Different Digestive Tract Complications of Neonatal-Onset Infants with Severe Cow Milk Protein Allergy

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We retrospectively analyzed various digestive tract complications of the five infants who were hospitalized at Guangzhou Women and Children’s Medical Center from July 2016 to June 2020. All five cases were full-term infants, with age at onset ranging from three to 28 days. Three neonates were formula-fed, and two were mixed-fed. The principal clinical manifestations included fever, diarrhea, vomiting, hematochezia, weight loss, edema, and skin ulcers. One infant was diagnosed with necrotizing enterocolitis (NEC) and underwent surgery. Milk-specific IgE was elevated in three cases, and other food-specific IgE antibodies were elevated in two cases. Case 1 revealed severe erosive esophagitis and pyloric stenosis upon gastroscopy; case 2 revealed intestinal lymphatic dilation upon gastroscopy; case 3 showed scattered crater-like ulcers of varying sizes under colonoscopy, with some of the ulcerated tissues around the ulcers showing polypoid changes; case 4 showed ascites of approximately 16 mm in depth upon abdominal ultrasonographic scan; and case 5 depicted colonic stenosis and erosive colitis upon colonoscopy. All five children were cured after receiving either amino acid formula milk (AAF) or extensively hydrolyzed formula (eHF) for enteral nutrition feeding and supportive treatment. Severe CMPA in neonates presented with atypical clinical manifestations, and a variety of complications in various parts of the digestive tract occurred—including inflammation and stenosis—which were easily misdiagnosed as NEC or very-early-onset inflammatory bowel disease (IBD). We posit that early diagnosis will reduce unnecessary operations and shorten treatment time. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Cow milk protein allergy (CMPA) is the most common food hypersensitivity in infants [ 1 – 2 ] . Although immune mechanisms are immature in newborns and the incidence of milk protein allergy is low [ 3 ] , there have been in recent years cases of milk protein allergy misdiagnosed as necrotizing enterocolitis or sepsis in newborns [ 4 – 5 ] . For this study, we reviewed five cases of disparate gastrointestinal manifestations of children diagnosed with late neonatal onset of severe CMPA to engage the attention of pediatricians (particularly neonatologists) to diagnose milk protein allergy early and to avoid progression and minimize complications. Materials and Methods We conducted a retrospective case-series analysis at a tertiary children’s hospital in Guangzhou, China. We included all infants who were hospitalized and diagnosed with severe CMPA with onset in the neonatal period between July 2016 and June 2020. Patient clinical features, feeding patterns, laboratory tests, imaging examinations, and treatment outcomes were reviewed. All infants underwent routine evaluation for acute infection, including blood culture for bacteria and fungus, stool culture for bacteria ( Escherichia coli , Salmonella , Shigella , Campylobacter , and Enterobacter aerogenes ), and stool viral antigen tests (rotavirus and adenovirus). Patients with documented immunodeficiency—or with kidney, liver, or heart disorders—were excluded. The diagnosis of neonatal CMPA needs to be made by combining family history, clinical manifestations, physical examination, and exclusion of infections and surgical diseases, followed by a diagnostic avoidance test, and the diagnosis is confirmed by an oral provocation test after the disappearance of symptoms [ 6 ] . Informed consent was obtained from the guardians of this study and approved by the institutional ethics committee of Guangzhou Women and Children’s Medical Center. Results As shown in Table 1 , a total of five infants were diagnosed with neonatal-onset severe milk protein allergy. The age at admission ranged from one hour to seven months and included three boys and two girls. The five infants were all born at full term, three by normal delivery and two by cesarean delivery. Three infants were formula-fed and two were mixed-fed. The mean age at onset of symptoms was 15.8 days, with a range of three to 28 days. One infant was treated surgically for NEC. None of the five infants had a significant family history of allergies. Four infants presented with diarrhea at a frequency of seven to 20 times per day. One infant presented with hematochezia, two infants experienced concomitant vomiting, and one infant was febrile. Physical examination showed three infants with failure to thrive, two infants manifested edema, and one infant exhibited skin ulceration. Laboratory tests indicated that four patients were anemic (Hb < 100 g/L), two patients had elevated WBC (≥ 12.5 × 109/L), and one patient had an elevated platelet count (≥ 440 × 10 9 /L). One patient showed an elevated eosinophil count, and two patients had elevated CRP (≥ 8 mg/L). Three patients had hypoalbuminemia (16.6–28.2 g/L; normal range, 35–50 g/L), three patients were positive for serum allergen-specific IgE (sIgE) to cow milk protein, and two patients were positive for sIgE to other food allergies. Table 1 Basic characteristics, clinical features and laboratory tests in infants with neonatal-onset severe cow's milk protein allergy Sex Gestational age Delivery model birth weight(kg) Age of admission age of onset Feeding pattern Symptoms WBC HB(g/L) PLT Serum albumin(g/L) Milk sIgE Case1 Male 38W Cesarean section 2.85 2m 3d Formula feeding Diarrhea Hematochezia Vomiting Normal 101 Normal Normal 0.6 Case2 Female 39 + 1W natural labour 3.19 2m 28d mixed feeding. Diarrhea Normal 97 Normal 28.2 negative Case3 Male 38 + 4 natural labour 3.2 2m 16d Formula feeding Diarrhea Fever 24.2x10 9 /L 76 998 x10 9 /L 26.7 negative Case4 Female 38W + 5 natural labour 3.0 7m 28d Formula feeding Diarrhea Vomiting acrodermatitis enteropathica 14.8 x10 9 /L 86 Normal 16.6 1.63 Case5 Male 37 + 5W Cesarean section 2.4 4d 4d mixed feeding. Hematochezia NEC colonic perforation Normal 94 Normal Normal 2.0 Gastrointestinal imaging, endoscopy, and pathologic changes varied from patient to patient. For Case 1, gastrointestinal imaging suggested intestinal malrotation and gastroscopy revealed erosive esophagitis (severe) and pyloric stenosis (Fig. 1–1, 1– 2 ). In Case 2, gastroscopy showed dilated intestinal lymphatics, enteroscopy suggested chronic colitis, and pathology indicated marked dilatation of some villous lymphatics in the duodenal mucosa and elevated eosinophils in the colonic mucosa (Fig. 2 − 1, 2–2). With regard to Case 3, gastroscopy did not show any abnormality, while with enteroscopy we observed scattered crater-like ulcer foci of varying sizes; the lesions were segmental, and portions of the periphery of the ulcers demonstrated polypoid changes suggestive of Crohn’s disease (Fig. 3 − 1, 3 − 2). Pathology suggested chronic inflammation with normal eosinophil count. As to Case 4, abdominal ultrasonography suggested ascites at about 16 mm in depth. For Case 5, abdominal plain film suggested NEC with portal vein pneumoperitoneum; gastroscopy after NEC suggested erosive gastritis; and colonoscopy suggested colonic stenosis and erosive colitis (Fig. 4 − 1, 4 − 2). Pathology showed chronic inflammation with a normal eosinophil count. The treatment history for each child was as follows. In Case 1, bloody stools appeared after three days of normal formula feeding after birth. He was then hospitalized for diarrhea, vomiting, and weight loss, and was subsequently treated with continuous feeding of amino acid formula, after which his symptoms were alleviated and he transitioned to intermittent feeding. However, he was re-admitted to the hospital at the age of one year and nine months due to recurrent vomiting and bloody emesis, and gastroscopy suggested esophagitis and pyloric stenosis. After he was treated with Methylprednisolone.he sustained amino acid formula feeding and underwent balloon dilation twice for pyloric stenosis; he showed significant improvement in his esophagitis and pyloric stenosis after two months, and he was fed routinely one-half year later. We added complementary foods to his diet but had him avoid allergenic foods, and his vomiting and diarrhea did not recur; his weight also gradually returned to normal for his age and size. Case 2 experienced diarrhea at 28 days after birth, hospitalization for swollen limbs, and repeated hypoproteinemia, and gastroenteroscopy suggested lymphatic dilatation of the small intestine and colitis. He was treated with eHF and was regularly infused with albumin for 10 months; his albumin level then returned to normal and after diarrhea improved, and he was fed with Peptamen Junior. Gastroscopy and colonoscopy were reviewed after three years of follow-up and showed no abnormalities, and his weight returned to normal. Case 3 manifested persistent, uncorrectable diarrhea (watery stools and mucousy, bloody stools) accompanied by fever, and laboratory tests primarily revealed metabolic acidosis, electrolyte disorders, hepatic impairment, anemia, hypoproteinemia, and ultrasensitive CRP; leukocytes and platelets were also significantly increased. A serum ingesta sIgE group test was negative. Colonoscopy showed segmental, volcano-like ulcers and mucosal defects in the colonic mucosa. After treatment with amino acid formula for four weeks, the patient was discharged from the hospital with clinical improvement and continued to be fed with amino acid formula after discharge. A repeat colonoscopy six months later suggested that the ulcers had disappeared, and his weight returned to normal; however, a rash appeared after the addition of eggs, fish, and shrimp to his diet, suggesting multiple food allergies. Tolerance to allergenic foods was ultimately achieved one-and-one-half years later. Case 4 experienced diarrheal dehydration 28 days after birth, was hospitalized at the local ICU for one day, and was automatically discharged from the hospital after imbibing formula. She experienced vomiting and self-administered rice pudding feeding and was hospitalized at six months of age due to diarrheal fever and skin ulcers. She was provided amino acid formula via continuous nasal feeding by tube and received anti-infectives, fluid replacement, plasma, albumin, and an erythrocyte suspension transfusion with vitamin and trace-element supplementation; she then underwent rehabilitation with newly wet compresses on her skin lesions. Sixteen days later, the rash subsided; feeding commenced with 120 ml/3 h by mouth, without vomiting; stools manifested a paste-like form 2–3 times/day, and albumin at 33.5 g/L was reevaluated. The girl was then discharged from the hospital on the doctor’s advice. Four weeks after discharge, her stools were formed and her albumin was 37.3 g/L. Eight weeks after discharge, the girl’s diet was changed to partially hydrolyzed formula, and she experienced no discomfort and was of normal weight. Case 5 exhibited bloody stools on the 5th day after birth, and NEC stage IIb was considered; a caesarean section + perforated colon repair + ileostomy was then performed. After the operation, several attempts were undertaken to provide full-protein formula feeding, but vomiting and diarrhea subsequently occurred. The baby’s diet was changed to breastfeeding, and upon the mother avoiding allergy-prone foods, symptoms improved. Six months later, gastroenteroscopy suggested erosive gastritis and erosive colitis, and the diet was changed to breastfeeding + amino acid formula feeding; eight months after the closure of the fistula (i.e., one year later), the baby received deeply hydrolyzed formula feeding that was well tolerated, and her reactions were suggestive of milk, egg white, and wheat allergies. The patient was ultimately able to tolerate other foods, and her weight gradually increased to normal. Discussion CMPA is an adverse reaction to cow milk proteins mediated by immune mechanisms, and the incidence of CMPA is estimated to be 0.5–3% in developed countries within one year of age [ 7 – 10 ]; the incidence of CMPA is approximately 2.69% in China [ 11 ] . Neonates constitute a special group due to their immature immune mechanisms and other factors. The incidence of milk protein allergy is relatively low, its clinical manifestation lacks specificity, and it is often misdiagnosed as necrotizing small bowel colitis and sepsis in neonates—leading to unnecessary surgery or antibiotic use [ 12 ] . Although reports of milk protein allergy in neonates have been increasing in recent years, there is a lack of definitive epidemiologic data. Morita et al. [ 13 ] depicted an incidence of CMPA of about 1.98% among 2,116 neonates in neonatal intensive care units (NICUs), with their multicenter analysis revealing that 69,796 were hospitalized. A multicenter study also showed that the incidence of CMPA was 0.21% in 69,796 hospitalized neonates [ 14 ] . Lin et al. [ 15 ] reported that CMPA allergy was diagnosed in 160 (53.3%) of 300 hospitalized children with bloody stools in the neonatal unit of their hospital, of which 112 (51.1%) were full-term infants and 48 (59.3%) were preterm infants. Pssariello et al. [ 16 ] analyzed 39 cases of diarrhea in their NICU, of whom 20.5% were caused by food allergy, and Miyazawa et al. [ 17 ] observed that among 263 NICU infants, 53 cases showed CMPA (with a mean onset age of 6 d) and 41% of them were low-birth-weight infants. In the present study, five cases were full-term infants, and we showed that the onset of disease in full-term infants was 1–2 weeks; the onset of disease in ultra-low-birthweight infants was also significantly later than in low-birthweight infants (LBWI) or normal birthweight infants [ 14 , 17 ] . There are also reports of allergic colitis in the first few hours and one day after birth [ 18 ] . In the present study, the children showed disease onset at three to 28 days, and it was evident that the age at onset of disease could be in either the early or late neonatal period. It is hypothesized that neonates with milk protein allergy have a history of eating dairy products one week before the onset of the disease. In our analysis, all neonates had eaten dairy products, including three cases with artificial feeding and two cases with mixed feeding. We suggest that infants administered artificial feeding may be more prone to severe milk protein allergy. The clinical manifestations of neonatal CMPA are primarily gastrointestinal symptoms such as diarrhea, bloody stools, vomiting, abdominal distension, and diminished milk intake—some of which are accompanied by skin symptoms such as eczema and atopic dermatitis; respiratory symptoms are less common. Depending on the severity, neonatal food allergy can be categorized as mild-moderate and severe [ 19 ] : mild-moderate digestive symptoms may be manifested as diarrhea, bloody stools, abdominal distension, vomiting, colic, and, in a few cases, constipation, and these symptoms may occur alone or in combination. In addition to gastrointestinal symptoms, chronic diarrhea and vomiting can cause growth retardation, feeding difficulties, nutritional iron-deficiency anemia, protein-losing enteropathy, and severe ulcerative colitis in some cases. Siu et al. [ 20 ] reported a case of chronic diarrhea in a Chinese newborn due to CMPA, and this was followed by severe developmental disorders, metabolic acidosis, hypoalbuminemia, severe atopic dermatitis combined with hypoalbuminemia, and severe diarrhea. Atopic dermatitis combined with hypoalbuminemia or combined with growth restriction or iron-deficiency anemia, circulatory failure, and shock may also be present. In our study, of five cases, four children presented with diarrhea and one with bloody stools showing vomiting, fever, malnutrition, edema, and skin ulceration. Laboratory tests showed anemia, hypoproteinemia, elevated leukocytes, and CRP. Gastroenteroscopy suggested various degrees of mucosal inflammation, including esophagitis, pyloric stenosis, lymphatic dilatation of the small intestine, erosive gastritis, erosive colitis, and colonic ulceration with polypoid hyperplastic changes. It is acknowledged that children with severe disease often have anemia, hypoproteinemia, elevated inflammatory indices, differing degrees of inflammation upon gastroenteroscopy, hyperplastic stenosis, and even erosive ulceration that is similar to the manifestation of Crohn’s disease—which is prone to misdiagnosis. The diagnosis of neonatal CMPA necessitates being conducted in combination with clinical manifestations, laboratory tests, and the exclusion of infections and surgical diseases. Once neonatal CMPA is considered, a milk avoidance test, oral provocation test, specific IgE assay, skin prick test (SPT), patch test (atopy patch test [APT]), and eosinophil count are performed to confirm the diagnosis [ 21 ] . But a multicenter survey study in the UK surfaces that 84% of the current diagnoses of neonatal CMPA are clinical diagnoses only [ 22 ] .Milk avoidance reflects both diagnostic and therapeutic value, and the foods consumed during the avoidance period should be extensively hydrolyzed formula (eHF), AAF, or soy-based formula [ 21 ] . AAF is preferred for those babies presenting with severe allergic or life-threatening manifestations, and soy-based formulas are preferred for those babies and families who cannot tolerate the bitter taste or cost of eHF. If symptoms do not improve within two weeks, only AAF should be chosen. Further diagnosis requires oral provocation testing that is potentially risky and requires appropriate resuscitative preparations. Soy-based formulas are also not implemented in neonates. In our study, three of the five children showed positivity for milk IgE, one had an elevated eosinophil count in the colonic mucosa, and one exhibited a positive oral provocation test. The remaining four children presented with severe gastrointestinal lesions that were difficult to treat with recurrent illnesses, and the provocation test was not performed after avoidance of the diet for 2–4 weeks for safety reasons; thus, all were diagnosed therapeutically. Three children were relieved by switching to amino acid formula feeding and one by switching to lactose-free deeply hydrolyzed formula, and one improved after the mother avoided the diet. For the treatment of CMPA, the WAO 2010 Food Allergy Guidelines reflected a comparison of the dietary treatment guidelines for CMPA in different countries and organizations, and the common points were that breastfeeding was encouraged, but mothers needed to avoid high-risk foods, and dietary substitutions were recommended vis-à-vis amino acid formula or eHF [ 23 ] . According to China’s infant milk protein allergy guidelines, formula-fed children with mild-moderate degrees of milk protein allergy should be given eHF, and if milk protein allergy still occurs after consumption of eHF, then the amino acid formula should be replaced; in severe cases, amino acid formula is preferred [ 23 ] , and avoidance time is at least six months, or until nine to 12 months of age. In the present study, four of five children with severe CMPA were fed with amino acid formula, and lactose-free eHF was administered in one case due to a diagnosis of lymphatic dilatation of the small intestine and recurrent hypoproteinemia. The avoidance time for four of the children was over six months and as long as two years; this was mainly due to obvious gastroenteroscopic inflammation and manifested by hyperplasia and stenosis, erosions, or ulcers. It also took a much longer period of time for the intestinal mucosa to return to normal. One child with recurrent hypoproteinemia exhibited dietary avoidance for two months, but could be transitioned to partially hydrolyzed milk powder feeding and thus recovered more quickly. This suggests that children with severe CMPA often require a longer avoidance time and that gastroenteroscopy is a reliable examination modality that can be used for evaluating the condition and also to guide feeding. Milk protein allergy in newborns is not uncommon, often reflecting gastrointestinal symptoms as the chief manifestations, including diarrhea, bloody stools, and vomiting. Some of the children with severe milk protein allergy also showed anemia, hypoproteinemia, malnutrition, and other complications; the condition was recurring and the treatment was complicated. Therefore, early gastroenteroscopy is considered an excellent assessment of the scope of the lesions in gastrointestinal inflammation and their severity within the gastrointestinal tract; these symptoms can accumulate in many parts of the gastrointestinal tract, including the esophagus, stomach, duodenum, and colon. The jejunum and ileum, however, are not visualized due to endoscopic limitations. The endoscopic presentation is variable and may consist of hyperplastic strictures, erosions, or even ulcers. Severely affected children are additionally prone to misdiagnosis of sepsis, NEC, and very-early-onset inflammatory bowel disease. Early recognition of CMPA during the neonatal period can thereby avoid misdiagnosis and unnecessary antibiotic or surgical treatment, shorten treatment time, and improve prognosis. Whether early intervention can avoid the progression of gastrointestinal inflammation, however, requires further study. Conclusions We report different digestive tract complications of five neonatal-onset infants with severe CMPA which were easily misdiagnosed as NEC or VEO-IBD. The diagnosis relied more on clinical presentation and resolution of symptoms after CMP avoidance.It is difficult to do oral provocation test in the clinic for safety reasons. Prompt treatment with CMP-free formula is effective and leads to clinical remission. Declarations Ethics approval and consent to participate Written informed consent was obtained from the mothers of the babies. Consent for publication was granted by the institutional ethics committee of Guangzhou Women and Children’s Medical Center. Authors’ contributions Liping Ye and Min Yang participated in acquisition, analysis and interpretation of data, statistical analysis, and drafting of the initial manuscript; Peiyu Chen, Jing Xie, Huiwen Li all participated in acquisition, analysis, and interpretation of data; Sitang Gong and Lanlan Geng conceptualized the study, revised the manuscript for important intellectual content and supervised the project. Funding Not Applicable Availability of data and materials The data underlying this article are available in the article. Consent for publication No individual images or pictures are included in the report. Competing interests The authors declare no competing interests. References Host A. Frequency of cow’s milk allergy in childhood. Ann. Allergy Asthma Immunol. 2002; 89 (6 Suppl. 1): 33–7. Sicherer SH. 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Mahadevan J, Gupta A, Harikumar C,et al.PO-0597 A Nationwide Survey Of Neonatal Cow's Milk Allergy In The Uk[J].Archives of Disease in Childhood, 2014, 99(Suppl 2):A446-A446.DOI:10.1136/archdischild-2014-307384.1237. Fiocchi A, Brozek J, Schǖnemann H, et al. World allergy organization(WAO) diagnosis and retionale for action against cow's milk allergy (DRACMA) guidelines[J]. World Allergy Organ J, 2010, 3(4): 157-161. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4338710","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307532032,"identity":"bf3b1718-f80e-4e68-8d79-fb6aefc9ad09","order_by":0,"name":"Liping Ye","email":"","orcid":"","institution":"Guangzhou Women and Children's Medical Center, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Ye","suffix":""},{"id":307532033,"identity":"21c44ad1-e049-4f93-a3eb-777e6cd9d661","order_by":1,"name":"Lanlan Geng","email":"","orcid":"","institution":"Guangzhou Women and 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erosion\u003c/p\u003e","description":"","filename":"11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/c0a516e91970d3f6f40d0a50.jpg"},{"id":57629636,"identity":"559d4852-5529-4b4a-aa05-a7473007c35b","added_by":"auto","created_at":"2024-06-03 14:37:10","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24732,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 1-2 pyloric stenosis\u003c/p\u003e","description":"","filename":"12.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/0aebc2a7919bf881d34be5d6.jpg"},{"id":57629635,"identity":"81130161-d72d-4165-bd8d-8557778a9130","added_by":"auto","created_at":"2024-06-03 14:37:10","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":26198,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2-1 Rice-like hyperplasia in the mucosa of the descending duodenum\u003c/p\u003e","description":"","filename":"21.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/dfd5c578bbec1bd18fd5edf5.jpg"},{"id":57629631,"identity":"a2d162fe-3a4d-4c7b-ae6b-34b8648193bc","added_by":"auto","created_at":"2024-06-03 14:37:10","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":27411,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2-2 chronic colitis\u003c/p\u003e","description":"","filename":"22.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/789d61b12bfcde4e83c247bc.jpg"},{"id":57629632,"identity":"ccfc9018-38f2-4c15-9044-ff0ea8ec7c08","added_by":"auto","created_at":"2024-06-03 14:37:10","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":22192,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 3-1 Crater-like ulcer in the colon\u003c/p\u003e","description":"","filename":"31.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/3a9a2888efe0a0fb06bba142.jpg"},{"id":57629634,"identity":"ee9fa838-a9de-4c06-8f67-2eb3dd87836e","added_by":"auto","created_at":"2024-06-03 14:37:10","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":21776,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 3-2 Polypoid hyperplasia in the colon\u003c/p\u003e","description":"","filename":"32.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/2d010b18b6ce69d807de7d5d.jpg"},{"id":57629638,"identity":"a268b219-0006-4f98-8e98-c8fe2024db70","added_by":"auto","created_at":"2024-06-03 14:37:11","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":13198,"visible":true,"origin":"","legend":"\u003cp\u003eFigure4-1 mucous membrane erosion in the colon\u003c/p\u003e","description":"","filename":"41.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/5100ddbec86f730e08ba38b5.jpg"},{"id":57629633,"identity":"d480c966-7631-404d-9217-79507edfa7b1","added_by":"auto","created_at":"2024-06-03 14:37:10","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":13372,"visible":true,"origin":"","legend":"\u003cp\u003eFigure4-2 colonic stenosis\u003c/p\u003e","description":"","filename":"42.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/1fec7031469d8a31647acc71.jpg"},{"id":69873051,"identity":"1cfaedc7-168c-4605-bb5f-a624d132d134","added_by":"auto","created_at":"2024-11-26 08:01:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":537255,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4338710/v1/44b2e9de-9426-4e6c-9645-d0eb60820e7e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Different Digestive Tract Complications of Neonatal-Onset Infants with Severe Cow Milk Protein Allergy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCow milk protein allergy (CMPA) is the most common food hypersensitivity in infants\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Although immune mechanisms are immature in newborns and the incidence of milk protein allergy is low\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e, there have been in recent years cases of milk protein allergy misdiagnosed as necrotizing enterocolitis or sepsis in newborns\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. For this study, we reviewed five cases of disparate gastrointestinal manifestations of children diagnosed with late neonatal onset of severe CMPA to engage the attention of pediatricians (particularly neonatologists) to diagnose milk protein allergy early and to avoid progression and minimize complications.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eWe conducted a retrospective case-series analysis at a tertiary children\u0026rsquo;s hospital in Guangzhou, China. We included all infants who were hospitalized and diagnosed with severe CMPA with onset in the neonatal period between July 2016 and June 2020. Patient clinical features, feeding patterns, laboratory tests, imaging examinations, and treatment outcomes were reviewed. All infants underwent routine evaluation for acute infection, including blood culture for bacteria and fungus, stool culture for bacteria (\u003cem\u003eEscherichia coli\u003c/em\u003e, \u003cem\u003eSalmonella\u003c/em\u003e, \u003cem\u003eShigella\u003c/em\u003e, \u003cem\u003eCampylobacter\u003c/em\u003e, and \u003cem\u003eEnterobacter aerogenes\u003c/em\u003e), and stool viral antigen tests (rotavirus and adenovirus). Patients with documented immunodeficiency\u0026mdash;or with kidney, liver, or heart disorders\u0026mdash;were excluded.\u003c/p\u003e \u003cp\u003eThe diagnosis of neonatal CMPA needs to be made by combining family history, clinical manifestations, physical examination, and exclusion of infections and surgical diseases, followed by a diagnostic avoidance test, and the diagnosis is confirmed by an oral provocation test after the disappearance of symptoms\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Informed consent was obtained from the guardians of this study and approved by the institutional ethics committee of Guangzhou Women and Children\u0026rsquo;s Medical Center.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, a total of five infants were diagnosed with neonatal-onset severe milk protein allergy. The age at admission ranged from one hour to seven months and included three boys and two girls. The five infants were all born at full term, three by normal delivery and two by cesarean delivery. Three infants were formula-fed and two were mixed-fed. The mean age at onset of symptoms was 15.8 days, with a range of three to 28 days. One infant was treated surgically for NEC. None of the five infants had a significant family history of allergies.\u003c/p\u003e \u003cp\u003eFour infants presented with diarrhea at a frequency of seven to 20 times per day. One infant presented with hematochezia, two infants experienced concomitant vomiting, and one infant was febrile. Physical examination showed three infants with failure to thrive, two infants manifested edema, and one infant exhibited skin ulceration. Laboratory tests indicated that four patients were anemic (Hb\u0026thinsp;\u0026lt;\u0026thinsp;100 g/L), two patients had elevated WBC (\u0026ge;\u0026thinsp;12.5 \u0026times; 109/L), and one patient had an elevated platelet count (\u0026ge;\u0026thinsp;440 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L). One patient showed an elevated eosinophil count, and two patients had elevated CRP (\u0026ge;\u0026thinsp;8 mg/L). Three patients had hypoalbuminemia (16.6\u0026ndash;28.2 g/L; normal range, 35\u0026ndash;50 g/L), three patients were positive for serum allergen-specific IgE (sIgE) to cow milk protein, and two patients were positive for sIgE to other food allergies.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBasic characteristics, clinical features and laboratory tests in infants with neonatal-onset severe cow's milk protein allergy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" 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\u003cp\u003e3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFormula\u003c/p\u003e \u003cp\u003efeeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e24.2x10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e998 x10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e26.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003enegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38W\u0026thinsp;+\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003enatural labour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFormula\u003c/p\u003e \u003cp\u003efeeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003cp\u003eacrodermatitis enteropathica\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14.8 x10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e16.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u0026thinsp;+\u0026thinsp;5W\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCesarean section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003emixed\u003c/p\u003e \u003cp\u003efeeding.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHematochezia\u003c/p\u003e \u003cp\u003eNEC\u003c/p\u003e \u003cp\u003ecolonic perforation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eGastrointestinal imaging, endoscopy, and pathologic changes varied from patient to patient. For Case 1, gastrointestinal imaging suggested intestinal malrotation and gastroscopy revealed erosive esophagitis (severe) and pyloric stenosis (Fig.\u0026nbsp;1\u0026ndash;1, 1\u0026ndash;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In Case 2, gastroscopy showed dilated intestinal lymphatics, enteroscopy suggested chronic colitis, and pathology indicated marked dilatation of some villous lymphatics in the duodenal mucosa and elevated eosinophils in the colonic mucosa (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1, 2\u0026ndash;2). With regard to Case 3, gastroscopy did not show any abnormality, while with enteroscopy we observed scattered crater-like ulcer foci of varying sizes; the lesions were segmental, and portions of the periphery of the ulcers demonstrated polypoid changes suggestive of Crohn\u0026rsquo;s disease (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1, 3\u0026thinsp;\u0026minus;\u0026thinsp;2). Pathology suggested chronic inflammation with normal eosinophil count. As to Case 4, abdominal ultrasonography suggested ascites at about 16 mm in depth. For Case 5, abdominal plain film suggested NEC with portal vein pneumoperitoneum; gastroscopy after NEC suggested erosive gastritis; and colonoscopy suggested colonic stenosis and erosive colitis (Fig.\u0026nbsp;4\u0026thinsp;\u0026minus;\u0026thinsp;1, 4\u0026thinsp;\u0026minus;\u0026thinsp;2). Pathology showed chronic inflammation with a normal eosinophil count.\u003c/p\u003e \u003cp\u003eThe treatment history for each child was as follows. In Case 1, bloody stools appeared after three days of normal formula feeding after birth. He was then hospitalized for diarrhea, vomiting, and weight loss, and was subsequently treated with continuous feeding of amino acid formula, after which his symptoms were alleviated and he transitioned to intermittent feeding. However, he was re-admitted to the hospital at the age of one year and nine months due to recurrent vomiting and bloody emesis, and gastroscopy suggested esophagitis and pyloric stenosis. After he was treated with Methylprednisolone.he sustained amino acid formula feeding and underwent balloon dilation twice for pyloric stenosis; he showed significant improvement in his esophagitis and pyloric stenosis after two months, and he was fed routinely one-half year later. We added complementary foods to his diet but had him avoid allergenic foods, and his vomiting and diarrhea did not recur; his weight also gradually returned to normal for his age and size. Case 2 experienced diarrhea at 28 days after birth, hospitalization for swollen limbs, and repeated hypoproteinemia, and gastroenteroscopy suggested lymphatic dilatation of the small intestine and colitis. He was treated with eHF and was regularly infused with albumin for 10 months; his albumin level then returned to normal and after diarrhea improved, and he was fed with Peptamen Junior. Gastroscopy and colonoscopy were reviewed after three years of follow-up and showed no abnormalities, and his weight returned to normal. Case 3 manifested persistent, uncorrectable diarrhea (watery stools and mucousy, bloody stools) accompanied by fever, and laboratory tests primarily revealed metabolic acidosis, electrolyte disorders, hepatic impairment, anemia, hypoproteinemia, and ultrasensitive CRP; leukocytes and platelets were also significantly increased. A serum ingesta sIgE group test was negative. Colonoscopy showed segmental, volcano-like ulcers and mucosal defects in the colonic mucosa. After treatment with amino acid formula for four weeks, the patient was discharged from the hospital with clinical improvement and continued to be fed with amino acid formula after discharge. A repeat colonoscopy six months later suggested that the ulcers had disappeared, and his weight returned to normal; however, a rash appeared after the addition of eggs, fish, and shrimp to his diet, suggesting multiple food allergies. Tolerance to allergenic foods was ultimately achieved one-and-one-half years later. Case 4 experienced diarrheal dehydration 28 days after birth, was hospitalized at the local ICU for one day, and was automatically discharged from the hospital after imbibing formula. She experienced vomiting and self-administered rice pudding feeding and was hospitalized at six months of age due to diarrheal fever and skin ulcers. She was provided amino acid formula via continuous nasal feeding by tube and received anti-infectives, fluid replacement, plasma, albumin, and an erythrocyte suspension transfusion with vitamin and trace-element supplementation; she then underwent rehabilitation with newly wet compresses on her skin lesions. Sixteen days later, the rash subsided; feeding commenced with 120 ml/3 h by mouth, without vomiting; stools manifested a paste-like form 2\u0026ndash;3 times/day, and albumin at 33.5 g/L was reevaluated. The girl was then discharged from the hospital on the doctor\u0026rsquo;s advice. Four weeks after discharge, her stools were formed and her albumin was 37.3 g/L. Eight weeks after discharge, the girl\u0026rsquo;s diet was changed to partially hydrolyzed formula, and she experienced no discomfort and was of normal weight. Case 5 exhibited bloody stools on the 5th day after birth, and NEC stage IIb was considered; a caesarean section\u0026thinsp;+\u0026thinsp;perforated colon repair\u0026thinsp;+\u0026thinsp;ileostomy was then performed. After the operation, several attempts were undertaken to provide full-protein formula feeding, but vomiting and diarrhea subsequently occurred. The baby\u0026rsquo;s diet was changed to breastfeeding, and upon the mother avoiding allergy-prone foods, symptoms improved. Six months later, gastroenteroscopy suggested erosive gastritis and erosive colitis, and the diet was changed to breastfeeding\u0026thinsp;+\u0026thinsp;amino acid formula feeding; eight months after the closure of the fistula (i.e., one year later), the baby received deeply hydrolyzed formula feeding that was well tolerated, and her reactions were suggestive of milk, egg white, and wheat allergies. The patient was ultimately able to tolerate other foods, and her weight gradually increased to normal.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCMPA is an adverse reaction to cow milk proteins mediated by immune mechanisms, and the incidence of CMPA is estimated to be 0.5\u0026ndash;3% in developed countries within one year of age \u003csup\u003e[\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e];\u003c/sup\u003e the incidence of CMPA is approximately 2.69% in China \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Neonates constitute a special group due to their immature immune mechanisms and other factors. The incidence of milk protein allergy is relatively low, its clinical manifestation lacks specificity, and it is often misdiagnosed as necrotizing small bowel colitis and sepsis in neonates\u0026mdash;leading to unnecessary surgery or antibiotic use\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Although reports of milk protein allergy in neonates have been increasing in recent years, there is a lack of definitive epidemiologic data. Morita et al. \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e depicted an incidence of CMPA of about 1.98% among 2,116 neonates in neonatal intensive care units (NICUs), with their multicenter analysis revealing that 69,796 were hospitalized. A multicenter study also showed that the incidence of CMPA was 0.21% in 69,796 hospitalized neonates \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Lin et al.\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e reported that CMPA allergy was diagnosed in 160 (53.3%) of 300 hospitalized children with bloody stools in the neonatal unit of their hospital, of which 112 (51.1%) were full-term infants and 48 (59.3%) were preterm infants. Pssariello et al. \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e analyzed 39 cases of diarrhea in their NICU, of whom 20.5% were caused by food allergy, and Miyazawa et al. \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e observed that among 263 NICU infants, 53 cases showed CMPA (with a mean onset age of 6 d) and 41% of them were low-birth-weight infants. In the present study, five cases were full-term infants, and we showed that the onset of disease in full-term infants was 1\u0026ndash;2 weeks; the onset of disease in ultra-low-birthweight infants was also significantly later than in low-birthweight infants (LBWI) or normal birthweight infants \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. There are also reports of allergic colitis in the first few hours and one day after birth\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. In the present study, the children showed disease onset at three to 28 days, and it was evident that the age at onset of disease could be in either the early or late neonatal period. It is hypothesized that neonates with milk protein allergy have a history of eating dairy products one week before the onset of the disease. In our analysis, all neonates had eaten dairy products, including three cases with artificial feeding and two cases with mixed feeding. We suggest that infants administered artificial feeding may be more prone to severe milk protein allergy.\u003c/p\u003e \u003cp\u003eThe clinical manifestations of neonatal CMPA are primarily gastrointestinal symptoms such as diarrhea, bloody stools, vomiting, abdominal distension, and diminished milk intake\u0026mdash;some of which are accompanied by skin symptoms such as eczema and atopic dermatitis; respiratory symptoms are less common. Depending on the severity, neonatal food allergy can be categorized as mild-moderate and severe \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e: mild-moderate digestive symptoms may be manifested as diarrhea, bloody stools, abdominal distension, vomiting, colic, and, in a few cases, constipation, and these symptoms may occur alone or in combination. In addition to gastrointestinal symptoms, chronic diarrhea and vomiting can cause growth retardation, feeding difficulties, nutritional iron-deficiency anemia, protein-losing enteropathy, and severe ulcerative colitis in some cases. Siu et al.\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e reported a case of chronic diarrhea in a Chinese newborn due to CMPA, and this was followed by severe developmental disorders, metabolic acidosis, hypoalbuminemia, severe atopic dermatitis combined with hypoalbuminemia, and severe diarrhea. Atopic dermatitis combined with hypoalbuminemia or combined with growth restriction or iron-deficiency anemia, circulatory failure, and shock may also be present. In our study, of five cases, four children presented with diarrhea and one with bloody stools showing vomiting, fever, malnutrition, edema, and skin ulceration. Laboratory tests showed anemia, hypoproteinemia, elevated leukocytes, and CRP. Gastroenteroscopy suggested various degrees of mucosal inflammation, including esophagitis, pyloric stenosis, lymphatic dilatation of the small intestine, erosive gastritis, erosive colitis, and colonic ulceration with polypoid hyperplastic changes. It is acknowledged that children with severe disease often have anemia, hypoproteinemia, elevated inflammatory indices, differing degrees of inflammation upon gastroenteroscopy, hyperplastic stenosis, and even erosive ulceration that is similar to the manifestation of Crohn\u0026rsquo;s disease\u0026mdash;which is prone to misdiagnosis.\u003c/p\u003e \u003cp\u003eThe diagnosis of neonatal CMPA necessitates being conducted in combination with clinical manifestations, laboratory tests, and the exclusion of infections and surgical diseases. Once neonatal CMPA is considered, a milk avoidance test, oral provocation test, specific IgE assay, skin prick test (SPT), patch test (atopy patch test [APT]), and eosinophil count are performed to confirm the diagnosis \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. But a multicenter survey study in the UK surfaces that 84% of the current diagnoses of neonatal CMPA are clinical diagnoses only\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.Milk avoidance reflects both diagnostic and therapeutic value, and the foods consumed during the avoidance period should be extensively hydrolyzed formula (eHF), AAF, or soy-based formula \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. AAF is preferred for those babies presenting with severe allergic or life-threatening manifestations, and soy-based formulas are preferred for those babies and families who cannot tolerate the bitter taste or cost of eHF. If symptoms do not improve within two weeks, only AAF should be chosen. Further diagnosis requires oral provocation testing that is potentially risky and requires appropriate resuscitative preparations. Soy-based formulas are also not implemented in neonates. In our study, three of the five children showed positivity for milk IgE, one had an elevated eosinophil count in the colonic mucosa, and one exhibited a positive oral provocation test. The remaining four children presented with severe gastrointestinal lesions that were difficult to treat with recurrent illnesses, and the provocation test was not performed after avoidance of the diet for 2\u0026ndash;4 weeks for safety reasons; thus, all were diagnosed therapeutically. Three children were relieved by switching to amino acid formula feeding and one by switching to lactose-free deeply hydrolyzed formula, and one improved after the mother avoided the diet.\u003c/p\u003e \u003cp\u003eFor the treatment of CMPA, the WAO 2010 Food Allergy Guidelines reflected a comparison of the dietary treatment guidelines for CMPA in different countries and organizations, and the common points were that breastfeeding was encouraged, but mothers needed to avoid high-risk foods, and dietary substitutions were recommended vis-\u0026agrave;-vis amino acid formula or eHF \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. According to China\u0026rsquo;s infant milk protein allergy guidelines, formula-fed children with mild-moderate degrees of milk protein allergy should be given eHF, and if milk protein allergy still occurs after consumption of eHF, then the amino acid formula should be replaced; in severe cases, amino acid formula is preferred \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, and avoidance time is at least six months, or until nine to 12 months of age. In the present study, four of five children with severe CMPA were fed with amino acid formula, and lactose-free eHF was administered in one case due to a diagnosis of lymphatic dilatation of the small intestine and recurrent hypoproteinemia. The avoidance time for four of the children was over six months and as long as two years; this was mainly due to obvious gastroenteroscopic inflammation and manifested by hyperplasia and stenosis, erosions, or ulcers. It also took a much longer period of time for the intestinal mucosa to return to normal. One child with recurrent hypoproteinemia exhibited dietary avoidance for two months, but could be transitioned to partially hydrolyzed milk powder feeding and thus recovered more quickly. This suggests that children with severe CMPA often require a longer avoidance time and that gastroenteroscopy is a reliable examination modality that can be used for evaluating the condition and also to guide feeding.\u003c/p\u003e \u003cp\u003eMilk protein allergy in newborns is not uncommon, often reflecting gastrointestinal symptoms as the chief manifestations, including diarrhea, bloody stools, and vomiting. Some of the children with severe milk protein allergy also showed anemia, hypoproteinemia, malnutrition, and other complications; the condition was recurring and the treatment was complicated. Therefore, early gastroenteroscopy is considered an excellent assessment of the scope of the lesions in gastrointestinal inflammation and their severity within the gastrointestinal tract; these symptoms can accumulate in many parts of the gastrointestinal tract, including the esophagus, stomach, duodenum, and colon. The jejunum and ileum, however, are not visualized due to endoscopic limitations. The endoscopic presentation is variable and may consist of hyperplastic strictures, erosions, or even ulcers. Severely affected children are additionally prone to misdiagnosis of sepsis, NEC, and very-early-onset inflammatory bowel disease. Early recognition of CMPA during the neonatal period can thereby avoid misdiagnosis and unnecessary antibiotic or surgical treatment, shorten treatment time, and improve prognosis. Whether early intervention can avoid the progression of gastrointestinal inflammation, however, requires further study.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe report different digestive tract complications of five neonatal-onset infants with severe CMPA which were easily misdiagnosed as NEC or VEO-IBD. The diagnosis relied more on clinical presentation and resolution of symptoms after CMP avoidance.It is difficult to do oral provocation test in the clinic for safety reasons. Prompt treatment with CMP-free formula is effective and leads to clinical remission.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the mothers of the babies. \u0026nbsp;Consent for publication was granted by the institutional ethics committee of Guangzhou Women and Children\u0026rsquo;s Medical Center.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiping Ye and Min Yang participated in acquisition, analysis and interpretation of data, statistical analysis, and drafting of the initial manuscript; Peiyu Chen, Jing Xie, Huiwen Li all participated in\u003c/p\u003e\n\u003cp\u003eacquisition, analysis, and interpretation of data; Sitang Gong and Lanlan Geng conceptualized the study, revised the manuscript for important intellectual content and supervised the project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Funding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot Applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data underlying this article are available in the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo individual images or pictures are included in the report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHost A. Frequency of cow\u0026rsquo;s milk allergy in childhood. Ann. Allergy Asthma Immunol. 2002; 89 (6 Suppl. 1): 33\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eSicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics. 2003; 111: 1609\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003eSwart JF, Ultee K. Rectal bleeding in a preterm infant as a symptom of allergic colitis. Eur J Pediatr 2003; 162: 55-56.3\u003c/li\u003e\n\u003cli\u003eSrinivasan P, Brandler M, D\u0026apos;Souza A, Millman P, Moreau H. Allergic enterocolitis presenting as recurrent necrotizing enterocolitis in preterm neonates. J Perinatol. 2010 Jun;30(6):431-3. doi: 10.1038/jp.2009.153. PMID: 20508631. \u003c/li\u003e\n\u003cli\u003eDifferent presentations of cow`s milk protein allergy during neonatal period. Turk J Pediatr. 2017;59(3):322-328. doi: 10.24953/turkjped.2017.03.015. PMID: 29376580.\u003c/li\u003e\n\u003cli\u003eKoletzko S, Niggemann B, Arato A, et al. Diagnostic approach and management of cow\u0026apos;s-milk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr 2012;55:221-9.\u003c/li\u003e\n\u003cli\u003eDunlop JH, Keet CA. Epidemiology of Food Allergy[J].Immunol Allergy Clin North Am, 2018, 38(1): 13‑25. DOI:10.1016/j.iac.2017.09.002.\u003c/li\u003e\n\u003cli\u003eLifschitz C, Szajewska H. Cow\u0026prime;s milk allergy:evidence‑based diagnosis and management for the practitioner [J]. Eur J Pediatr, 2015, 174(2): 141‑150. DOI:10.1007/s00431‑014‑2422‑3.\u003c/li\u003e\n\u003cli\u003eGupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States [J]. Pediatrics, 2011, 128(1):e9‑17. DOI:10.1542/peds.2011‑0204.\u003c/li\u003e\n\u003cli\u003eBoyce JA, Assa\u0026prime;ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID‑Sponsored Expert Panel report [J]. J Am Acad Dermatol, 2011, 64(1): 175‑192. DOI:10.1016/j.jaad.2010.11.020.\u003c/li\u003e\n\u003cli\u003eYang M, Tan M, Wu J, et al. Prevalence, characteristics, and outcome of cow\u0026prime;s milk protein allergy in Chinese infants:A population‑based survey [J]. JPEN J Parenter Enteral Nutr, 2019, 43(6): 803‑808. DOI:10.1002/jpen.1472.\u003c/li\u003e\n\u003cli\u003eLenfestey MW, de la Cruz D, Neu J. Food Protein-Induced Enterocolitis Instead of Necrotizing Enterocolitis? A Neonatal Intensive Care Unit Case Series. J Pediatr. 2018 Sep;200:270-273. doi: 10.1016/j.jpeds.2018.04.048. Epub 2018 May 24. PMID: 29803301.\u003c/li\u003e\n\u003cli\u003eMorita Y, Iwakura H, Ohtsuka H, Kohno Y, Shimojo N. Milk allergy in the neonatal intensive care unit: comparison between premature and full-term neonates. 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PMID: 25257836; PMCID: PMC4298661.\u003c/li\u003e\n\u003cli\u003eMahadevan J, Gupta A, Harikumar C,et al.PO-0597 A Nationwide Survey Of Neonatal Cow\u0026apos;s Milk Allergy In The Uk[J].Archives of Disease in Childhood, 2014, 99(Suppl 2):A446-A446.DOI:10.1136/archdischild-2014-307384.1237.\u003c/li\u003e\n\u003cli\u003eFiocchi A, Brozek J, Schǖnemann H, et al. World allergy organization(WAO) diagnosis and retionale for action against cow\u0026apos;s milk allergy (DRACMA) guidelines[J]. World Allergy Organ J, 2010, 3(4): 157-161.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4338710/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4338710/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe objective of this study was to summarize different digestive tract complications of five neonatal-onset infants with severe cow milk protein allergy (CMPA) to improve early diagnosis, treatment, and prognosis of CMPA. We retrospectively analyzed various digestive tract complications of the five infants who were hospitalized at Guangzhou Women and Children\u0026rsquo;s Medical Center from July 2016 to June 2020. All five cases were full-term infants, with age at onset ranging from three to 28 days. Three neonates were formula-fed, and two were mixed-fed. The principal clinical manifestations included fever, diarrhea, vomiting, hematochezia, weight loss, edema, and skin ulcers. One infant was diagnosed with necrotizing enterocolitis (NEC) and underwent surgery. Milk-specific IgE was elevated in three cases, and other food-specific IgE antibodies were elevated in two cases. Case 1 revealed severe erosive esophagitis and pyloric stenosis upon gastroscopy; case 2 revealed intestinal lymphatic dilation upon gastroscopy; case 3 showed scattered crater-like ulcers of varying sizes under colonoscopy, with some of the ulcerated tissues around the ulcers showing polypoid changes; case 4 showed ascites of approximately 16 mm in depth upon abdominal ultrasonographic scan; and case 5 depicted colonic stenosis and erosive colitis upon colonoscopy. All five children were cured after receiving either amino acid formula milk (AAF) or extensively hydrolyzed formula (eHF) for enteral nutrition feeding and supportive treatment. Severe CMPA in neonates presented with atypical clinical manifestations, and a variety of complications in various parts of the digestive tract occurred\u0026mdash;including inflammation and stenosis\u0026mdash;which were easily misdiagnosed as NEC or very-early-onset inflammatory bowel disease (IBD). We posit that early diagnosis will reduce unnecessary operations and shorten treatment time.\u003c/p\u003e","manuscriptTitle":"Different Digestive Tract Complications of Neonatal-Onset Infants with Severe Cow Milk Protein Allergy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 14:37:00","doi":"10.21203/rs.3.rs-4338710/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"762b3b7b-04da-4f6a-a183-a968ddf2bc18","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-26T07:53:07+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-03 14:37:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4338710","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4338710","identity":"rs-4338710","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}