Universita’ “Federico II” Dip.to Scienze Mediche Traslazionali DIDATTICA OPZIONALE: IL CICLO DELLA VITA CORSO INTEGRATO L’evoluzione dell’Essere Umano: dalla concezione alla senilità. Fetal programming: le malattie respiratorie possono avere origine prima della nascita? FRANCESCA SANTAMARIA ovvero Dal bambino malato all’adulto con broncopneumopatia cronica ostruttiva: un viaggio nelle vie aeree

Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Risk factors for developing pulmonary disease Low nutrients intake in the pregnant diet Exposure to maternal smoke in pregnancy and/or postnatal life Abnormal lung development due to premature birth Chronic lung disease associated to preterm mechanical ventilation Exposure to chorioamnionitis Excess exposure to antenatal/postnatal steroids Low birth weight Weight gain in infancy Santamaria, Obes Rev 2012

Risk factors for developing pulmonary disease Low nutrients intake in the pregnant diet - Maternal vit. D intake & childhood asthma: no association Devereux, Pediatr Pulmonol Low maternal vit. D intake related to  asthma risk at 5 yrs Erkkola, Clin Exp Allergy  vit.D intake in pregnancy protects vs wheeze/eczema Miyake, Eur Respir J n-3 polyunsaturated fatty acids: supplementing the pregnant diet might influence neonatal immune responses to allergens and reduce the risk of children developing asthma/allergy Olsen, Am J Clin Nutr 2008 Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Ongoing clinical trials should clarify whether or not vit. D supplementation to pregnants prevents asthma or reduces asthma morbidity The potential of dietary intervention in pregnancy to prevent childhood asthma will only be elucidated by intervention studies Ongoing clinical trials should clarify whether or not vit. D supplementation to pregnants prevents asthma or reduces asthma morbidity The potential of dietary intervention in pregnancy to prevent childhood asthma will only be elucidated by intervention studies

Risk factors for developing pulmonary disease Exposure to maternal smoke in pregnancy and/or postnatal life Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Environmental Tobacco Smoke (ETS) 1. Second hand: product of smoldering ends of cigarettes + exhaled mainstream smoke 2.Third hand: inhalation of gases/minute particles from air contaminated by either previously smoked cigarettes or objects such as carpets, upholstery, fabrics that absorb cigarette smoke Over 4000 chemical compounds carcinogenic, mutagenic, teratogenic Developing lung & ETS -Transplacental transfer of cigarettes products (CO) -Reduction of uterus blood flow -Up-regulation of nicotinic acetylcholine receptors (  changes in lung development) -Thickened placental villous -Increased placenta vascular resistance -  in infant BW -  incidence of airway disease in the 1st 18 mo of life -Slowing of fetal growth -Preterm delivery & fetal mortality

Risk factors for developing pulmonary disease Exposure to maternal smoke in pregnancy and/or postnatal life Maternal smoking in pregnancy only (no in the 1st year) and wheeze, 4 to 6 yrs Maternal smoking during the 1st year only (no in pregnancy) and wheeze, 4 to 6 yrs Neuman, AJRCCM 2012 Fetal programming: le malattie respiratorie possono avere origine prima della nascita? OR 1.39 OR 0.91 No increased risk for current wheeze Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth. Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth.

Risk factors for developing pulmonary disease Exposure to maternal smoke in pregnancy and/or postnatal life Hollams, AJRCCM 2014 Maternal smoking during pregnancy increases risk for asthma and wheeze that persist into adolescence Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Associations between Maternal Smoking during Pregnancy and Respiratory Conditions at Age 14, Nonsmokers Only

Risk factors for developing pulmonary disease Abnormal lung development due to premature birth Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Endodermal bud Lung development: a continuum beginning early in embryonic life progressing through to adolescence

Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Risk factors for developing pulmonary disease Abnormal lung development due to premature birth Chronic lung disease associated to preterm mechanical ventilation (Northway, 1967) (Northway, 1990)

O 2 dependence for at least 28 postnatal days Grading at 36 postmenstrual wk for infants born at <32 wk or at 56 days of life for infants born at ≥32 wk Mild — F I O Moderate — F I O –0.29 Severe — F I O 2 ≥0.30 or cPAP or MV required BPD: gestational age < 30 wks and BW < 1500 g ~ 60,000 infs < 1500 g/yr (= 1.5% of all US newborns ) BPD  in ~ 20% of them The most common chronic lung disease of infancy (US) BPD: multisystem disorder  growth delay, hearing defects, pulmonary hypertension, neurodevelopmental delay, retinopathy Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Bronchopulmonary Dysplasia (BPD)

Originally described in slightly preterm newborns with RDS exposed to aggressive MV + high F I O 2  extensive disruption of relatively immature lung structures (1967) (1990) PREVENTION AND TREATMENT OF RDS and a more conservative respiratory care  Reduction in old BPD + improved survival of infants born at earlier gestational ages  “new” BPD= lung development disorder Often only mild RDS at birth. At this early stage, even minimal exposure to injury affect the normal processes of pulmonary growth. Airways are spared, and inflammation is usually less prominent than in old BPD Fetal programming: le malattie respiratorie possono avere origine prima della nascita?

 susceptibility to lung damage by pathogens or environmental factors  adolescence/young adulthood ASTHMA >than at-terms and significantly greater use of inhaled asthma drugs  Strict measures to prevent viral infection and avoid passive smoke Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Bronchopulmonary Dysplasia (BPD)

Developmental trajectories of airway function: the example of chronic lung disease of prematurity ‘‘developmental window of susceptibility’’: the same noxious stimulus that can cause severe disease in a 24-week premature baby can have very mild or no effect in a term child. BPD is associated with significant decreases in lung function in early life. These deficits track along childhood, and persist until early adult life and perhaps beyond Baraldi, NEJM 2007 Northway, NEJM % of adults with a history of BPD had airway obstruction

Risk factors for developing pulmonary disease Abnormal lung development due to premature birth Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Endodermal bud Factors that interfere with the developmental program during any of the phases of development may result in altered lung function and/or  risk of disease in later life.

Substantial airflow limitation in BPD survivors during the first 3 yrs of life Lung injury plus prematurity at a time when the infants are growing rapidly Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Preterm infants, especially extreme preterms, may have recurrent episodes of airway obstruction during their first yrs of life Distinguishing this pure asthma from chronic lung disease of infancy caused by prematurity is challenging Although asthma and chronic lung disease after premature birth share some clinical and physiological features, the underlying mechanisms are different

Risk factors for developing pulmonary disease Abnormal lung development due to premature birth Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Premature birth or intrauterine growth retardation recognizes several causes, for instance exposure to air pollution (traffic emissions) during pregnancy Environ Health Perspect 2005

Risk factors for developing pulmonary disease Exposure to chorioamnionitis CA + preterm delivery prime lungs  fewer, larger alveoli and less surface for gas exchange HIGH RISK of PRE-SCHOOL or SCHOOL-AGE ASTHMA Low grade, clinically silent for wks/months chorioamnionitis (CA)  20 to 30 wks labour Acute infection of fetal membranes, amniotic fluid and potentially the fetus by organisms from lower genital tract (Listeria, B Streptococci, Ureaplasma, Mycoplasma, E. coli, Gardnerella) Fetal programming: le malattie respiratorie possono avere origine prima della nascita?

Risk factors for developing pulmonary disease Excess exposure to antenatal/post-natal steroids Fetal programming: le malattie respiratorie possono avere origine prima della nascita? Excess steroids retard fetal growth Lung maturation delayed in steroid receptor deficient mice Antenatal steroids given late to pregnant women inhibit alveolar development Inhibition of alveolarization caused by steroids given at wks would probably have less dramatic consequences than when given 4–6 wks later (full alveolar stage)  STEROIDS  STEROIDS  STEROIDS  STEROIDS

Fetal programming: le malattie respiratorie possono avere origine prima della nascita? (1967) (1987) Risk factors for developing pulmonary disease Excess exposure to antenatal/post-natal steroids Steroids in very low BW infants to prevent/treat chronic lung disease High doses steroids prolonged use may - impair lung structure development -  the susceptibility to autoimmune disease Karemaker, Pediatrics 2008 Steroids in very low BW infants to prevent/treat chronic lung disease High doses steroids prolonged use may - impair lung structure development -  the susceptibility to autoimmune disease Karemaker, Pediatrics 2008 Currently - antenatal steroids should be restricted to single-course treatment - routine administration of high-dose systemic steroids for prevention/treatment of chronic lung disease in premature newborns should be discouraged (serious short-term adverse effects; risk of neurodevelopmental impairment)

Risk factors for developing pulmonary disease Low birth weight Fetal programming: le malattie respiratorie possono avere origine prima della nascita? - Associated with  risk of asthma and  lung function in adulthood - Contradictory data on the relation to childhood lung disease (low/high BW) - At term infants with low BW, and infants born at a low-normal GA, may have transient and not persistent recurrent wheezing Weight gain in infancy Due to fetal growth decline in late pregnancy or to a high-calorie diet -Inversely related both to lung function in the first year of life and to pre-school transient, but not to later persistent asthma

Le malattie broncopolmonari ostruttive croniche dell’adulto hanno origine nella vita intrauterina e/o nella prima infanzia?

PREMESSA 1.Alta prevalenza di malattie respiratorie croniche (asma bronchiale allergico e non, BPCO, malattie professionali, riniti allergiche e non, rinosinusiti, apnee ostruttive nel sonno, ipertensione polmonare) -circa 300 milioni con asma -80 milioni con BPCO di grado moderato/grave -altri milioni soffrono di BPCO lieve, rinite atopica, m.respiratorie croniche Organizzazione Mondiale Sanità Malattie respiratorie in Italia Terza causa di morte e, di queste, la BPCO è responsabile di circa il 50% dei decessi GARD Italia

PREMESSA 1.Alta prevalenza di malattie respiratorie croniche 2. Difficile individuazione dell’origine di bronchite cronica e BPCO in almeno in 25% dei casi.

Broncopneumopatia cronica ostruttiva (BPCO o COPD) Malattia respiratoria cronica caratterizzata da ostruzione al flusso persistente ed evolutiva legata a rimodellamento delle vie aeree periferiche ed enfisema. L’ostruzione, il rimodellamento delle vie aeree periferiche e l’enfisema sono associati ad un’abnorme risposta infiammatoria delle vie aeree e del parenchima polmonare all’inalazione di fumo di sigaretta o di altri inquinanti Una delle più importanti cause di morbilità e mortalità nel mondo con una prevalenza in aumento.

PREMESSA 1.Alta prevalenza di malattie respiratorie croniche 2. Difficile individuazione dell’origine di bronchite cronica e BPCO in almeno in 25% dei casi. 3. Persistenza di anomalie funzionali respiratorie in adolescenti/adulti che da bambini avevano funzione polmonare ridotta Martinez, Proc Am Thorac Soc 2009 TRACKING respiratorio

Linee di lavoro GARD-I (Global Alliance Respiratory Diseases Italia) : 1.promuovere il miglioramento dell’educazione sanitaria della popolazione generale; 2. promuovere la diffusione della valutazione del rischio individuale; 3. promuovere il miglioramento e la diffusione della diagnosi precoce specie nella prima infanzia e nell’età evolutiva; 4. ………

Dati 2011 BPCO: 4 al 10% nella popolazione adulta Alcuni numeri

Le malattie broncopolmonari ostruttive croniche dell’adulto hanno origine nella vita intrauterina e/o nella prima infanzia? Malattie pediatriche con potenziali effetti a lungo termine nell’adulto 1.Bronchiolite virale 2.Broncospasmo ( o wheezing o respiro sibilante ) in età prescolare 3. Asma bronchiale in età scolare/ adolescente 4.Malattia polmonare cronica del lattante ex-prematuro

1.Bronchiolite virale +++ da Virus Respiratorio Sinciziale o Molto frequente nel 1^ anno di vita, con picco novembre-marzo o Nel 40% dei casi  broncospasmo ricorrente età prescolare o Rischio elevato asma fino all’età scolare, ridotto nelle epoche successive (adolescenti). Frequent wheeze (4 epis. in last year) and infrequent wheeze (< 4 epis. in the last year) MORE frequent at 6 yrs in infants with RSV than in infants without (RR 4.3). Subsequently, the risk decreased and is not significant at 13 years. Frequent wheeze Infrequent wheeze p= Stein, The Lancet 1999

Early wheezing rhinovirus illnesses predict asthma Jackson, AJRCCM ’08 Viruses and preschool wheeze I bambini affetti da Rhinovirus hanno rischio 10 volte più alto di asma a 6 anni

Viral infections may initiate lung injury and remodeling at any age Children are most prone to respiratory tract infections in the 1st yr of life which corresponds with the period of alveolarization There is an elevated risk of altering the developmental progression of the gas-exchange region of the lung; and hence, lung function when viral infections occurs during infancy. Openshaw, Bronchiolite virale

2.Broncospasmo ( o wheezing o respiro sibilante ) in età prescolare Molto frequente- fino al 50% dei b.ni ha almeno 1 epis. < 3 aa Solo una parte (circa il 40%) svilupperanno asma in età scolare ≥ 4 episodi di wheezing nell’ultimo anno più oppure 1 criterio maggiore  un genitore con asma  dermatite atopica  sensibilizzazione ad aeroallergeni 1 criterio maggiore  un genitore con asma  dermatite atopica  sensibilizzazione ad aeroallergeni 2 criteri minori  sensibilizzazione ad alimenti  wheezing al di fuori di episodi infettivi  eosinofilia (>4%) 2 criteri minori  sensibilizzazione ad alimenti  wheezing al di fuori di episodi infettivi  eosinofilia (>4%) Guilbert, J Allergy Clin Immunol 2004 Fattori di rischio per asma in bambini età prescolare

No: Eos/↑IgE Fam. asthma Yes: virus infs ↑ risk adults COPD, +++ if smoking (smaller airways) Continue wheeze beyond 3rd yr after early LRI (RSV/RV) at 6 y: 60% atopy + 40% atopy - ASTHMA PHENOTYPE IN CHILDREN Tucson CRS, JACI ‘03 Age at onset Natural history

↑↑ IgE Obese girls (no atopy; early menarche) Guerra, AJRCCM ‘04 ASTHMA PHENOTYPE IN CHILDREN Tucson CRS, JACI ‘03 Age at onset Natural history ASTHMA PHENOTYPE IN CHILDREN Severity More severe children wheeze phenotypes are less likely to remit in later life. Phelan,( Melbourne study ) JACI ’02 Sears, NEJM ‘03 Severe intermittent wheeze in pre- school children Bacharier, JACI 07 (severe acute episodes separated by asymptomatic periods)

% children with a history of asthma at 10 yrs 30 – 20 – 10 – % 24.3% p=0.01 Above the median At-below the median Tidal breathing Flow-Volume loops (t PTEF /t E ) at 3 days of life % children with current asthma at 10 yrs 30 – 20 – 10 – 0 7.5% 14.6% p=0.005 Above the median At-below the median Reduced lung function at birth and the risk of asthma at 10 yrs. Haland, N Engl J Med 2006

Wheezy Bronchitis in Childhood: A Distinct Clinical Entity With Lifelong Significance? Edwards, Chest 2003 Childhood asthma Childhood wheezy bronchitis Healthy controls p < 0.01 Childhood asthma Healthy controls FEV 1 decline Childhood asthma: reduced FEV 1 + rapid decline in adulthood Childhood wheezy bronchitis: normal FEV 1 in adulthood, but accelerated decline through middle age (= asthma). Progress to COPD? Childhood wheezy bronchitis (Liters)

Funzionalità polmonare: evoluzione nella vita umana Ostruzione vie aeree non reversibile  FEV 1 /FVC < 70% Riduzione del FEV 1 di circa 30 ml all’anno tanto minore è il massimo valore raggiunto e tanto più velocemente il rapporto FEV 1 /FVC raggiungerà il valore di 70%

DEVELOPMENTAL TRAJECTORIES OF AIRWAY FUNCTION IN TERM INFANTS: ROOTS OF COPD IN INFANCY Is the remarkable tracking of lung function from infancy to early adult life observed in BPD also present in term children not subject to the injury associated with RDS? James, AJRCCM ‘05 …only a fraction of smokers develop COPD and no less than one- fourth of cases of COPD are unrelated to smoking

DEVELOPMENTAL TRAJECTORIES OF AIRWAY FUNCTION IN TERM INFANTS: ROOTS OF COPD IN INFANCY Is the remarkable tracking of lung function from infancy to early adult life observed in BPD also present in term children not subject to the injury associated with RDS? The Tucson Children’s Respiratory Study suggest that the normal spectrum of airway function is established very early in life and even in utero in term children Stern, Lancet ‘07

Fletcher & Peto BMJ 1977 Model of changes of lung function in healthy subjects

Infections (RSV, RHV) Allergy Smoking

Individual who enter adult life with lung-function deficits are at risk of COPD later in life COPD Infections (VRS, HRV) Allergy Passive smoking

Model of changes of lung function across the life 20 sigarette/d riducono di ~ 4,6 anni la vita media di un giovane che inizia a fumare a 25 aa  1 settimana fumo= perdita di 1 g vita Previsione cause morte in maschi adulti fumatori 1 % o morte violenta 6 % o incidente stradale 250 % o patologie correlate al fumo Ministero del Lavoro, della Salute e delle Politiche Sociali febbraio ‘09

Forced Vital Capacity FVC Forced Expiratory Volume at 1 sec FEV1 Annual decrease in FEV 1 : approximately 20 mL in subjects aged 25±39 yrs, rising to 38 mL in subjects aged > 65 yrs Model of changes of lung function in healthy subjects from early to later ages Janssens, ERJ ‘99

FVC FEV 1 TLC FEV 1 /FVC FRC 188 obese subjects (8-76 yrs) Mean BMI: 38.7 BMI-SDS: % moderate obesity 39% severe obesity Santamaria et al, Obesity (Silver Spring) 2011 Overall, close to normal lung function, but p < 0.05 FEV % for each 5-yr-length of obesity

ASTHMA AND AIRWAY FUNCTION: TRACKING AND DIVERGING Adults with asthma are at increased risk of developing COPD, and many studies have shown that asthmatics have reduced airway function, and more specifically, reduced FEV1/FVC ratio than normal subjects (d) acceleration of lung function decline in adults impaired lung growth with a lower plateau phase but a normal rate of decline compared with line a © normal plateau with rapid initial decline in lung function and a subsequent normal rate of decline (a) normal growth and decline Guerra, Proc Am Thorac Soc ‘09 Hypothetical mechanisms that may lead to a critically low level of lung function in adult life and to chronic airway obstruction (horizontal line)

Se pure i sintomi di asma si riducono in una parte degli adolescenti, essi sono destinati a ripresentarsi successivamente in età più avanzata in una percentuale di casi compresa tra il 30 e l’80%. Vi è poi un certo numero di pazienti asmatici che ha sintomi presenti fin dall’infanzia e persistenti per tutta la vita adulta senza significative fasi di remissione. Fattori di rischio sesso femminile presenza di funzione polmonare ridotta già in età scolare comparsa di sensibilizzazione ad aeroallergeni (acaro; gatto) esposizione attiva e passiva al fumo di sigaretta. Le caratteristiche di gravità dell’asma nel bambino sono predittive di eventuali alterazioni respiratorie in età adulta. 3. Asma bronchiale in età scolare/ adolescente

More severe children are less likely to remit in later life. Phelan,( Melbourne study ) JACI ’02 Mild wheeze Wheeze Asthma Severe Asthma School age & adult asthma Continue with significant wheeze as adults. Benign course, with many ceasing by adult life

3. Asma bronchiale in età scolare/ adolescente Albero delle malattie respiratorie croniche. Holt & Sly, CEA 2009