Cows’ milk protein allergy & Lactose intolerance: The use & Abuse of specialised infant formulae 2011

Aim To outline the differences between cows’ milk  protein allergy (CMPA) and lactose intolerance To give guidance on how to suspect lactose intolerance & CMPA To show the algorithm for CMPA in bottle fed babies; Vandenplas 2007, including the use of specialised infant formulae To discuss the role of soya, rice & goat’s milks etc To show some illustrative cases

CMPA and lactose intolerance Allergy is a reaction to a foreign protein (allergen) Allergy involves the immune system Intolerance does not Lactose is a sugar, therefore not an allergen Lactose is present in all animal milks including breast milk Cows’ milk protein allergy (CMPA) & lactose  intolerance are two very different things

Lactose intolerance Allergy

Lactose; “milk sugar” Lactase Glucose Galactose Lactose

Lactase; brush border of duodenum Lactase levels highest at birth, tend reduce thereafter

Lactose intolerance; 3 types Congenital Acquired Primary

Congenital lactose intolerance Extremely rare autosomal recessive disorder associated with a complete absence of lactase expression. Finns & Russians

Primary lactose intolerance; childhood/teenage & adult onset Lactase deficiency: extremely common in this age group Lactase levels genetically programmed to decline steadily after 2 years of age, but rarely become symptomatic until after 7 years of age

Acquired lactose intolerance Transient by nature After gastroenteritis, bowel surgery etc Takes about 3 months to resolve

Who gets it? Prevalence Northern Europeans (ie most of UK!) have the lowest prevalence of primary lactose intolerance; usually only manifest over the age of 5 years Central & Southern Europeans have higher rates Hispanic, African and Indians have much higher prevalence, maybe apparent over the age of 2+ years Premature babies; < 34 weeks gestation (70% term lactase levels at 34 weeks)

So what happens to the lactose? Reaches large bowel undigested Creates abnormal osmotic load to bowel This causes; Bacterial fermentation of lactose to hydrogen gas, Increased faecal water, Increased gut transit time, Explosive acid stools with Excoriated bottom

Lactose intolerance; clinical Mainly relating to (bacterial fermentation of lactose in) the large bowel Bloating Pain & discomfort “Gassy” Diarrhoea Explosive stools; no blood except from Sore bottom

Lactose intolerance; investigation Making the diagnosis; History is the key Stool pH & reducing substances (hot fresh sample, within the hour!) Normal stool pH ~6 < 5.3 is acidic and diagnostic of carbohydrate (sugar) malabsorption Breath hydrogen test; rarely done in children

Lactose intolerance; management Lactose intolerance; suitable milks; Enfamil O Lac SMA LF Soya over 6 months of age

Colief is lactase drops

CMPA

Cows milk protein allergy; CMPA CMPA is; Much more common than lactose intolerance Easily missed, can be difficult to diagnose Causes infant distress, impaired growth & a wide variety of clinical symptoms Spectrum of disease; no one pathognomonic  symptom There is no diagnostic test

CMPA; how big is the problem? 5-15% of infants show symptoms suggestive of  adverse reaction to cows’ milk protein

Symptoms of CMPA Often, but not always occur within first few weeks after introduction of CMP, e.g. after period of breast feeding  Median onset of symptoms from exposure =24 hrs Many develop symptoms in at least 2 systems; Gastro intestinal tract: 50-60% Skin : 50-60% Respiratory tract: 20-30% Mild, moderate or severe

Most frequent symptoms of CMPA Irritability, distress, colic, arching, regurgitation, vomiting, difficulty feeding Loose stools, bloody stools Iron deficiency anaemia Atopic dermatitis/eczema Swelling of lips & tongue Runny nose, otitis media, chronic cough & wheeze

Alarm symptoms; refer when Failure to thrive Macroscopic blood loss; colitis Hypoalbuminaemia (Protein Losing Enteropathy) Severe, difficult to manage eczema Acute laryngeal oedema or bronchospasm Anaphylaxis

Management of cows milk allergy in the UK Guest et al 2008 1000 infants with CMPA Study period =12 month period following initial visit to GP Mean age at presentation to GP; 3 months Time to be put on a diet; 2.2 months Time to symptom resolution; 2.9 months Time to diagnosis; 3.6 months Average of 18.2 visits to GP in 12 month period, 4.2 visits before appropriate milk introduced 42% referred to a specialist Average of 7.6 visits before specialist referral Objective To determine how infants with cow milk allergy (CMA) are managed in the UK and the time taken to achieve symptom resolution.  Methods 1,000 infants with CMA were randomly selected from the Health Improvement Network (THIN) database, which comprises the longitudinal medical records of 5 million UK patients from the time they initially present to their GP.  The records were analysed for treatment patterns and outcomes over the first 12 months following initial presentation to a GP.  Results Patients presenting with a combination of gastrointestinal (GI) and atopic symptoms accounted for 55% of all patients.  Those with GI symptoms alone and atopic symptoms alone accounted for a further 22% and 9% respectively.  Those with acute IgE symptoms accounted for <10% of all patients. Patients’ age at the time of presentation was a mean 3.0 months.  Treatments varied according to symptoms with the number of algorithms for each symptomatic group ranging from as little as one pathway for anaphylaxis to as many as 16 pathways for those presenting with a combination of atopic and GI symptoms. It took a mean 2.2 months to be put on a diet after initially seeing a GP. However, it took a mean 3.6 months from the initial GP visit for the CMA diagnosis to be made. 60% of all infants were initially treated with soy, 18% with an extensively hydrolysed formula (EHF) and 3% with an amino acid formula (AAF).  A mean 9% of patients were intolerant of soy and 29% were intolerant of an EHF.  Time to symptom resolution from the initial GP visit was a mean 2.9 months, however this varied from 3.4 months for those initially treated with an EHF to 2.6 months for those initially treated with an AAF.  Patients had a mean 18.2 GP visits over the 12 months.  A mean 42% of patients were referred to a specialist physician and the waiting time for a referral was a mean 3.7 months.  Patients who saw a hospital physician had a mean 7.6 GP visits before the referral.  Conclusion Consensus guidelines are required for the management of CMA in order to shorten the time to treatment, time to diagnosis and time to symptom resolution and to decrease the consumption of healthcare resources. 

How did they initially present? Combination of GI & atopic/skin symptoms = 55% GI symptoms alone = 22% Atopic/skin symptoms alone = 9% Acute IgE symptoms in less than 10% What other milks were they put on initially? 60% soya formula 18% with extensively hydrolysed formula 3% with an amino acid formula

What is a suitable alternative to cows’ milk? Any extensively hydrolysed protein formula (EHF) will be suitable for ~80-90% Extensively hydrolysed protein With added MCT (55%) Aptamil Pepti (whey) Aptamil Pepti Junior Nutramigen (casein) Pregestimil For the other 10-20%: Single amino acid (“elemental”) formula Neocate LCP Nutramigen AA

Nutricia/Cow & Gate/Milupa Danone Nutricia/Cow & Gate/Milupa Standard infant formula Cow and Gate 1 & 2 Aptamil products SMA products Cost Taste Allergen-icity Extensively hydrolysed formula Aptamil Pepti Whey formula Contains LCPs (omega 3&6) 80-85% short peptide chains 15-20% single amino acids 63% protein chains < 1000 daltons Calcium & iron enriched 34% residual lactose Per 400g tin £8.62 Mead Johnson Nutramigen Casein formula Lactose free 95% protein chains < 1000 daltons Per 400 g tin £8.95 Low High Good Poor EHF + MCT Pepti Junior (+50% MCT) Appropriate for malabsorption disorders Per 400 g tin £10.68 Pregestimil (+55% MCT) Per 400 g tin £9.81 Single amino acid formulae Neocate LCP 100% amino acid formula Calcium enriched Produced in a milk free environment Per 400g tin £23.83 Nutramigen AA with LIPIL* (blend of Omega 3 (DHA and Omega 6 ARA fatty acids present in breast milk) Per 400 g tin £22.05

Formula fed infants with mild – moderate CMPA Diagnostic elimination diet (DED) >80% will respond to an EHF (extensively hydrolysed formula) Some casein based (Nutramigen, Pregestimil) Some whey based – taste better! (Aptamil Pepti) Allow at least 2 weeks, up to 4 weeks for some symptoms to resolve. But many improve in 48-72 hours ~10-20% will not respond and will need single amino acid formula (Neocate LCP, Nutramigen AA) Infants < 6 months of age Stop all supplementary feeds/weaning during DED

Prescribable indications Aptamil Pepti Extensively hydrolysed protein formula Whey based (improved palatability) >97% of infants with CMPA will respond clinically Low levels of lactose (not lactose free) May be some clinical benefits to small amounts of residual lactose (improves calcium absorption & lactase is an inducible enzyme)

What about breast fed babies? Continue to breast feed CMP elimination diet in mum, exclude egg too Supplement with calcium Vandenplas guidelines

Prognosis Cows’ milk protein allergy persists in only a minority Most outgrow by teenage years (~75%) 20% by 4 years of age Those with positive IgE based tests more likely to  have persistent allergy Risk factors for persistent allergy: Co existent asthma  & rhinitis

FAQs-1 Why not soya milk? CMO update 37 January 2004  “Soya should not be used as first line management of CMPA, lactose intolerance or galactokinase deficiency” Soya milks have high phyto-oestrogen content; long term risk to reproductive health of infants (COT 2003) Significant risk of cross reactivity of ~30% (-50%); soy is a potential allergen SACN advises no unique clinical condition which  particularly requires the use of soya based formulae www.sacn.gov.uk  www.foodstandards.gov.uk SACN = Scientific Advisory Committee on Nutrition COT = Committee onToxicity

FAQs-2 Is soya ever ok? Child over 6 months of age Refusing to drink EHF or AA formula Vegans

FAQs-3 Why not goat’s milk? 2006 DoH advice; Goat’s milk protein formulae not suitable for  infants under 12 months of age High chance of cross reaction, ~30%; proteins are  very similar Low in folate Similar levels of lactose to cows’ milk (all animal milks contain lactose) Rice milk High levels of arsenic Not recommended under 4 years of age

FAQs-4 What about investigations? GOLD standard is history + improvement on DED Other tests not usually necessary, unless history of  anaphylaxis Problems with IgE based tests eg RAST & Skin Prick Tests: Only about 50% of CMPA is IgE mediated 50% of healthy newborns have circulating IgE to cow’s milk IgE antibodies may appear & be present with no clinical history of CMPA Negative tests do NOT exclude allergy

FAQs-5 CMPA and associations Significant overlap between CMPA and Gastro- oesophageal reflux disease of infancy (~40% of those with GORDI have CMPA) Associated with other food allergies (eg soya up to 50%) Associated with atopic dermatitis Associated with positive family history of food allergy and atopy

FAQs -6 What about the lactose? Theoretical reasons to suggest that a lactose-free formula may not be beneficial in the longer term. Lactase is an inducible enzyme and requires the presence of some lactose in the intestine for optimal development (Shulman et al, 2005) Removing lactose unnecessarily from diet risks lactase levels permanently declining

Illustrative case 1 Corey aged 3 months Presented to children’s ward with bloody stool for 2 months Began when mum stopped breast feeding and changed to formula @ 4 weeks of age No vomiting, irritability or colic Mother has allergy to cats, dogs, peanuts, and has asthma  Dad’s sister had problems tolerating cows milk as a baby Clinical diagnosis of CMPA; start EHF (Aptamil Pepti in this case)  No tests necessary Clinic 4 weeks later, 4 months old Thriving  Well  No blood in stools since 36 hours after EHF introduced Referral to dietitian for weaning advice

Corey

Illustrative case 2 Oliver aged 2 months Admitted at 2 months of age with vomiting, loose stools & colic Formula fed (“hungry baby” formula as not settling with feeds) Taking Colief with little effect Mum allergic to cows milk (diagnosed at 3 years of age) Clinical diagnosis of CMPA Changed to EHF Seen 3 weeks later: “much better” Diarrhoea stopped Less irritable, much happier, sleeping longer No longer on Colief Still some vomiting and regurgitation Started on anti reflux treatment

Best Practice: Identifying and managing cow's milk protein allergy George du Toit et al Archives of Disease in Childhood; 2010;95:134-144

References and resources http://www.cks.nhs.uk/colic_infantile/evidence/references Vandenplas et al Archives of Disease in Childhood  October 2007: 92; 10; 902 Lactose Intolerance in Infants, Children, and Adolescents Pediatrics 2006;118;1279- 1286 Melvin B. Heyman and for the Committee on Nutrition Influence of changes in lactase activity and small intestinal mucosel growth on lactose digestion and absorption in preterm infants, Robert J. Shulman, William W. Wong, and E. O’Brian Smith, Am J Clin Nutr 2005; 81: 472-9 Early feeding, feeding tolerance, and lactase activity in preterm infants, Robert J. Shulman, Richard J. Schanler, Chantal Lau, Margaret Heitkemper, Ching-Nan Ou, and E. O’Brian Smith,, J Pediatr 1998; 133: 645-9 NICE guidelines April 2011

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