maior benefício por um menor custo. A economia por paciente submetido ao TPO foi estimada em R$ 1.272 para comparação com pesquisa de IgE e R$ 526 em comparação com teste cutâneo. Houve benefício com TPO para anos de vida ajustados pela qualidade, pois com TPO a proporção de falso-negativo é menor (pacientes falso-negativos têm a doença mas não são tratados, apresentando pior qualidade de vida). Adicionalmente, foi estimada minimização de gastos com pacientes que não apresentam a doença mas que são tratados por serem falsopositivos: R$ 1.563 em comparação com IgE e R$ 811 em comparação com teste cutâneo. Os resultados da análise probabilística corroboram o resultado principal, sendo que 100% das simulações retornaram maior efetividade por menor custo. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O impacto orçamentário da substituição dos testes diagnósticos atualmente disponíveis (pesquisa de IgE e teste cutâneo) foi calculado com base em dois cenários: Cenário 1, no qual 100% dos casos suspeitos realizariam TPO, devido à sua facilidade de execução e por ser o teste padrão-ouro para diagnóstico de APLV e Cenário 2, no qual 60% dos casos suspeitos realizariam TPO no primeiro ano (2022), enquanto os outros 40% estariam divididos entre pesquisa de IgE e teste cutâneo de leitura imediata, com aumento gradativo linear da utilização de TPO até se atingir o valor de 100% ao final de 5 anos. A população-alvo foi baseada na população brasileira de 0 a 24 meses e na prevalência de casos suspeitos de APLV. Ao longo de 5 anos, foi estimada uma economia entre R$ 470.085.225 a R$ 589.253.518 com a incorporação do TPO para APLV. RECOMENDAÇÕES INTERNACIONAIS: Não foram localizados documentos avaliando a acurácia, segurança ou aspectos econômicos do TPO para APLV. CONSIDERAÇÕES FINAIS: No que tange a relação clínica, os estudos demonstraram que o TPO ainda é padrão-ouro diante de outras tecnologias incorporadas, vez que nas análises que envolvem acurácia e segurança, os outros testes apresentaram evidências com baixo nível de qualidade. Em relação à evidência econômica, a utilização de TPO como teste diagnóstico para APLV gera economia. Isto se deve, especialmente, à maior acurácia deste teste, o que permite a otimização de gastos com fórmulas nutricionais, ou seja, é reduzido o uso de fórmulas por crianças que não apresentam APLV mas que são diagnosticadas incorretamente quando testes menos acurados são empregados. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, os membros da Conitec, em sua 104ª reunião ordinária, realizada no dia 08 de dezembro de 2021, deliberaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação do teste de provocação oral (TPO) para diagnóstico e monitoramento de pacientes até 24 meses com alergia à proteína do leite de vaca (APLV). Foi considerado que o TPO é o padrão-ouro para o diagnóstico de APLV compotencial de gerar economia ao SUS. CONSULTA PÚBLICA: Das 234 contribuições recebidas com opinião sobre o tema, 52 estavam em branco, restando 182 com algum comentário. Destas, 174 se declararam a favor da incorporação da tecnologia em análise. Os assuntos abordados pelos participantes foram: TPO proporciona diagnóstico correto, reduz o uso desnecessário de fórmulas nutricionais, trata-se do teste padrão-ouro para diagnóstico de APLV, necessidade de ambiente adequado para realização devido ao risco de reação anafilática. Em relação às 7 opiniões contrárias à incorporação, os pontos citados foram: necessidade de maior detalhamento sobre a capacitação profissional para realização do teste, falta de estrutura para oferta em nível nacional, a demora para execução do TPO pode restringir a oferta das fórmulas aos pacientes. Em referência à única contribuição em que o contribuinte assinalou não ter opinião formada, o comentário é acerca de a exigência do TPO ser uma barreira para acesso às fórmulas. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do plenário, presentes na 109ª Reunião Ordinária da Conitec, no dia 10 de março de 2022, deliberaram, por unanimidade, recomendar a incorporação no SUS do teste de provocação oral (TPO) para diagnóstico e monitoramento de pacientes até 24 meses com alergia à proteína do leite de vaca (APLV). Foi assinado o Registro de Deliberação nº 716/2022. DECISÃO: Incorporar o teste de provocação oral (TPO) para o diagnóstico e monitoramento de pacientes até 24 meses com alergia à proteína do leite de vaca (APLV), no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 32, publicada no Diário Oficial da União nº 63, seção 1, página 331, em 1 de abril de 2022.

Hidrolizada con alto contenido de trigliceridos de cadena media en pacientes pediátricos con linfangiectasia intestinal primaria y alergia a la leche de vaca / Hydrolyzed with high content of medium chain triglycerides in pediatric patients with primary intestinal lymphangiectasia and allergy to cow's milk

ANTECEDENTES En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de la fórmula extensamente hidrolizada con alto contenido de triglicéridos de cadena media en pacientes pediátricos con linfangiectasia intestinal primaria y alergia a la leche de vaca. Así, el Dr. Marco Antonio Morales Acosta, médico especialista en Pediatría del Servicio de Pediatría Especializada del Hospital Nacional Edgardo Rebagliati Martins de la Red Prestacional Rebagliati, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI la solicitud de uso fuera del petitorio del producto fórmula extensamente hidrolizada alta en triglicéridos de cadena media. ASPECTOS GENERALES La linfangiectasia intestinal primaria (LIP) es una enfermedad poco frecuente caracterizada por una dilatación de los vasos linfáticos de la mucosa o submucosa del intestino delgado. Debido a la estasis y, finalmente, a la rotura de los vasos linfáticos, el líquido linfático, rico en albúmina y otras proteínas, se filtra hacia el tracto gastrointestinal (Brownell and Piccoli 2021). La LIP afecta principalmente a niños y adultos jóvenes, y generalmente se diagnostica antes de los 3 años de edad. El síntoma principal es el edema predominantemente bilateral de miembros inferiores relacionado con la gastroenteropatía perdedora de proteínas. También puede haber fatiga, dolor abdominal, pérdida de peso, incapacidad para aumentar de peso, retraso del crecimiento en los niños, diarrea moderada, deficiencias de vitaminas liposolubles debido a malabsorción, o deficiencia de hierro con anemia moderada (Brownell and Piccoli 2021; Orphanet 2021). La etiología y la prevalencia de la LIP es desconocida. En todo el mundo, se han notificado menos de 500 casos (Orphanet 2021). Su diagnóstico se confirma por la observación endoscópica de los vasos linfáticos intestinales dilatados con la correspondiente histología de las muestras de biopsia intestinal (Orphanet 2021). Y los objetivos del tratamiento incluyen maximizar el estado nutricional y la calidad de vida de los pacientes, mediante la reducción de los síntomas y de las secuelas. El pilar de la terapia dietética es una dieta baja en grasas, alta en proteínas y alta en triglicéridos de cadena media (TCM) (Brownell and Piccoli 2021). METODOLOGÍA: Se realizó una búsqueda sistemática utilizando las bases de datos PubMed, Cochrane Library y LILACS. Además, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorporacáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros. Asimismo, se revisó la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en nutrición en pediatría como la North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN), la European Society for Clinical Nutrition and Metabolism (ESPEN), y la American Society for Parenteral and Enteral Nutrition (ASPEN). De manera adicional, se hizo una búsqueda en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.qov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/) para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados. Las estrategias de búsqueda para identificar la evidencia de ensayos clínicos aleatorizados (ECA) se encuentran en las Tabla 1, 2 y 3 del Material Suplementario. ANÁLISIS DE LA EVIDENCIA: En la presente evaluación no se identificaron guías, consensos de expertos o estudios que ayudaran a responder la pregunta PICO establecida en este dictamen. En ese sentido la evaluación se centró en la evidencia descrita previamente por el IETSI para el uso de la FEH en niños con APLV y la fórmula con alto contenido de TCM en niños con LIP, la plausibilidad biológica de la eficacia de la intervención de interés, y la opinión de los expertos de EsSalud. CONCLUSIONES: Por todo lo expuesto, el IETSI recomienda el uso de la fórmula extensamente hidrolizada con alto contenido de TCM en pacientes pediátricos con LIP y alergia la leche de vaca. Dado que actualmente el producto farmacéutico fórmula extensamente hidrolizada con alto contenido de triglicéridos de cadena media no cuenta con registro sanitario en el mercado peruano; de requerirse la autorización de este producto farmacéutico se recomienda seguir el procedimiento TUPA 118 "Autorización excepcional para la importación y uso de productos farmacéuticos, dispositivos médicos o productos sanitarios para la prevención y tratamiento individual" en el marco de lo establecido en el artículo 16 de la Ley N° 29459 "Ley de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios".

Assessment of the Cow's Milk-related Symptom Score (CoMiSS) as a diagnostic tool for cow's milk protein allergy: a prospective, multicentre study in China (MOSAIC study).

OBJECTIVES: The MOSAIC study aimed to evaluate if the Cow's Milk-related Symptom Score (CoMiSS) can be used as a stand-alone diagnostic tool for cow's milk protein allergy (CMPA). DESIGN: Single-blinded, prospective, multicentre diagnostic accuracy study. SETTING: 10 paediatric centres in China. PARTICIPANTS: 300 non-breastfed infants (median age 16.1 weeks) with suspected CMPA. INTERVENTIONS: After performing the baseline CoMiSS, infants commenced a cow's milk protein elimination diet with amino acid-based formula for 14 days. CoMiSS was repeated at the end of the elimination trial. Infants then underwent an open oral food challenge (OFC) with cow's milk-based formula (CMF) in hospital. Infants who did not react during the OFC also completed a 14-day home challenge with CMF. A diagnosis of CMPA was made if acute or delayed reactions were reported. PRIMARY OUTCOME MEASURES: A logistic regression model for CoMiSS to predict CMPA was fitted and a receiver-operator characteristic (ROC) curve generated. An area under the curve (AUC) of ≥0.75 was deemed adequate to validate CoMiSS as a diagnostic tool (target sensitivity 80%-90% and specificity 60%-70%). RESULTS: Of 254 infants who commenced the OFC, 250 completed both challenges, and a diagnosis of CMPA made in 217 (85.4%). The median baseline CoMiSS in this group fell from 8 (IQR 5-10) to 5 (IQR 3-7) at visit 2 (p<0.000000001), with a median change of -3 (IQR -6 to -1). A baseline CoMiSS of ≥12 had a low sensitivity (20.3%), but high specificity (87.9%) and high positive predictive value (91.7%) for CMPA. The ROC analysis with an AUC of 0.67 fell short of the predefined primary endpoint. CONCLUSIONS: The present study did not support the use of CoMiSS as a stand-alone diagnostic tool for CMPA. Nevertheless, CoMiSS remains a clinically useful awareness tool to help identify infants with cow's milk-related symptoms. TRIAL REGISTRATION NUMBER: NCT03004729; Pre-results.

A Prospective Assessment of Clinical Characteristics and Responses to Dietary Elimination in Food Protein-Induced Allergic Proctocolitis.

BACKGROUND: Some aspects of diagnostic elimination/challenge diets in food protein-induced allergic proctocolitis (FPIAP) are still poorly defined. OBJECTIVE: This study investigated the symptom spectrum, time required for resolution of each symptom, triggering foods, and risk factors for multiple food allergies (MFA) in FPIAP. METHODS: Infants referred with visible blood in stool were enrolled after etiologies other than FPIAP had been excluded. Laboratory evaluation, clinical features, and elimination/challenge steps were performed prospectively during diagnostic management. RESULTS: Ninety-one of 102 infants (53 boys) were diagnosed with FPIAP. Eleven children did not bleed during challenges. Visible blood in stool began before 2 months of age in 63.6% of the infants not diagnosed with FPIAP, compared with 18.9% of the patients with FPIAP (P = .003). Offending foods were identified as cow's milk (94.5%), egg (37.4%), beef (10.9%), wheat (5.5%), and nuts (3.3%). MFA was determined in 42.9% of patients. Multivariate logistic regression analysis identified atopic dermatitis (AD) (odds ratio [OR]: 2.98, 95% confidence interval [CI]: 1.18-7.55, P = .021) and an eosinophil count ≥300 cells/µL (OR: 2.72, 95% CI: 1.09-6.80, P = .032) as independent risk factors for MFA. Blood and mucus in stool disappeared in a median 3 days (interquartile range [IQR]: 1-14.5 days) and 30 days (IQR: 8-75 days), respectively. CONCLUSIONS: A tendency to transient bleeding occurs in infants who present with bloody stool before 2 months of age. A 2-week duration of elimination for blood in stool is sufficient to reach a judgment of suspected foods for FPIAP. Mucus in stool is the last symptom to disappear. Concurrent AD suggests a high probability of MFA in FPIAP.

Consensus statement on the epidemiology, diagnosis, prevention, and management of cow's milk protein allergy in the Middle East: a modified Delphi-based study.

BACKGROUND: This study aimed to develop an expert consensus regarding the epidemiology, diagnosis, and management of cow's milk protein allergy (CMPA) in the Middle East. METHODS: A three-step modified Delphi method was utilized to develop the consensus. Fifteen specialized pediatricians participated in the development of this consensus. Each statement was considered a consensus if it achieved an agreement level of ≥ 80%. RESULTS: The experts agreed that the double-blind placebo-controlled oral challenge test (OCT) should be performed for 2-4 weeks using an amino acid formula (AAF) in formula-fed infants or children with suspected CMPA. Formula-fed infants with confirmed CMPA should be offered a therapeutic formula. The panel stated that an extensively hydrolyzed formula (eHF) is indicated in the absence of red flag signs. At the same time, the AAF is offered for infants with red flag signs, such as severe anaphylactic reactions. The panel agreed that infants on an eHF with resolved symptoms within 2-4 weeks should continue the eHF with particular attention to the growth and nutritional status. On the other hand, an AAF should be considered for infants with persistent symptoms; the AAF should be continued if the symptoms resolve within 2-4 weeks, with particular attention to the growth and nutritional status. In cases with no symptomatic improvements after the introduction of an AAF, other measures should be followed. The panel developed a management algorithm, which achieved an agreement level of 90.9%. CONCLUSION: This consensus document combined the best available evidence and clinical experience to optimize the management of CMPA in the Middle East.

Symptom scores in the diagnosis of pediatric cow's milk protein allergy: A systematic review.

BACKGROUND: Cow's milk protein allergy (CMPA) is an immune-mediated allergic response to proteins in milk that is common in infants. Broad CMPA symptoms make diagnosis a challenge, particularly in primary care. Symptom scores may improve a clinician's awareness of symptoms, indicating a need for further testing. This systematic review examined the development and evaluation of such symptom scores for use in infants. METHODS: CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched from inception to 3 December 2019 (Updated 14 November 2020) for diagnostic accuracy studies, randomised controlled trials, observational studies, economic evaluations, qualitative studies and studies reporting development of the tools. Data were not suitable for meta-analysis due to clinical and methodological heterogeneity, so were narratively synthesised. RESULTS: We found two symptom scores evaluated in one and fourteen studies, respectively. Estimated sensitivity and specificity ranged from 37% to 98% and 38% to 93%. The evaluations of each tool were at high risk of bias or failed to address issues such as clinical and cost-effectiveness. CONCLUSIONS: Estimates of accuracy of symptom scores for CMPA offered so far should be interpreted cautiously. Rigorous, conflict-free research based on well-defined roles for the tools is urgently required.

Assessment of Inflammatory Markers in Children with Cow's Milk Allergy Treated with a Milk-Free Diet.

BACKGROUND: The aim of the study was to establish whether the use of a strict milk-free diet in children with cow's milk allergy, resulting in the resolution of clinical symptoms of the disease, also extinguishes the inflammatory reaction induced by the allergy. METHODS: We examined 64 children (aged 3-6 years) with a diagnosed cow's milk allergy who had been treated with an elimination diet for at least six months and showed remission of the disease's clinical symptoms as a result of the treatment. The control group consisted of 30 healthy children of the same age following an unrestricted age-appropriate diet. Concentrations of cytokines, calprotectin, and adipokines (leptin, resistin, chemerin, neutrophilic lipocalin associated with gelatinase-NGAL) were determined in the serum samples obtained from the studied children by immunoenzymatic assays. RESULTS: Patients with CMA had significantly higher median values of serum IL-6, TNF-α, resistin, chemerin and NGAL in comparison to the healthy children (p < 0.05, p < 0.001, p < 0.05, p < 0.01, p < 0.001, respectively). Serum concentrations of IL-10, leptin, calprotectin and CRP as well as in WBC count were in the same range in both studied groups. We observed direct statistically significant correlations between levels of IL-10 and CRP (p = 0.005), IL-10 and WBC (p = 0.045), TNF-α and WBC (p = 0.038), calprotectin and WBC (p < 0.001), chemerin and CRP (p < 0.001) as well as between NGAL and WBC (p = 0.002) in children with CMA. CONCLUSION: The use of a strict milk-free diet by children with CMA, resulting in the resolution of clinical symptoms of the disease, does not seem to extinguish the inflammation induced by the allergy. The findings of this study-elevated IL-6, TNF-α, resistin, chemerin and NGAL levels in patients with CMA-suggest that these parameters seem to be involved in the generation of a low-grade proinflammatory environment observed in cow's milk allergy and could be used to monitor the effectiveness of treatment.

Probabilistic risk assessment for milk in dark chocolate, cookies and other baked goods with PAL sold in Canada.

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 24 mg (dark chocolate), 3.9 mg (baked goods), and 0.20 mg (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%; 3802/100,000) 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.