Aiutarli a difendersi.
Cosa funziona e cosa no
Dal mito alla realtà
Alessandro Fiocchi – Sergio Arrigoni
Melloni Pediatria, Milano
• Care for a clean environment.
• Consider minor immunomodulators
• The evidences for immunostimulation
Health impact of exposure
to environmental tobacco smoke in Italy
Patologia
Basso peso alla nascita
SIDS
Numero di casi stimati
2033
87
Infezioni vie aeree < 2 anni
77.000
Asma
27.000
Sintomi respiratori cronici
48.000
Otite media sierosa
64.000
Forastiere F. Epidemiol Prev. 2002; 26:18-29
“Io fumo solo in balcone dottore!”
• Numerosi studi dimostrano che anche quando i genitori dicono
di fumare all’aperto l’esposizione del bambino al fumo passivo
non viene ridotta.
• Perché?
Johansson A et al. Indoor and outdoor smoking: impact on
children's health. Eur J Public Health. 2003; 13:61-6
Nelson R. Smoking outside still causes second-hand
smoke exposure to children.Lancet 2002;359:1675
Bahcecilier N. Parental smoking behaviour and the urinary
cotinine level of asthmatic children. J Asthma 1999;36:171-5
Air pollution and mortality
Inquinante
Incremento mortalità
PM10
+ 5% mortalità post-neonatale per
qualsiasi causa
1
PM10
+22% mortalità post-neonatale per
cause respiratorie
1
PM10
+ 12 % mortalità per cause
respiratorie in ↓ SES
2
Lacasana M. Exposure to ambient air pollution and prenatal and early childhood health
effects. Eur J Epidemiol. 2005;20:183-99.
Erbas B. Air pollution and childhood asthma emergency hospital admissions:estimating
intra-city regional variations. Int J Environ Health Res. 2005;15:11-20
Air pollution and morbidity
Inquinante
Incremento ricoveri
PM10
Bronchiti < 4 anni
Polmoniti <4 anni
Asma <14 anni
1
PM2.5 - PM10
Asma <15 anni
2
PM2.5
Bronchiti < 4 anni
Polmoniti <4 anni
Asma <14 anni
1
NO2
Bronchiti < 4 anni
Polmoniti <4 anni
Asma <14 anni
1
SO2
Bronchiti < 4 anni
Polmoniti <4 anni
Asma <15 anni
1,2
CO
Asma <15 anni
1
Lin M. Coarse particulate matter and hospitalization for respiratory infections in children
younger than 15 years in Toronto: a case-crossover analysis.
Pediatrics. 2005;116:e235-40
Erbas B. Air pollution and childhood asthma emergency hospital admissions:estimating
intra-city regional variations. Int J Environ Health Res. 2005;15:11-20
PM10 ed accessi in PS per sintomi respiratori
R2 = 0.28; P < 0.02
PM10
mcg/m3
140
120
100
80
60
40
20
0
-20
0
50
100
150
200
250
-40
Numero accessi respiratori
Caddeo A. Impatto dell’esposizione al PM10 sulla frequenza di visite per patologie
respiratorie in un pronto soccorso pediatrico.
Dal Mito alla Realtà, 31 gennaio – 1 febbraio 2008
Air pollution and morbidity
Is there association between short-term exposure to ultrafine
particles and morbidity in Copenhagen, Denmark?
NCtot (6-700 nm in diameter) in 2001 – 2004 vs. hospital
admissions due to asthma in children (5-18 years)
PM10 vs. PM2.5 vs. ambient gasses
NO2 and PM2.5 > PM10 for pediatric asthma
Traffic sources are related with paediatric asthma attacks
Andersen ZJ. Size distribution and total number concentration of ultrafine and
accumulation mode particles and hospital admissions in children and the elderly in
Copenhagen, Denmark. Occup Environ Med. 2007 Nov 7; [Epub ahead of print]
Fungal levels in the home and lower respiratory tract
illnesses in the first year of life
RR
Any LRI
LRI without
wheeze
LRI with
wheeze
Male sex
1.64
2.32
1.54
Born in winter
0.65
0.84
0.50
Breastfed ever
0.74
0.54
0.82
Siblings
1.56
1.51
1.82
High fungal levels
1.86
3.88
1.58
Stark PC. Am J Respir Crit Care Med 2003; 168:232–7
Regimen Sanitatis Salerni
Secolo XI
Che
l’aria
sia
pura,
• Caput XIV : De aere
tersa e luminosa,
“ Aere fit purus,fit lucidus, et bene clarus,
che neque
nonsit,sia
infetta
infectus
nec olens
foetore
cloacae.”
o graveolente.
Rinse-free hand sanitizers reduce school
absenteism
60
50
40
30
20
10
0
White
Dyer
Hammond
Guinan
Thompson
Meadows E, Le Saux N. A systematic review of the effectiveness of antimicrobial
rinse-free hand sanitizers for prevention of illness-related absenteeism in
elementary school children. BMC Public Health. 2004;4:50-7
Pneumonia < 5 years
Luby SP. Effect of handwashing on child health: a randomised controlled trial.
Lancet 2005;366:225-33
URTIs < 15 years
Luby SP. Effect of handwashing on child health: a randomised controlled trial.
Lancet 2005;366:225-33
Cough & dyspnoea < 15 years
Luby SP. Effect of handwashing on child health: a randomised controlled trial.
Lancet 2005;366:225-33
Regimen Sanitatis Salerni
Secolo XI
Se vuoi vivere
• Caput XXIII :De utilitate lotionis manuus
sano a lungo lavati
spesso
leconfert
manimunera bina:
“ Lotio post
mensam tibi
mundificat palmas, et lumina redit acuta,
si fore vis sanus,ablue saepe manus.”
• Care for a clean environment.
• Appropriate treatment of minor immunodeficiencies
• The evidences for immunostimulation
The direct and indirect costs of respiratory
infections to the community are substantial
•
•
•
•
•
A health diary from 600 families in Melbourne
80% at least one respiratory episode/15 months
2.2 respiratory episodes / person / year
mean episode duration: 6.3 days
children < 2 years:
- most likely to have at least one respiratory episode
- greater number of episodes per person
- the longest episode duration (6.8 days)
• 28.7% respiratory episodes  doctor's visit
• 23%  time off school
Leder K.A community-based study of respiratory episodes in Melbourne.
Aust N Z J Public Health. 2003; 27:399-404
Allergic children have more numerous and severe respiratory
infections than non-allergic children
Number and duration of RI in children with RRI
# RI
Non allergic
(n=71)
Allergic (n=46)
Total RI # (p=0.0001)
0.94±1.37
1.26 ± 073
Mild RI # (p<0.000001)
0.53±.64
1.02±0.70
Total RI duration (days; p=0.009)
4.85±5.24
8.92±9.64
Mild RI duration (days; p=0.0007)
2.99±3.91
7.82±9.87
Ciprandi G. Pediatr Allergy Immunol 2006: 17: 389–91
Respiratory infections in schoolchildren:
co-morbidity and risk factors.
aOR
Otitis media
(n=470)
Tonsillopharyngitis
(n=737)
Lower RI
(n=275)
Female sex
1.2
(1.0-1.5)
1.2
(1.0-1.4)
0.9
(0.7-1.1)
Atopy
1.4
(1.1-1.8)
1.4
(1.0-1.7)
2.4
(1.8-3.1)
Home dampness
1.2
(1.0-1.5)
1.4
(1.1-1.6)
1.3
(1.0-1.7)
Smoking
1.2
(0.9-1.5)
1.1
(0.9-1.3)
1.2
(0.9-1.6)
Siblings
1.2
(0.8-1.6)
1.1
(0.8-1.4)
1.0
(0.6-1.4)
Karevold G. Arch Dis Child 2006; 91:391–5
Certain children constitute a group
with high morbidity
Annual incidence of bacterial RTI:
Age
Group a
Group b
P
2 yrs
6.2
1.4
< 0.001
7 yrs
3.1
1.2
< 0.01
8 yrs
2.4
0.8
< 0.05
 Children with high morbidity are susceptible to RTIs
and other illnesses over a long period of years
Soderstrom M Respiratory tract infections in children with recurrent episodes
as preschoolers. Acta Paediatr Scand. 1991;80:688-95
Recurrent respiratory infections and phagocytosis
AIM: do phagocytosis (FAG) and reactive oxygen intermediates
(ROI) production deficiencies impact on pediatric RRI?
STUDY POPULATION: 90 children with RRI vs, 19 healthy
children.
RESULTS: FAG and ROI significantly decreased compared to the
control values
CONCLUSIONS: a possible etiological role of FAG and ROI
deficiencies of polymorphonuclear neutrophils in the genesis
of pediatric RRI
Don M. Recurrent respiratory infections and phagocytosis in childhood.
Pediatr Int. 2007;49:40-7
Mannose-binding lectin
MBL insufficiency
•
•
•
•
bacterial infection
meningococcal sepsis
predispose to HIV infection
TB
Eisen DP. Impact of mannose-binding lectin on susceptibility to infectious
diseases. Clin Infect Dis. 2003; 37:1496-505
Recurrent respiratory infections and immune
defects
IgG2 subclass deficiency  pneumonia, sinusitis, invasive
pneumococcal disease
IgA deficiency  pneumonia, otitis, diarrhoea
G2m(n) allotype of IgG2  susceptibility to encapsulated bacteria
Fc receptor IIa: H131 high affinity, FcRIIa-R131 low affinity for IgG2
Heterozygotic C2 deficiency in 1%–1.5% of the general population
Homozygous deficiency of C4A or C4B in 3% of the population
Mannose-binding lectin (MBL2) activates the complement system
Bossuyt X. Coexistence of (partial) immune defects and risk of recurrent
respiratory infections. Clin Chem. 2007;53:124-30
Recurrent respiratory infections and immune
defects
Number of (partial)
Immune defects
Patients (n=55)
Control (n=43)
0
6
27
1
20
10
2
21
3
3
8
1
Bossuyt X. Coexistence of (partial) immune defects and risk of recurrent
respiratory infections. Clin Chem. 2007;53:124-30
Ribosomial Immunotherapy
Natural Vector
Specific antigens
Adjuvant
Immunostimulant
Specific
Immune
response
Aspecific
Immune
Response
Ribosomial Immunotherapy
Ribosome
Epitopes
Natural Vector
Specific antigens
Adjuvant
Specific
Immune
response
Proteoglicans
Immunostimulant
Aspecific
Immune
Response
 Microbiology
 Extraction
 Purification
 Conjugation
 Sterile conditioning
The ribosome
8 nm
X
14 nm
30 S
50 S
16 nm
• Care for a clean environment.
• Consider minimal immunodeficiences
• The evidences for immunostimulation
Levels of evidence
Level I a
meta-analysis of randomised controlled trials (RCT)
Level I b
at least one RCT
Level II a
at least one controlled study without randomisation
Level II b
at least one other type of study
Level III
non-experimental descriptive studies
Level IV
expert committee reports
or opinions
or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines.
BMJ, 1999; 318: 593 -6
Immunoistimulants and ARTIs:
a meta-analysis
DATA SOURCES: Medline, EMBASE databases,
and register of Cochrane Acute Respiratory
Infection Group
REVIEW METHODS: RCTs on the prevention of
ARTIs in children
Jadad's instrument
Berber A.J A meta-analysis of randomized placebo-controlled clinical trials on the
prevention of respiratory tract infections in children using immunostimulants.
Investig Allergol Clin Immunol. 2001; 1: 235-46
Mean percent reduction of ARTIs
Ahrens - BV
Gomez-Barreto – BV
Jara – BV
Maestroni – BV
Schaad – BV
Zagar – BV
Careddu – pidotimod
Motta – pidotimod
Arroyave - biostim
Pauoe – biostim
Pech - biostim
Piquet - biostim
Vautel – immucytal
Fiocchi – Immucytal
Karan – thymomodulin
Scholer – thymomodulin
Global
Berber A.J. Investig Allergol Clin Immunol. 2001; 1: 235-46
Immunostimulants and ARTIs:
a meta-analysis
RESULTS: Four of five RCTs with Jadad's score > 3 showed
significant reduction of ARTIs in immunostimulant groups
- 42.64%, (95% confidence - 45.19 / - 40.08%);
- 60% mean number of ARTIs in treated vs. placebo group.
CONCLUSIONS: immunostimulants are an effective treatment
for the prevention of ARTI. Further high-quality RCTs are
required
Berber A.J
A meta-analysis of randomized placebo-controlled clinical trials on the prevention of
respiratory tract infections in children using immunostimulants.
Investig Allergol Clin Immunol. 2001; 1: 235-46
Immunostimulants for preventing respiratory
tract infection in children.
1. ISs reduce the incidence of ARTIs in children by
40% on average
2. Heterogeneity and poor quality of the trials
3. Safety profile is good
4. Further high-quality trials are needed
Del Rio-Navarro BE. Cochrane Database Syst Rev. 2006;(4):CD004974.
Levels of evidence
Level I a
meta-analysis of randomised controlled trials (RCT)
Level I b
at least one RCT
Level II a
at least one controlled study without randomisation
Level II b
at least one other type of study
Level III
non-experimental descriptive studies
Level IV
expert committee reports
or opinions
or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines.
BMJ, 1999; 318: 593 -6
Placebo-controlled RCT
randomization
active treatment
run-in
placebo
Immucytal in children
with otitis media + URTIs
- Trial: Double-blind placebo study over 6 months
- 84 children aged 4-14 years with otitis media with at least
2 years of recurrent or chronic respiratory tract infections,
and/or at least 3 episodes requiring doctor visit and
treatment during previous winter
- Assessment criteria:
- Frequency, duration, severity of otitis
- Hearing test
MorainR.
Int J Pediatr Otorhinolaryngol. 2002;63:1-8
Pr Fiocchi - RRTIs
Children:
43
Definition and interest of
Immucytal in children
with otitis media + URTIs
Results
- Reduction infectious episodes by 50%
- Reduction by 50% episode duration
- 62 % vs. 21% patients ameliorated at hearing tests (p > 0.001)
62%
80%
60%
40%
20%
0%
Immucytal
Placebo
Mora R. Int J Pediatr Otorhinolaryngol. 2002;63:1-8
Levels of evidence
Level I a
meta-analysis of randomised controlled trials (RCT)
Level I b
at least one RCT
Level II a
at least one controlled study without randomisation
Level II b
at least one other type of study
Level III
non-experimental descriptive studies
Level IV
expert committee reports
or opinions
or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines.
BMJ, 1999; 318: 593 -6
Levels of evidence
Level I a
meta-analysis of randomised controlled trials (RCT)
Level I b
at least one RCT
Level II a
at least one controlled study without randomisation
Level II b
at least one other type of study
Level III
non-experimental descriptive studies
Level IV
expert committee reports
or opinions
or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines.
BMJ, 1999; 318: 593 -6
Efficacy of Ribomunyl® in children
with RRTIs & bronchospasm
– Patients: 338 children (range:4-17y) with recurrent
respiratory tract infections and bronchospasm
– Treatment: Ribomunyl® for 7 months
– Assessment criteria:
• Change in clinical score
• Immunological parameters (D0, M4, M7)
• Plasma IgG, IgA & IgM levels; plasma bacterial strainspecific IgE
• T-lymphocyte counts
Hofman
JA. Efficacy
in Children:
RRTIs and bronchospastic symptoms.
Pr Fiocchi
- RRTIs in
47
Abstract
XXI Congress of EAACI, 2002
Definition and
interest 616,
of
Efficacy of Ribomunyl® in children
with RRTIs & bronchospasm
- Clinical results:
•
62%  in severity score
•
71%  in antibiotic use
•
76%  in RRTI
- Immunological parameters: in line with clinical improvement
•
Signif.  sp IgE against bacterial antigen from M4 till M7 P<0.001)
•
Signif.  IgA from M4 till M7 (P<0.05)
•
Signif.  IgG and IgM at M7 (P<0.05)
•
Signif.  total T lymphocytes at M7 (P<0.05)
Conclusions: Ribomunyl reduces RRTIs in children with
bronchospastic symptoms. Ribomunyl reduces sIgE
Efficacy
in RRTIs and bronchospastic symptoms.
PrHofman
Fiocchi -JA.
RRTIs
in Children:
48
Abstract
616,
XXI
Congress
of
EAACI,
2002
Definition and interest of
Levels of evidence
Level I a
meta-analysis of randomised controlled trials (RCT)
Level I b
at least one RCT
Level II a
at least one controlled study without randomisation
Level II b
at least one other type of study
Level III
non-experimental descriptive studies
Level IV
expert committee reports
or opinions
or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines.
BMJ, 1999; 318: 593 -6
Ribosomal immunostimulation
DATA SOURCES: review of studies [1983 – 2003]
of 3 and 6 months' duration comprising part of the
international registration file
CASELOAD: Nineteen RCTs
2117 patients (1215 children and 902 adults)
Ribosomal immunostimulant n = 1062
Placebo n = 1055
Bellanti J.
Ribosomal immunostimulation: assessment of studies evaluating its clinical relevance
in the prevention of upper and lower respiratory tract infections in children and adults.
BioDrugs. 2003; 17: 355-67.
Ribosomal immunostimulation
3 months’ duration
Number of
recurrences
Duration of
infection
Antibacterial
requirement
ENT
- 27-68%
- 28-66%
-29-60%
Otitis media
- 10-53%
- 16-56%
- 18-47%
ENT + LTRI
- 32-61%
These results clearly demonstrate that ribosomal
immunostimulant is effective in preventing and in
reducing upper and lower respiratory tract infections in
children and adults
Bellanti J.
Ribosomal immunostimulation: assessment of studies evaluating its clinical relevance
in the prevention of upper and lower respiratory tract infections in children and adults.
BioDrugs. 2003; 17: 355-67
Conclusioni
1. Il problema delle IRR ha un notevole peso sul bambino, sulla
famiglia e sulla società in termini di morbilità, qualità della vita,
costi sociali ed economici
2. Esistono bambini che sia per fattori immunologici che per stile e
condizioni di vita hanno un rischio aumentato di IRR
3. E’ possibile influire sullo stile di vita per ridurre il rischio di IRR
4. L’efficacia degli immunomodulatori è validato da diverse metanalisi
5. E’ auspicabile un utilizzo integrato di interventi volti a modificare lo
stile di vita “ a rischio” insieme ad un uso mirato dei modulatori
della risposta immune