Download Management of paediatric IBD

Milk intolerance in infants
Food intolerance or food allergy ?
Intolerance is not immune mediated
For cow’s milk = lactose intolerant
Lactose intolerance in infants = enteropathy
Allergy is immune mediated
IgE-mediated - local or systemic
Non-IgE-mediated - local or systemic
Lactose intolerance
Normal in most adults in the world
Tolerance mutation arose since dairy
farming
North Europeans usually tolerant as adults
Lactase downregulated in teens
Always abnormal in infants
Very rare - congenital absence (Lapps)
Very common - enteropathy
Temporary – following rotavirus etc
Persistent – with mucosal allergic sensitisation
Eczema,
GI symptoms
Respiratory
GI symptoms
Urticaria,
anaphylaxis
T cells
Eosinophils
Mast cells
David Hill et al
Types of milk allergy
IgE-mediated – rapid onset
Systemic – anaphylaxis response
Localised to gut – secretion, dysmotility
Non-IgE-mediated – slow onset
Systemic – Eczema, asthma
Localised to gut – Enteropathy, colitis,
eosinophilic GI disorders
Mixed IgE and Non-IgE-mediated
Detection of IgE-mediated food
allergy usually straightforward
Usually rapid onset of symptoms
Symptoms are visible and easily related to
food
Usually supportive diagnostic tests
Skin prick tests, specific IgE often positive
Open food challenge easy to interpret
Difficulties mainly occur if complex
mixture of food antigens ingested
Contrasting difficulty in non
IgE-mediated food allergy
N =14
Often delayed onset
symptoms
True association missed
N=4
Symptoms often chronic
Eczema, loose stools, ± poor
weight gain
Motility disturbance - colic,
reflux, constipation
Tests often negative
Skin prick tests, specific IgE
Skin patch tests – variable
reports
Hill et al, J Pediatr 1999
Cow’s milk sensitive
enteropathy
T cells become milk-sensitised
Causes villous shortening, crypt
lengthening
Variable antibody response
Epithelial function impaired
Lactose malabsorbed
Protein, fat malabsorption less striking
Barrier function ↓ - 2o sensitisations
Reflux or milk allergy?
The screaming back-arching baby almost
always is milk allergic – not simple GOR
Even more likely if the baby has:
Eczema, cradle-cap
Colic
Red swollen anus
Nappy rash
Candida
Prolonged viral infections
FH of atopy, autoimmunity (ask about thyroid
disease)
Causes of milk allergy
Impaired oral tolerance mechanisms
Loss of previously acquired tolerance
Often pathogens break epithelial barrier
eg Cow’s milk allergy after rotavirus
Secondary sensitisation to soya etc
Failure to establish oral tolerance initially
Immunological abnormalities
Inadequate innate immune exposures
eg breast-milk sensitisation, multiple food allergy
Oral tolerance
Dependent on the gut flora
Innate immune responses to flora are critical
Mediated by regulatory T cells (TREG)
Different mechanisms for low and high
doses
High doses – induce anergy of T cells
Antigen presented by the epithelium
Low doses – require active TREG generation
Antigen taken up in lymphoid follicles
Diagnosis of CMSE
Depends on clinical recognition
Skin prick test -ve
Specific IgE -ve
Features include:
Post prandial distension, acid stools
Weight gain often impaired
May have eczema, colic, dermatographia
Micronutrient deficiencies
Coeliac diseasE
Sir Samuel Gee
The first modern description of coeliac disease
'chronic indigestion met with in persons of all ages,
Yet especially apt to affect children between 1 and 5
years old‘
Lecture at GOS, 5th October, 1887
Hongerwinter – the Dutch
famine 1944-5
Dicke WK (1950) Coeliakie. MD Thesis, Utrecht.
Diagnostic aids
Antibodies
Anti-gliadin – moderate sensitivity- not
specific
Anti-reticulin – possibly more specific
Anti-endomyseal/ TTG – sensitive and
specific
HLA association
B8 – first described
DR3 or DR5/7 - Much more predictive
DQ2/DQ8 – actual association
Coeliac disease
Farrell and Kelly,
NEJM 2002
Limitations of biopsy
Changes may be non-specific.
Similar appearances in other diseases
Lesion may be patchy
Capsule biopsies are jejunal, endoscopic
are not
Possibly less marked in D2 and D3
May even be absent in D2/3.
IBD in childhood
Rising incidence and change in
phenotype
Advances in genetics
Immunological basis
Inflammation required to establish tolerance
The central role of the gut flora
Pointers from epidemiology
IBD and the “Clean-Child” hypothesis
Dalziel’s report BMJ 1913
Autopsies on 13 patients with
intestinal obstruction
Inflamed jejunum, ileum or
colon in all
Transmural inflammation
seen on histology
“Crohn’s disease”
Weiner 1914, Moschowitz & Wilensky
1923, 1927, Goldfarb & Suissman 1931
Ginzburg &
Oppenheimer
(for Berg) 1927,1928
Ginzburg & Oppenheimer
with Crohn. May 2, 1932,
AGA
Crohn. May 13 1932, AMA
Crohn BB, Ginzburg L, Oppenheimer GD.
Regional ileitis: A pathologic and clinical entity.
J Am Med Assoc 1932; 99: 1323 – 1328.
Crohn’s or UC
Crohn’s – Transmural. Focal chronic
inflammation. Fibrosis. Granulomas.
Anywhere along GI tract. Th1 response.
UC – Largely mucosal. Diffuse acute and
chronic inflammation. Essentially confined
to colon.
Indeterminate colitis. Definite IBD.
Features between UC and Crohn’s. May
evolve with time.
IBD incidence
Highest Scandinavia, Scotland
Increased incidence on migration from low
to high-risk countries
Indian subcontinent origin in UK
Ethnic groups
Ashkenazi Jews
IBD susceptibility genes
European twin-birth registries
Concordance for CD: MZ 37%, DZ 7%
Concordance for UC: MZ 10%, DZ 3%
Susceptibility loci from genome-scanning
IBD1 – chromosome 16. CD. NOD2 gene
IBD2 – chromosome 12q. UC > CD
IBD3 - chromosome 6p. MHC locus
IBD4 – chromosome 14q. CD
IBD – breakdown of tolerance to
the normal gut flora
Enteric bacteria provide continuous
immune challenge
Evidence of specific unreactivity to own
flora
This is lost in active IBD
Flora reactive T cells, antibody
Reaction to normal flora causes
experimental IBD
Paediatric inflammatory bowel
disease
Similarities to adult IBD
Essential inflammatory processes
Mucosal lesion
Differences to adult IBD
Management emphasis
Growth, puberty, psychosocial
Indications for steroids, surgery
Patterns of Paediatric IBD
“Classical” Crohn’s disease and UC
CD now becoming more prevalent
Marked increase in incidence
Ileocaecal involvement most common in CD
Oral (/anal) Crohn’s
Indeterminate colitis
Aims of management
Minimise impact of disease on:
Linear growth
Psychosocial development
Pubertal development
The family
ie
Multidisciplinary specialised therapy
Diagnosis
Clinical assessment
exclude infectious aetiologies
Upper endoscopy
Colonoscopy (incl. ileoscopy)
+/- Barium follow-through/ MR enteroclysis
Mucosal healing
Minimal
Steroids, Mesalazine, Antibiotics
Slow but definite healing
Enteral nutrition, Azathioprine, 6MP
Rapid but definite healing
Infliximab, adlimumab
Mucosal healing in Crohn’s disease
Mucosal healing in UC
Mucosal healing
Only 29% of patients with colonic Crohn’s
disease heal with corticosteroids
Role of enteral nutrition
Healing with azathioprine
70% heal with Infliximab
single infusion improved histology / mucosal
inflammation
Current success...
Induction of remission
75-85% within 2-4 weeks
Maintenance of remission
60-70% relapse at 12 months
30% steroid dependent
but..40-70% in remission on Aza at 12 months
IBD Therapies
Aminosalicylates
Nutrition
Antibiotics
Corticosteroids
Immunosuppressants
Immunologic
Surgery
Steroid therapy
Avoid when possible in children
Poor effect on mucosa
Second line agent
relapsing disease
severe exacerbation (i.v. hydrocortisone)
Reducing course 2mg/kg (max 60mg /
day)
Enteral nutrition in paediatric
IBD
Highly effective first-line therapy
Polymeric formulas more palatable
Reduce pro-inflammatory cytokines
Increase regulatory cytokines
Animal models suggest alteration of gut flora
Motivation of child and family critical
Infliximab safety
Short-term
infusion related
Medium term
infectious complications
delayed hypersensitivity
antibody formation
Long-term
Malignancy – Hepato-splenic T cell
lymphoma