Severe upper gastrointestinal hemorrhage due to milk protein allergy: A case report

Abstract

BACKGROUND

Upper gastrointestinal hemorrhage is a life-threatening manifestation of cow’s milk protein allergy (CMPA). We analyze the clinical characteristics of a case of milk protein allergy manifested as severe upper gastrointestinal hemorrhage.

CASE SUMMARY

The hospital admitted a 2-month-old male infant due to “melena for 6 days, hematemesis twice”. The main symptom was melena, initially occurring once or twice per day, then gradually increasing to five or six times per day at their peak. During the course of the illness, the infant vomited blood, but there were no reports of vomiting, fever, pale complexion, dyspnea, wheezing, or difficulty breathing. Laboratory tests showed hemoglobin level of 87 g/L, platelet count of 349 × 10⁹/L, and eosinophil percentage of 0.031. Coagulation studies were normal. After avoiding certain foods and feeding with an amino acid formula for 2 weeks, a repeat gastroscopy revealed less bleeding. After six weeks, a positive oral food challenge test confirmed a severe CMPA. At the 4-month follow-up, there was no gastrointestinal bleeding, and the infant was growing and developing well.

CONCLUSION

The manifestations of milk protein allergy are diverse and nonspecific, with gastrointestinal bleeding being less common, especially in infants. When infants present with unexplained massive hematemesis, it’s critical to investigate the possibility of CMPA.

Key Words: Cow’s milk protein allergy; Gastrointestinal bleeding; Hematemesis; Melena; Infants; Case report

Core Tip: Milk protein allergy is the most common food allergy reaction in infants and children under three years old, with diverse and non-specific clinical manifestations. Severe clinical symptoms such as gastrointestinal bleeding can be life-threatening, requiring doctors to be vigilant. This study, by reporting a case of severe milk protein allergy in children, will play a warning role in future clinical application.

INTRODUCTION

The cow’s milk protein allergy (CMPA) is characterized by an aberrant immune response of the body towards cow’s milk protein, exhibiting a wide range of clinical manifestations that affect multiple bodily systems, including the respiratory, digestive, and integumentary systems. The most prevalent cause of food allergies in infants and children under 3 years old is CMPA[1,2]. The prevalence of CMPA in children ranges from 1.3% to 2.9%[3]. The onset of milk protein allergy typically occurs within the first two years of life, particularly in the initial year, unlike other allergies such as peanuts, nuts, fish, and shellfish which may manifest later in childhood or adulthood[4]. The incidence of CMPA in the first year of life is estimated to be between 2% and 7.5%[5]. The risk of CMPA in infants is increased by factors such as premature birth, low birth weight, being the first child, being born in spring or summer, mixed or artificial feeding practices, and having a family history of allergies[6]. Allergen-specific T cells may play a role in non-immunoglobulin (Ig) E-mediated CMPA and CD8⁺ T cells may have a role in food allergy-induced gastrointestinal symptoms[5,7,8]. T cell-mediated immune reaction cause damage after stimulation from antigens. The Cow’s milk contains many different proteins including caseins and whey. A much severe allergic reaction may result from the rapid transportation of whey protein through epithelial cells[9]. Allergen-specific IgE antibodies are bound to mast cells and basophils, resulting IgE-mediated allergic responses include abdominal cramping, hypotension, disorientation, and shock. This response may be fatal[10]. The typical gastrointestinal symptoms associated with milk protein allergy encompass diarrhea, emesis, constipation, and hematochezia[11]. The occurrence of severe milk protein allergy-related clinical symptoms, such as hematemesis and gastrointestinal bleeding, is rare both domestically and globally. This study reported a case of a severe milk protein allergy who presented with hematemesis and severe upper gastrointestinal hemorrhage, along with providing an overview of CMPA associated with severe upper gastrointestinal hemorrhage.

CASE PRESENTATION

Chief complaints

A 2-month-old male infant who presented with a history of passing melena for 6 days and experiencing two episodes of hematemesis.

History of present illness

The predominant symptom observed was melena, initially occurring once or twice daily and later escalating to 5-6 episodes per day. There were no accompanying signs of pyrexia, pallor, dyspnea, wheezing, or respiratory distress. During the illness, the infant experienced two episodes of hematemesis, characterized by a significant presence of fresh blood in milk-like vomitus. Subsequently, after a 3-day hospitalization at the local medical facility, the diagnosis of “massive gastrointestinal bleeding” was established. The treatment consisted of administration of a hemostatic drug and supplementation with vitamin K1, as well as transfusion of 0.5 units of leuko-reduced red blood cells. Following the intervention, the infant experienced recurrent hematemesis. Therefore, he was transferred to our hospital for further medical intervention.

History of past illness

No significant past illness.

Personal and family history

The patient was a full-term vaginal delivery. There was no history of cyanosis or asphyxia at birth, and the mother did not receive any specific prenatal medication. During the neonatal stage, everything was in good condition. The infant was formula-fed after birth, and there was no family history of allergic disease and hereditary disease. The patient’s family denied that the patient has a history of drug allergies and adverse drug reaction history.

Physical examination

Physical examination revealed a moderate anemic appearance. Vital signs on presentation showed a heart rate of 135 beats/minute, respiratory rate of 26/minute, and body temperature of 37.2 °C. Facial eczema was observed, while examinations of the heart, lungs, and abdomen showed no abnormalities. Neurological examination yielded normal results.

Laboratory examinations

The laboratory examination revealed a hemoglobin level of 87 g/L, a platelet count of 349 × 10⁹/L, and an eosinophil percentage (EOS%) of 0.031%. Liver function tests indicated an albumin level of 34.3 g/L. Renal function was normal. The coagulation profile demonstrated a prothrombin time of 9.8 seconds, an international normalized ratio of 0.88, an activated partial thromboplastin time of 30.8 seconds, a fibrinogen level of 3.74 g/L, and a prothrombin activity of 140%. D-dimer quantification was measured at the value of 903 ng/mL. The fecal occult blood test is positive. Allergen test results showed no positive. The IgE level is 200 IU/mL.

Imaging examinations

Gastroscopy suggests extensive erosive hemorrhagic gastritis (Figure 1). Results of histopathologic examinations demonstrated chronic non-atrophic active gastritis of the gastric mucosa with 2 eosinophils/high power field (HPF) and chronic active duodenitis with 11 eosinophils/HPF.

Figure 1 Endoscopic changes seen before and after therapy. A: Gastroscopy showed that there were ulcers in the esophagus (at the initial stage of the disease); B: Extensive erosive hemorrhagic gastritis (at the initial stage of the disease); C: Scattered hemorrhagic spots in the gastric antrum (at the initial stage of the disease); D: The subsequent gastroscopic reexamination after a milk protein-free diet and administration of an amino acid-based formula showed healed esophageal results; E: The subsequent gastroscopic reexamination after a milk protein-free diet and administration of an amino acid-based formula showed healed gastric body results; F: The subsequent gastroscopic reexamination after a milk protein-free diet and administration of an amino acid-based formula showed healed gastric antrum results.

FINAL DIAGNOSIS

Elevation of the IgE level is typically not a diagnostic criterion for CMPA and there was no specific serum IgE in 23.6% of all children with CMPA[12]. Although a higher EOS% is strongly associated with food allergies, this is not a diagnostic criterion for CMPA. The EOS% level in about 39.9% of children with food allergies is less than 5%[13]. Base on the patient’s medical history, the patient was final diagnosed with CMPA. Since the inflammatory markers were negative and there were no indications of infection during the illness, infection is not taken into consideration. The treatment lasted six weeks. Six weeks later, the oral food challenge (30 mL milk) test returned positive, showing facial eczema again, which confirmed the diagnosis of severe CMPA.

TREATMENT

The patient subsequently prescribed a milk protein-free diet, followed by administration of an amino acid-based formula. The subsequent gastroscopic reexamination revealed improved hemostasis after 4 weeks compared to the initial bleeding episode (Figure 1).

OUTCOME AND FOLLOW-UP

At the 6-month follow-up, the patient’s adherence was well. There was no gastrointestinal bleeding and adverse event, and the patient exhibited good growth and development. A timeline of the episode of care showcases in Figure 2.

Figure 2 The timeline of care: A 2-month-old male child reported in this case was not treated at the initial stage of the disease, but his symptoms worsened later. After a 3-day hospitalization at the local medical facility, the diagnosis of “massive gastrointestinal bleeding” was established. The treatment consisted of administration of a hemostatic drug and supplementation with vitamin K1, as well as transfusion of 0.5 units of leuko-reduced red blood cells. However, his symptoms continued to repeat. He was transferred to our hospital for further medical intervention. Physical examination showed atopic dermatitis of the face. The laboratory examination showed eosinophilia increase. Gastroscopy suggests extensive erosive hemorrhagic gastritis. Results of histopathologic examinations demonstrated chronic non-atrophic active gastritis of the gastric mucosa with 2 eosinophils/High power field and chronic active duodenitis with 11 eosinophils/High power field. The symptoms and signs improved after diet avoidance and an amino acid-based formula. Six weeks later, the positive oral food challenge test was performed to diagnose milk protein allergy. After 4 months of follow-up, the growth and development of the children were normal.

DISCUSSION

The incidence of self-reported food allergies in Chinese children aged 0-5 tends to increase as they grow older[14]. The three most common allergens in pediatrics are milk, eggs, and peanuts[15]. The milk avoidance test is a typical way to diagnose CMPA. This is the best method for confirming CMPA because asymptomatic infants will re-establish symptoms after reintroducing milk protein[10]. The diverse clinical manifestations of CMPA, lacking clear specificity, can lead to both underdiagnosis and overdiagnosis[5]. A rare yet potentially life-threatening clinical manifestation of milk protein allergy is severe upper gastrointestinal hemorrhage[16]. The clinical characteristics of the cases reported in this study include the onset of symptoms in an infant after 2 months of birth, with significant upper gastrointestinal hemorrhage as the main clinical presentation. Auxiliary examinations showed severe anemia, extensive mucosal erosion under endoscopy, and a positive open diet provocation test. Following the dietary avoidance and switching to amino acid formula feeding, the gastrointestinal hemorrhage improved. There have been few reported occurrences of upper gastrointestinal hemorrhage caused by CMPA. We conducted a literature review on cases of CMPA with upper gastrointestinal hemorrhage mainly presenting as hematemesis, with a total of 7 cases that summarized in Table 1.

Table 1 Cases of cow’s milk protein allergy with upper gastrointestinal hemorrhage.

Case	Onset age	Sex	Clinical manifestation; growth status	Laboratory examination	Endoscopy	Treatment	Follow-up time outcomes
Case 1[21]	3-month	Boy	Bloody vomiting eczema; weight 7.035 kg, height 68 cm	Hb: 96 g/L; WBC: 7.8 × 1012/L; 3% eosinophils	The gastric mucosa was diffusely friable and erythematous, with multiple incomplete erosions	Trial feeding of cow’s-milk infant formula	Improved
Case 2[22]	Newborn (1-day)	Boy	Bloody gastric aspirates, bloody stools, anemia	Hb 139 g/L; WBC: 25 × 1012/L; 6% eosinophils; IgE (-)	Erythema in the stomach	Amino acid milk formula	11weeks; improved
Case 3[23]	3-month	Boy	Bloody vomiting, bloody stool, eczema, fever, refuse feeding, anemia; weight loss	Hb: 57 g/L	-	Homogenized milk; mullsoy formula; soybean formula	22 months; improved
Case 4[24]	Premature infant	Girl	Coffee colored mucoid gastric content, eczema, anemia; low birth weight infants	Hb: 99 g/L; IGE (+)	-	Amino; acid milk formula	2 months; improved
Case 5[25]	8-months	Boy	Vomiting; of fresh blood, melena, diarrhea, wheezy, anemia; weight 8.5 kg, length 72 cm	Hb: 78 g/L; IGE (+)	Mild diffuse gastritis, erythematous, erosive and hemorrhagic mucosa of duodenum	Dietary restriction	Improved
Case 6[26]	24-months	Boy	Vomiting, hematemesis, regurgitate, irritability, anemia; weight loss	Hb: 102 g/L; WBC: 15.6 × 1012/L; 3% eosinophils	Hemorrhagic erosive pangastritis, 24.1 eosinophils/HPF HP negative	Dietary restriction, soya based; formula	2 years; improved
Case 7[26]	24-months	Girl	Vomiting, hematemesis, diarrhea, anemia; weight loss	-	Esophagitis, erosive, gastritis on the cardia and anterior corpus wall and duodenitis	Dietary restriction, semi-elemental formula	2 years; improved

Hb: Hemoglobin; WBC: White blood cell; IgE: Immunoglobulin E; HPF: High power field; HP: Helicobacter pylori.

CMPA is categorized into IgE-mediated, non-IgE-mediated, and mixed types. Non-IgE-mediated reactions usually occur 2 hours after the intake of milk protein, while IgE-mediated reactions typically occur within a few minutes to 2 hours after intake. A positive skin prick test or serum-specific IgE test helps identify IgE-mediated food allergens. The clinical manifestations of CMPA are non-specific, primarily affecting the respiratory tract, digestive system, and skin. Regarding the severe digestive system diseases, CMPA can present as food protein-induced proctocolitis, food protein-induced enteropathy syndrome, and food protein-induced enterocolitis syndrome. In addition to respiratory symptoms such as non-infectious cough and wheezing, children with mild to moderate CMPA may also experience gastrointestinal symptoms including vomiting, diarrhea, and abdominal distension. Furthermore, they may exhibit manifestations of atopic dermatitis. Severe cases are characterized by the presence of one or more of system symptoms[17,18]: (1) In terms of the gastrointestinal system, growth retardation caused by food refusal, diarrhea, vomiting, or reflux; (2) Severe gastrointestinal bleeding resulting in anemia; and (3) Protein-losing enteropathy or ulcerative colitis. Although rare, severe gastrointestinal bleeding in infants can occasionally be fatal[19,20]. In the reviewed literature on cases of CMPA, the age of onset is predominantly observed between 2 months and 2 years old. Anemia was found in varying degrees in 6 cases (85.7%), hematemesis in 5 cases, accompanied by rash in 3 cases (42.9%), vomiting in 2 cases (28.6%), bloody stools in 2 cases (28.6%), black stool in 1 case (14.3%), fever in 1 case (14.3%), and growth and development restriction in 2 cases (28.6%). The case we documented included symptoms such as bloody vomiting, bloody stools anemia and rash, but no fever. Among the cases undergoing upper gastrointestinal endoscopy, 100% (5/5) of the CMPA patients had lesions affecting the gastrointestinal mucosa. The endoscopy of these children showed extensive mucosal erosion, which were consistent with our report. The treatment plans mostly involved switching to the amino acid-based formula or the extensively hydrolyzed protein formula, and significant therapeutic effects were achieved.

The patient in this case had previously been formula-fed, thus, direct care with amino acid formula was commenced. A subsequent endoscopy confirmed that the bleeding had improved, and after a 4-month follow-up, there was no gastrointestinal bleeding as the child grew and developed normally. In the reviewed CMPA cases, 100% (7/7) of the children showed clinical improvement after avoiding certain food and switching to formula milk. Among the cases, 60% (3/5) of the children experienced growth and development restrictions, while 40% (2/5) of the children showed good growth and development during follow-up. Results and treatment approaches are in line with the case we reported. Despite the infant’s positive clinical results, more extensive clinical research is still required to produce higher standards of evidence-based medicine.

CONCLUSION

In conclusion, the clinical manifestations of CMPA are diverse and nonspecific, with severe upper gastrointestinal bleeding being particularly rare. When infants present with unexplained massive hematemesis, it is important to be alert to the possibility of CMPA. Dietary avoidance and amino acid formula feeding are the optimal feeding methods for CMPA. The limitation of this study lies in the small number of cases. To inform therapeutic treatment, more research with a bigger sample size is required.