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

2. 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

3. 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

4. Lactose intolerance
Allergy

5. Lactose; “milk sugar” Lactase
Glucose
Galactose
Lactose

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

7. Lactose intolerance; 3 types
Congenital
Acquired
Primary

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

9. 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

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

11. 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)

12. 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

13. 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

14. 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

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

16. Colief is lactase drops

17. CMPA

18. 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

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

20. 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: % Skin : % Respiratory tract: %
Mild, moderate or severe

21. 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

22. 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

23. Management of cows milk allergy in the UK
Guest et al 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. 

24. 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

26. 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

27. 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

28. 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 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

29. 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)

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

31. 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

32. FAQs 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
SACN = Scientific Advisory Committee on Nutrition
COT = Committee onToxicity

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

34. 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

35. 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

36. 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

37. 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

38. 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 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

39. Corey

40. 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

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

42. References and resources
Vandenplas et al Archives of Disease in Childhood  October 2007: 92; 10; 902
Lactose Intolerance in Infants, Children, and Adolescents Pediatrics 2006;118; 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

43. Any questions?