FPIES in exclusively breastfed infants: two case reports and review of the literature

A two-month-old, exclusively breastfed male infant presented to the Emergency Department after two episodes of vomit and five episodes of diarrhea without blood or mucus. In the previous week, the baby had some occasional episodes of loose stools and a mild, but persistent, abdominal distension. He was born at term (39 weeks of gestational age) from spontaneous vaginal birth after an uncomplicated pregnancy, with a birth weight of 3480 g. Before he came to our attention, the boy was always in good health and his weight was regularly increasing. On physical examination, the child appeared pale and irritable, with low-grade fever (37.8 C°), heart rate 178 beats per minute and a prolonged capillary refill time (3 s). An intravenous bolus of 0.9% saline at 20 ml/Kg was administered in 20 min, followed by continuous intravenous hydration. Blood tests were in range, except for an increased C-reactive protein (3.5 mg/dl) and hypoalbuminemia (2.7 g/dl). The arterial blood gas analysis (ABG) was normal, except for a significant increase in methemoglobin (13%, normal range between 0 and 1.5%). Two urinary dipsticks in two different samples showed no signs of infection, later confirmed by a negative urine culture. Six hours after the admission, the child became irritable and his skin was mottled. Blood cultures were obtained before starting an intravenous antibiotic therapy with ceftriaxone. Central nervous system, thoracic and abdominal ultrasounds were negative. Eventually, the blood cultures and stool analysis (for bacteria, viruses, fungi and parasites) tested negative as well. The day after, through fluid resuscitation and antibiotic therapy, the boy’s conditions generally improved, and his mother kept breastfeeding him. However, he continued to present numerous episodes of diarrhea, around 12–15 per day, with greenish liquid stools, that led to a mild weight loss (− 200 g in 48 h). Two days after the admission, despite intravenous support, the child developed a severe dehydration, with hypernatremia (152 mmol/L), hypokalemia and hyperchloremic metabolic acidosis (pH 7.26, bicarbonate 18 mmol/L, base excess − 7.7, acid lactate 2.39 mmol/l). Blood tests showed anemia (hemoglobin 9 g/dl), thrombocytosis (platelets 552.000/mL), worsened hypoalbuminemia (1.7 g/dL) which required an IV supplementation, stably elevated methemoglobin (13%) and raised levels of transaminases (peak values: ALT 396 U/L, AST 121 U/L). Due to the worsening clinical condition and to a very poor suction, a central venous line was placed and parenteral nutrition was started. Remarkably, when breastfeeding was suspended because of the baby’s hypotonic suction, diarrhea started to improve and halved to five-six episodes per day. Serologies and PCR for cytomegalovirus, Parvovirus B19, Epstein Barr virus, Adenovirus, hepatotropic viruses, and a nasal-pharyngeal swab for viruses and bacteria were negative. In the following days, the patient regained good general clinical conditions, and laboratory tests were normalized, except for the methemoglobin, which was still very high (8–10%). However, when breastfeeding was reintroduced, his diarrhea worsened once again to 10–15 episodes per day. A metabolic disease was suspected but it was unlikely, as demonstrated by the negative neonatal screening, the clinical presentation and the values of ammonium, glucose, lactate and ABG, all in range. Congenital causes of diarrhea were ruled out because they should have appeared earlier, in the first days of life. Thus, according to some similar clinical cases reported in the literature, the close relationship between breastfeeding and diarrhea and the high level of methemoglobin were emphasized and Food Protein-Induced Enterocolitis Syndrome (FPIES) caused by maternal milk was suspected. Since the mother was already on a milk exclusion diet, breastfeeding was definitely stopped and replaced with an amino acid-based formula. Over the next 72 h, diarrhea gradually improved and then stopped, so that the intravenous hydration was reduced and subsequently suspended, and the infant started to gain weight. Skin prick test resulted negative for cow’s milk proteins (lactalbumin, lactoglobulin, and casein) and soy. After the hospital discharge, an oral food challenge test (OFC) was proposed to the child’s parents but they refused it, in consideration of the severe clinical symptoms that the infant previously developed. The boy was weekly checked through the following months and he kept gaining weight without presenting any clinical symptom. Therefore, the amino acid-base formula was continued, which he’s still taking at the age of 6 months.

A three-month-old, exclusively breastfed female baby presented to the Emergency Department for a 3 days history of persistent vomit and diarrhea without fever. She was born at term (39 weeks of gestational age) from spontaneous vaginal birth after an uncomplicated pregnancy, with a birth weight of 3210 g. Her previous medical history was silent and her growth has always been regular. On physical examination, the baby was pale and hypotonic and a weight loss of 6% was noticed. Blood tests showed mild anemia (hemoglobin 10.9 g/dL), lymphomonocytic leukocytosis (white blood cells 14.050/mmc, lymphocytes 7.370/mmc, monocytes 2.680/mmc), thrombocytosis (platelets 927.000/mmc), electrolyte imbalance (sodium 131 mEq/L, potassium 3.27 mEq/L, chloride 109 mEq/L, calcium 8.33 mg/dL), hypoproteinemia (3.2 g/dL) with hypoalbuminemia (1.8 g/dL) and slightly altered coagulation values (INR 1.6, aPTTr 1.85). Arterial blood gas was normal, except for a raised level of methemoglobin (7%, normal range between 0 and 1.5%). A venous catheter was placed and continuous intravenous hydration with 0.9% saline was started. Stool analysis tested negative for viruses, bacteria and parasites. Suspecting a post-viral intestinal colonization, an antibiotic therapy with rifaximin was started, later substituted by oral gentamicin, both without clinical improvement. Due to the persistent diarrhea and the alteration of blood tests, we integrated the girl’s therapy with vitamins, trace elements (such as zinc) and albumin, and we performed a red cells and a plasma transfusion. Even if she continued to assume breast milk regularly, we added supportive parenteral nutrition. Laboratory tests were requested to rule out myocarditis, metabolic diseases, botulinum intoxication, cystic fibrosis and pancreatic insufficiency, and they were all normal. The patient also developed a severe hypotonia with hypoexcitability of deep tendon reflexes. A cerebral MRI and an electromyography showed no remarkable alterations, and vitamin B12 and folate were in range as well. Because of the persistence of the intestinal symptoms, an esophagogastroduodenoscopy was requested. The histopathology of the biopsies showed an eosinophilic infiltration of the duodenal mucosa, raising the suspicion of a non-IgE mediated food allergy to cow’s milk proteins, conveyed by maternal breast milk. Therefore, the baby’s mother started an exclusion diet and stopped the consumption of cow’s milk and dairy products. In the following 2 days, we noticed a slow but steady improvement of the general conditions of the patient, which was still mildly hypotonic but showed reduced episodes of diarrhea. Therefore, an amino acid-based formula was started, leading to a rapid and stable regularization of the bowel function, a gradual increase in weight and a complete recovery of the muscle tone. Blood tests confirmed the clinical improvement with an increase in hemoglobin and total proteins and the normalization of coagulation parameters and methemoglobin. RAST and skin prick test for cow’s milk proteins tested negative. An oral food challenge test (OFC) was proposed to the child’s parents after the hospital discharge, but they preferred to not perform it. Therefore, the girl was kept on amino acid-base formula and her mother continued the exclusion diet. We monthly checked the infant for the following 9 months and she kept gaining weight, without presenting any clinical symptom. Weaning was regularly started at 6 months, with the exclusion of cow’s and soy milk and dairy products, which we’ll try to introduce in the next months.