State of the Art Lecture:

Transcription

1 State of the Art Lecture: Lung development and Respiratory Disease Andrew Bush MD FRCP FRCPCH FERS Imperial College & Royal Brompton Hospital

2 Faculty Disclosure AB is EIC of Thorax, otherwise has no financial disclosures relevant to this presentation In addition to income from permanent employment at Imperial College, I receive an all too small amount of royalties for books edited and chapters written

3 Aims of the Presentation To review normal and abnormal lung development, especially in light of new insights into phenotyping Transgenerational Antenatal Pre-school and childhood years Going downhill from age years Discuss what we have learned from survivors of premature and not so pre-term delivery Demonstrate the long term consequences of early life events and the implications for COPD

4 Barkerology: A Fundamental Observation! MALES FEMALES

5 COPD & Childhood ECFS study 13,359 aet Effect of Childhood Disadvantage Risk factors Maternal asthma Paternal asthma Childhood asthma Maternal smoking Childhood resp. infections = Effect of Heavy Smoking Age (yrs) 2 >3 Early childhood disadvantage: Lower lung function No catch-up Faster rate of decline More COPD 0 1 Thorax 2010; 65: 14-20

6 What we Know GLI data Males 97,759 records, healthy nonsmokers from 72 centres in 33 countries age years Constructed predictive equations for spirometry Eur Respir J 2012; 40:

7 Lung Development: Normal and abnormal Transgenerational effects Safe in the womb? Birth cohort studies: where we are Where we are going: smarter phenotyping The declining years: from age 20-25! Beyond the airway

8 Trans-generational Risk If Grandmother smoked: OR for maternal asthma = 1.3; 95% CI, 0.9 to 2.0 OR for grandchild asthma, even if mother did not smoke = 1.8; 95% CI, 1.0 to 3.3 OR for grandchild asthma, if mother and grandmother smoked = 2.6; 95% CI, 1.6 to 4.5 Mechanisms unclear: some suggestive DNA methylation data that this is epigenetic Chest 2005; 127:

9 Lung Development: Normal and abnormal Transgenerational effects Safe in the womb? Birth cohort studies: where we are Where we are going: smarter phenotyping The declining years: from age 20-25! Beyond the airway

10 Safe in the Womb? Remodelling Structural effects Collagen deposition RedJ 2002; 26: 31-4 Increased mucus deposition RedJ 2011; 44: 222-9

11 Nicotinic acid: Control Airway length METHODS Mice exposed to nicotinic acid Gest 7-21 Gest 14-Postnatal 7 Postnatal 3-15 Nicotinic Acid Α7 nachr - / - mice as controls RESULTS Gest 14-Postnatal 7 was key period Increased airway length, decreased diameter, reduced flows, increased methacholine sensitivity, even in the absence of allergen RedJ 2012; 46:

12 Is there a Physiological readout? Patients and Methods 23 asymptomatic infants age weeks, HO wheeze vs. 19 controls Results High-speed interrupter technique to measure input impedance up to 900 Hz (measure of airway wall compliance) Am J Respir Crit Care Med 2000; 161:

13 Airway Wall Compliance Different between wheezers (even asymptomatic) and non-wheezers This group could not determine the relationship with inflammation and remodelling Changes?secondary to ante-natal or post-natal insults The other evidence is that it is antenatal

14 Epidemiology: AHR matters (N=3) METHODS COPSAC n=411 children Neonatal RVRTC and methacholine AHR (n=403) Spirometry age 7, n=377 RESULTS Asthmatics at age 7 had impaired lung function at birth (c.f. Perth, not Tucson) Deficits progressed in first seven years of life Methacholine AHR predicted asthma p<0.01 Am J Respir Crit Care Med 2012;

15 Human Early Programming? N=10 survivors of PFC, 10 matched controls Echocardiographic estimates of PAP at sea level and altitude, at mean age 21 years Worse PHT in PFC survivors, SaO 2 changes same 26.2 vs mmhg 62.3 vs mmhg Lancet 1999; 353:

16 Antenatal exposures Maternal smoking (gene-environment) Maternal Atopy Antenatal air pollution Maternal HT/PET Maternal medication use Paracetamol, antibiotics,?others Maternal Diabetes Maternal diet

17 Pollution matters ANTENATALLY 241 healthy newborns Maternal exposure to PM10, NO 2 and O 3 monitored Effects especially for 2 nd and 3 rd trimester exposure Eur Respir J 2009; 33:

18 Lung Development: Normal and abnormal Transgenerational effects Safe in the womb? Birth cohort studies: where we are Where we are going: smarter phenotyping The declining years: from age 20-25! Beyond the airway

19 Lowest quartile of V max FRC (Age)

20 Tucson: evolution of Lung Function

21 Dunedin Multidisciplinary Health Study Sears, NEJM 2003

22 14 year cohort FU: Maternal smoking in pregnancy (MSP) What they did 1129 teenagers, FU Western Australian pregnancy cohort Spirometry, BHR, symptoms, total and specific IgE, IgG4, immune function and inflammatory markers

23 Immune tests performed

24 14 year cohort FU: Maternal smoking in pregnancy (MSP) What they did 1129 teenagers, FU Western Australian pregnancy cohort What they found Reduced lung function (FEF 25-75, FEV 1 /FVC ratio) Spirometry, BHR, symptoms, total and specific IgE, IgG4, immune function and inflammatory markers Related to MSP (237/1129) with regression analysis Increased risk of current asthma, current wheeze, exercise induced wheeze No change in risk for atopy or BHR 8% ADMITTED smoking! (and were excluded)

25 Who cares? We know MSP is BAD! Novel mechanisms: increased risk of asthma and wheeze not modified by gender, atopy or maternal history of asthma or atopy. IL-12 induction by LPS+IFN-γ was only factor lower with MSP, but was not an effect modifier; also independent of lower lung function So this sounds like another asthma. What are the mechanisms? The effect of bronchoconstriction? And not all asthma is asthma! And not all asthma has the same risk factors!

26 Prevalence of wheeze by age (All children with any wheezing episode age 5-7 years Atopic (n=94) Aeroallergen sensitization also associated with loss of lung function & AHR 1-5 years, atopy = non-atopy Non-Atopic (n=59) MAS Study: Lancet 2006; 368:

27 Pollution and Lung Function 64 healthy children studied Carbon particles in induced sputum macrophages The more carbon in the cells, the worse lung the function of the child NEJM 2006; 355: 21-30

28 Window for intervention?

29 FEV 1 /FVC Lung function Changes over time age at review (years) c mwb wb a sa

30 The Big Cohorts: Conclusions By six years of age, spirometry is set for life Downhill is the only way Key window is up to 4-6 years, wherein lungs are very vulnerable Early life events critically impact on adult lung function, and by implication, premature airflow obstruction

31 Lung Development: Normal and abnormal Transgenerational effects Safe in the womb? Birth cohort studies: where we are Where we are going: smarter phenotyping The declining years: from age 20-25! Beyond the airway

32 Better Together! MeDALL Harmonising established birth cohorts Greater statistical power combining cohorts Cross validation of findings in other cohorts

33 Epidemiological Classification of Infant Wheezing Phenotypes Never (51%) Transient (20%) Wheeze 0-3, not at age 6 Persistent (14%) Wheeze 0-3 still present age 6 Late onset (15%) Wheeze after age 3

34 Epidemiology: New Approaches Thorax 2008; 63: Also confirmed in Southampton in Paediatr Pulmonol 2013; 48: JACI 2011; 127:

35 Genetic Read-out TEW JACI 2013; 131: ALSPAC wheeze phenotypes Prolonged early wheezing Several thousand children Intermittent onset wheeze 17q21 locus (ORMDL3 amongst others) Late onset wheeze SNPs specific to wheeze phenotypes, not intermediates like atopy Persistent wheeze

36 IL-33 Polymorphisms ALSPAC (n=7247) & PIAMA (n=2007), 94 SNPs in IL-33 pathway Significant hits for IOW for IL-33 pathway at different levels JACI 2014; 134: 170-7

37 Transient Wheeze: Benign? 620 high allergy risk children (Melbourne Atopy Cohort Study) Symptoms and Spirometry age 12 and 18 Am J Respir Crit Care Med 2014; 189: (82-498) 210(62-359) 255(69-442)

38 Atopy : umbrella term Machine learning approach applied to the Manchester cohort (SPTs, sige) Five atopic clusters identified Multiple early atopy predicts asthma Am J Respir Crit Care Med 2010; 181:

39 Combining atopy and wheeze Manchester birth cohort phenotypes 4 (?) wheeze phenotypes None Transient Late onset Persistent 5 atopy phenotypes None Dust mite Non-dust mite Multiple early Multiple late

40 Conclusions Persistent wheeze, multiple early atopy, and exacerbations predict a bad trajectory Risk progressive loss of lung function age 3-11 More marked in boys Am J Respir Crit Care Med 2014; 189:

41 Lung Development: Normal and abnormal Transgenerational effects Safe in the womb? Birth cohort studies: where we are Where we are going: smarter phenotyping The declining years: from age 20-25! Beyond the airway

42 Eclipsed: Variable ΔFEV 1 Observational study of 2163 patients over 3 years, standard treatments permitted ΔFEV 1 highly variable: indeed, 31% had a decrease of <20 ml/yr (8% increased!) Increase rate of decline in current smokers, BDR, emphysema (No normal comparators; no mild COPD) NEJM 2011; 365:

43 COPD (2): Variable ΔFEV stable COPD patients (1100 males) Monitored for years; 751 analysed Rate of decline variable, similar to ECLIPSE Faster decline if higher starting FEV1 and low BMI predicted faster decline Am J Respir Crit Care Med 2011; 184:

44 VAW Lifelong Problem? FU of 1964 cohort 177 subjects, age years P<0.05 Adjust for age, height, gender, smoking, socioeconomic status P=NS FEV1 Chest 2003; 124: Contr VAW Asth

45 VAW Lifelong Problem? Rate of decline of FEV 1 over 12 years Conclusion VAW decline faster than normal, having attained normal lung function in adult life Chest 2003; 124: Contr P<0.05 P=NS VAW Asth ^FEV1

46 FEV 1 /FVC Lung function Changes over time Nearly 50% SA now have COPD! Stronger signal than smoking age at review (years) c mwb wb a sa

47 Variable ΔFEV 1 : What does it mean? COPD with normal ΔFEV 1 means EITHER there was an early accelerated decline which has stabilised, OR they failed to reach a normal plateau NO adult life biomarker accounts for variable ΔFEV 1 However, we know that early life events and genetics DO impact on ΔFEV 1 Further evidence that early life events are important LIFELONG

48 Lung Development: Normal and abnormal Transgenerational effects Safe in the womb? Birth cohort studies: where we are Where we are going: smarter phenotyping The declining years: from age 20-25! Beyond the airway

49 Does alveolar growth last longer than we think? Conventional view: virtually home and hosed by age 2 BUT: He 3 MRI studies

50 Hyperpolarized Helium N=109 healthy subjects age 7-21 years Spirometry & plethysmography Airspace dimensions X2 different methods using He 3 Modelled lung expansion with no neoalveolarisation vs. new lung growth Am J Respir Crit Care Med 2012; 185:

51 Does alveolar growth last longer than we think? Conventional view: virtually home and hosed by age 2 BUT: He 3 MRI studies BUT: Rhesus monkeys 26 monkeys (13 male) 1 st 7 years of life AJP 2007; 293: L570-9 BUT: Own observation!

52 Early and Not-so-early Birth Becoming MORE common Effects cannot be ameliorated by surfactant, etc. An important future COPD risk group!?

53 HRCT in adolescent survivor of preterm birth

54 Oximetry changes in the First Year of Life

55 Change in Lung Function in the First Year of Life There is no evidence of catch up growth

56

57 Lung Function age 7-9 There is evidence of airflow obstruction even in those who only needed oxygen in the newborn period Arch Dis Child 1989; 64:

58 Lung Function age 7-9 years: effect of birth weight Arch Dis Child 1989; 64:

59 Spirometry at age years 4 2 zfev Index study LBW VLBW Controls group Am J Respir Crit Care Med. 2008; 178: 74-80

60 2 1 0 zmef Birthweight in Index Study Group SGA Subjects Birth Weight in SGA, not AGA babies determines Lung function in adulthood, r 2 = 0.44, p<0.001

61 What about the late pre-termer? Does only very preterm delivery matter? ALSPAC: 25-32, 33-34, 34-35, >36 weeks gestation Spirometry at 8-9 and years Thorax 2012; 67: Spirometry age 8-9 Down As & term same Spirometry age FEV 1 /FVC FEF STILL down

62 What is the burden of Asthma? 44,173 women delivering between 1989 and 2008 N=2661 children had asthma meds reimbursed, controls mod preterm N= 968 late preterm N= 2355 early term N= 7704 Term N= late term, postterm N= Early term 108 extra cases, biggest burden <32/ / / /40 >41/40 Post-term seemed to be protective 3.9 ( ) 1.7 ( ) 1.2 ( ) ( )

63 Airway Inflammation & BPD N=17 asthmatics, normals, BPD survivors Spirometry, & FeNO and exhaled breath temperature as measures of airway inflammation BPD results Worse lung function Lower FeNO Exhaled breath temperature Conclusion: despite BHR, no evidence of ongoing inflammation in BPD Pediatr Pulmonol 2010; 45:

64 Birth Weight and Adult Spirometry 2368/2612 young adults, spirometry aged 21 Effect of BW on FEV1, unadjusted and adjusted for lifestyle in pregnancy, current smoking, and parental height Just significant if subject height considered Chest 2012; 142:

65 Alveolar catch-up? Four groups of children, age years Term born, n=61 Mild preterm (n=21, weeks) Extreme preterm (n= 19, <32 weeks, in air at 4 weeks) Extreme preterm with CLD(n=18, <32 weeks, O 2 dependant beyond 4 weeks) Lung function testing Spirometry and plethysmography Hyperpolarised helium to measure alveolar size BlueJ 2013; 187:

66 37-42/40 No resp support 32-36/40 Resp support <4 weeks <32/40 Resp support <4 weeks <32/40 Resp support >4 weeks

67 Scope for Recovery? Preterm Neonate Two years later

68 Respiratory Mass Spectrometry Amiss 2000 SF 6 = accessible lung volume C 2 H 2 = effective pulmonary blood (plasma) flow CO 18 = DLCO, surrogate for capillary volume

69 SF 6 C0 18 C 2 H 2

70 On exercise: Stress the system Cardiac output rises DLCO rises (capillary recruitment and distension) Normoxia is preserved (except in the superathletic)

71 Mean and 95% CI Qeffz scores.5 Control 0.0 AGA SGA -1.5 Rest Final exercise Recovery Exercise stage Exercise data at age years

72 What is this thing called COPD?

73 Normal or Diseased? Women aged 30, FEV 1 /FVC ratio of 75% is wildly abnormal Above age 50, increasing numbers of normal people will have FEV 1 /FVC ratio <70% Above age 70, >30% of normal people will have FEV 1 /FVC ratio <70%

74 So, what does the FEV 1 /FVC ratio actually mean? Interpretation depends on developmental stages A plague on fixed ratios FEV 1 /FVC ratio > 1.96 Z scores below the normal means that your FEV 1 /FVC ratio is > 1.96 Z scores below the normal! FEV 1 /FVC ratio > 1.96 Z scores below the normal is not a diagnosis I am discussing FEV 1 /FVC ratio > 1.96 Z scores below the normal, not COPD, in the conclusion of this talk Adult physicians, do likewise!

75 Summary and Conclusions-1 There are four key times of lung developmental vulnerability Transgenerational Pregnancy Timing, place and nature of delivery Early childhood years Early life risk factors for premature airflow obstruction include: Maternal or paternal asthma Maternal smoking Childhood asthma (which starts early) Childhood viral infections (the roots of which are also early)

76 Summary and Conclusions-2 If premature airflow obstruction is prevented, we must start early Reduce tobacco smoking Optimise other aspects of intra-uterine lung health Can antibiotics help (c.f. duodenal ulcer)? Optimise the extra-uterine environment, especially in the first six years of life Any view of adult obstructive airway disease which does not take account of childhood factors is fatally flawed

77 Thank you for listening!