Cow’s milk protein allergy in a neonate presenting with methaemoglobinaemia

Abstract

Cow’s milk protein allergy (CMPA) is the most common food allergy in infants. A previously healthy neonate fed with infant formula presented diarrhoea, vomiting and respiratory distress with cyanosis. Investigations showed thrombocytosis and leucocytosis with lymphocyte predominance. To our surprise blood gas analysis showed metabolic acidosis and a high methaemoglobin level of 33% (normal range <3%). Clinical status, metabolic acidosis and methaemoglobin level returned to normal following fluid resuscitation and methylene blue administration. The neonate was later managed with breast feeding and elemental formula. CMPA was diagnosed based on history and clinical improvement after elemental formula. Although not common in CMPA, methaemoglobinaemia should be recognised as a differential diagnosis in a hypoxic infant with metabolic acidosis and diarrhoea as early recognition and treatment with methylene blue can save a child’s life.

Background

Cow’s milk protein allergy (CMPA), the most prevalent food allergy in newborns and infants, has a prevalence of 2%–3% in early childhood.¹ CMPA enterocolitis is either an IgE-mediated or a T cell-mediated, non-IgE antibody-related food hypersensitivity and is often triggered by cow’s milk and/or soy. Classic IgE-mediated food reactions occur within minutes to 2 hours following intake. The skin as well as the respiratory, gastrointestinal and cardiovascular systems can all show signs and symptoms. The non-IgE-mediated variant has a delayed onset and is linked predominantly with gastrointestinal symptoms and less commonly with skin or respiratory symptoms.¹ CMPA symptoms, including vomiting and/or diarrhoea, usually appear in the first month of life and are associated with failure to thrive, metabolic acidosis and shock.² Metabolic acidosis and shock are more common in food protein-induced enterocolitis syndrome (FPIES) than in CMPA. Early identification and distinguishing it from neonatal sepsis help with optimum management. Methaemoglobinaemia is a functional anaemia that occurs when ferrous haemoglobin (Fe²⁺) is oxidised to its ferric (Fe³⁺) state, which the red blood cells are unable to reduce. This leads to hypoxia due to the shift in the oxygen dissociation curve to the left.³ While transient methaemoglobinaemia with acidosis has been documented in individuals with severe diarrhoea, methaemoglobinaemia in neonates with CMPA is uncommon.⁴

Case presentation

A 3.47 kg baby boy was born by caesarean section to a second gravida, non-consanguineous mother. The baby cried soon after birth, was breast fed immediately and was discharged out of hospital on the third postnatal day. On day 20, he was readmitted with complaints of watery stools after each feed, decreased urine output and one episode of fever. His mother started him on a cow’s milk formula on day 13 of age. On examination, the baby was active but showed features of some dehydration, including dry oral mucosa and depressed anterior fontanelle. His examination showed tachycardia (heart rate of 184 per minute), tachypnoea (respiratory rate of 68 per minute) and 86% saturation on room air, with cyanosis in the face, palm and sole. Peripheral pulse examination and systemic blood pressure systolic BP 89/ diastolic BP 43(Mean BP 63mm Hg) were normal. Emergency room venous blood gas showed a pH, PCO₂, PO₂, bicarbonate, base excess and lactate of 7.21, 33.8 mm Hg, 65.4 mm Hg, 12.2 mmol/L, −10.4 mmol/L and 4.5 mmol/L (normal range: 0.7–2.1 mmol/L), respectively. Complete blood count showed white cell count of 18.1×10⁹/L with lymphocyte predominance (72%), haemoglobin of 77 g/L, platelet count of 646×10⁹/L (normal 150–450×10⁹/L) and C reactive protein (CRP) of 90 mg/L (normal <10 mg/L). Blood glucose, electrolytes, and liver and renal functions were all normal (urea 2.99 mmol/L and creatinine 35.37 μmol/L). Routine urinary test, stool culture and stool antigen test for rotavirus were also normal. A peripheral blood smear showed toxic granules, which shifted to the left, and increased band forms. The baby received intravenous fluids and intravenous antibiotics after blood and urine were sent for culture. Cerebrospinal fluid (CSF) analysis was performed to rule out meningitis.

The infant remained cyanotic even after treatment of dehydration and his oxygen saturation (SaO₂) was 85%–88% on nasal cannula. Capillary blood gas revealed a pH, PCO₂, PO₂, bicarbonate, base excess, lactate and methaemoglobin level of 7.42, 23.8 mm Hg, 88.7 mm Hg, 15.2 mmol/L, −7.2 mmol/L and 2.8 mmol/L 26%, respectively. Because methylene blue was unavailable, this stable but symptomatic infant received vitamin C and riboflavin. The loose stools decreased and his urine output increased. Breast milk administration was started after 24 hours of admission. Repeat investigation showed decreasing CRP (30 mg/L) levels. After 5 days of sterile blood and urine cultures, the antibiotics were discontinued.

On day 7 of admission, the baby again developed watery diarrhoea with fever spikes. He looked duskier than before, and with desaturation he needed high-flow oxygen but did not show any respiratory distress. Chest X-ray showed normal lungs and heart, CRP level was 113 mg/L, peripheral smear and procalcitonin were normal (0.36 μg/L), and blood methaemoglobin was 33%.

Investigations

Initial evaluation showed leucocytosis, thrombocytosis, high CRP, metabolic acidosis and high methaemoglobin levels. Further work-up to identify the cause revealed normal echocardiography and abdominal and head ultrasound. Blood ammonia (123 mmol/L; normal range: 6–50 mmol/L) and blood lactate (4.5 mmol/L; normal range: 0.7–2.1 mmol/L) were mildly elevated. Extended newborn inborn error of metabolism screening including serum glucose 6 phosphate dehydrogenase (G6PD) levels and high-performance liquid chromatography haemoglobin electrophoresis for serum IgG, IgM, IgE and haemoglobin levels were all normal.

Differential diagnosis

Methaemoglobinaemia is suspected in a newborn or infant with cyanosis, out-of-proportion pulse oximetry and SaO₂ that fails to improve with oxygen supplementation. It is also associated with brownish to blue blood that does not turn red on room air (21% oxygen) or oxygen. Before diagnosing methaemoglobinaemia, other cardiac and pulmonary causes of hypoxia or cyanosis, sepsis, anaemia and polycythaemia should be ruled out. Biallelic pathogenic variants in CYB5R3 (which encodes cytochrome b5 reductase) cause congenital methaemoglobinaemia; cyanosis is usually present, although hypoxia is uncommon. Dapsone (an antimalarial), topical benzocaine, and environmental toxins such as nitrites, nitrates and aniline dyes can cause acquired methaemoglobinaemia. Abnormal haemoglobin such as carboxy-methaemoglobin and sulfhaemoglobin should also be considered. The patient had no family history of methaemoglobinaemia. To rule out late-onset sepsis, blood, urine and stool cultures were taken and a CSF examination was also performed. Congenital cyanotic heart disease, G6PD deficiency and haemoglobin M were ruled out. This neonate had no exposure to oxidant drug or nitrite (well water). As reported previously, methaemoglobinaemia is associated with diarrhoea and metabolic acidosis.

Sepsis, gastroenteritis, lactose intolerance, CMPA, FPIES and enterocolitis should all be investigated as differential diagnoses when a neonate or infant has diarrhoea. Unfortunately, no symptom is pathognomonic of CMPA. Many infants with CMPA develop symptoms related to at least two of the following organ systems: gastrointestinal system (50%–60%), skin (50%–60%) and respiratory tract (20%–30%).⁵ The timing and pattern of these symptoms can assist in making differential diagnoses, including metabolic disorders, anatomical abnormalities, coeliac disease, some rare enteropathies and pancreatic insufficiency such as cystic fibrosis. Non-immunological adverse food reactions (such as fructose malabsorption or secondary lactose intolerance, mostly in older children) and allergic reactions to food allergens (such as hen’s eggs, soy and wheat) or other substances (such as animal dander, moulds and dust) should be considered. Gastrointestinal and urinary tract infections and late-onset sepsis should be ruled out.⁶

Treatment

The baby was treated with intravenous fluid, intravenous antibiotics and methylene blue infusion and received parenteral vitamin C. CMPA was evaluated due to exposure to cow’s milk-derived infant formula, loose stools, thrombocytosis, and infection as a cause was ruled out. This time, elemental formula feeding was started. Although the mother had no history of consumption of considerable amounts of dairy products, she was advised to avoid dairy products while breast feeding. The baby’s diarrhoea resolved within a few days of initiating elemental formula feeding and started gaining weight. Repeat tests for methaemoglobin showed decreased levels (12.5%) and the baby showed clinical improvement.

Outcome and follow-up

Methaemoglobin levels and platelet counts were normal after hospital discharge at 1-month follow-up. At 4 months, the baby was thriving well, weighed 6.8 kg and was tolerating breast feeding. Strict avoidance of cow’s milk protein is currently the safest strategy in the management of CMPA. Mothers should be encouraged to continue breast feeding while avoiding all milk and milk products. In breastfed infants with severe symptoms (eg, severe atopic eczema or allergic (entero) colitis complicated by growth faltering and/or hypoproteinaemia and/or severe anaemia), the infant may be fed with a therapeutic formula from several days to a maximum of 2 weeks. Once CMPA is confirmed, the infant should be maintained on an elimination diet using therapeutic formula for at least 6 months or until 9–12 months of age.¹ Approximately 50% and >75% of affected children outgrow the condition by 1 year and 3 years, respectively, and >90% outgrow the condition and are tolerant by 6 years of age.⁷

Discussion

Methaemoglobinaemia in a neonate with dietary protein-induced enterocolitis caused by CMPA is described in this case report. It is characterised by frequent vomiting and diarrhoea in its severe form and can lead to dehydration and shock in 20% of patients.⁸ Depending on the blood levels, methaemoglobinaemia can cause a variety of symptoms, which generally arise when the total haemoglobin level is >20%. Methaemoglobinaemia levels of ≥30% cause dyspnoea, cyanosis, nausea, vomiting, tachycardia and poor perfusion. As methaemoglobin levels approach 55%, lethargy, stupor and deterioration of consciousness occur.³ Methaemoglobinaemia is mistakenly identified as oxyhaemoglobin by pulse oximetry due to a similar range of wavelength. The use of bedside multiwavelength co-oximetry or blood gas measurements to determine methaemoglobinaemia levels can aid in the diagnosis. Another useful diagnostic method is quantitative serum estimation.

Methaemoglobinaemia can be inherited (haemoglobin M or cytochrome b5 reductase deficiency) or acquired (drugs and poisons). Congenital causes can be asymptomatic or cause cyanosis. Acquired methaemoglobinaemia is more common and is caused by medicines, chemicals and nitrite exposure.⁹ Nitrites and nitrates can be found in various foods, including breast milk and infant formula. The body normally excretes nitrites via the gastrointestinal and renal systems. Catalase transforms nitrite to ammonia and nitrate in the colonocytes and erythrocytes. Methaemoglobin is generated when the erythrocytes convert nitrite to nitrate; however, it is soon changed back to haemoglobin by methaemoglobin reductase. Dehydration and diarrhoea are linked with methaemoglobinaemia in early infants (6 months). Young infants may be particularly sensitive due to low erythrocyte cytochrome b reductase levels, easy fetal haemoglobin oxidation, low stomach acid production and high nitrite-reducing gut bacteria.^{10 11} Methaemoglobin levels can increase in sepsis due to increased nitric oxide production, which is converted to methaemoglobin and nitrate.¹²

Methaemoglobinaemia has been reported in diarrhoea induced by hypersensitivity to cow’s milk protein. CMPA alters the gut microbiome and induces bacterial overgrowth, resulting in increased nitrite production. Mucosal inflammation reduces catalase activity, resulting in reduced nitrite clearance and increased methaemoglobin formation.^{4 13} Metabolic acidaemia further worsens methaemoglobinaemia by increasing nitrite-induced methaemoglobinaemia conversion.

Although rare, 33 cases of methaemoglobinaemia have been reported in the literature.¹⁴ The key similarity in all cases is the inclusion of infants aged <3 months who had been exposed to cow milk-based infant formula. After 1–2 weeks of diarrhoea, methaemoglobinaemia developed. There is no link between methaemoglobin levels and acidosis severity. This could be due to the differing CYB5R enzyme levels, which although low in babies increase to adult levels by 6 months of age.

To treat acquired methaemoglobinaemia, the precipitating agent must be discontinued. The first-line treatment for drug-induced methaemoglobinaemia is methylene blue infusion. When methaemoglobin levels reach 30% in asymptomatic and 20% in symptomatic patients, or when anaemia is present, treatment should be considered.¹⁵ Methylene blue acts by activating the alternative methaemoglobin reduction pathway. Methylene blue is fast-acting and produces good response at a dose of 1–2 mg/kg. Because its activity is dependent on the presence of nicotinamide adenine dinucleotide phosphate in red cells, it should be administered with dextrose, which aids in synthesis. It is contraindicated in patients with or suspected G6PD deficiency as it can induce haemolysis.¹⁶ If methylene blue is unavailable, ineffective or contraindicated, a high dosage of intravenous vitamin C solution can be used instead.¹⁷ Methaemoglobin due to haemoglobin M does not respond to vitamin C or methylene blue. After successful treatment, the patient should be followed up for rebound methaemoglobinaemia.

FPIES is a non-IgE, gastrointestinal-mediated acute food allergy that predominantly affects infants. Acute FPIES typically presents between 1 and 4 hours after ingesting the trigger food, with the principal symptom being profuse vomiting, accompanied by pallor and lethargy. Additional features can include hypotension, hypothermia, diarrhoea, neutrophilia and thrombocytosis. This clinical presentation may mimic sepsis, gastroenteritis, intussusception, other rare surgical abdominal emergencies and metabolic crisis. However, FPIES diagnosis is favoured if there is a rapid resolution of symptoms within hours of presentation, absence of fever and lack of a significant increase in CRP at presentation. When cow’s milk and soy milk FPIES coexist, the first-line options include an extensively hydrolysed or elemental infant formula when breast feeding is impossible. Many cases of methaemoglobinaemia have been reported with FPIES, where early identification is key.¹⁸

Learning points.

• Many cases of methaemoglobinaemia are reported with food protein-induced enterocolitis syndrome (FPIES) or cow’s milk protein allergy (CMPA), where early identification is key to treatment.

• Timely administration of methylene blue may improve the outcome.

• Methaemoglobinaemia secondary to CMPA should be considered as a differential in newborns with diarrhoea, acidaemia, cyanosis, out-of-proportion pulse oximetry and oxygen saturation that fails to improve with oxygen treatment.

• When cow’s milk and soy milk FPIES coexist, the first-line options include an extensively hydrolysed or elemental infant formula when breast feeding is not possible.

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