Current standards of care in the diagnosis and treatment of extraesophageal reflux in children

1. Current standards of care in the diagnosis and treatment of extraesophageal reflux in children Grand Rounds October 10, 2007 S Kherani

2. Objectives • Define extra-esophageal reflux disease and differentiate it from GERD • Describe the various clinical presentations of EERD • Identify and compare methods for diagnosing EERD • Discuss management strategies for EERD

3. Extra-esophageal Reflux (EER) • When stomach contents emerge from the esophagus into the upper and lower airways, nose, nasopharynx and oral cavity • Refluxate • acid, pepsin, bile and pancreatic enzymes

4. GERD vs EERD GER Esophagitis EER

5. Extra-esophageal Reflux Disease(EERD) • When refluxate results in a 2º disease • Ex: rhinosinusitis, chronic laryngitis, recurrent pneumonia, asthma • GERD and EERD have same root cause (mucosal irritation from refluxate), but the characteristics of the damaged mucosa and their anatomic relationships differ

6. Esophagus protected from refluxate by frequent swallows that clear esophagus Buffering action of saliva Squamous epithelium Tonic contraction of LES Brief refluxate exposure can have no effect on esophagus Upper aerodigestive tract protected by: Length of esophagus Esophagus peristalsis UES Damage with even brief refluxate exposure to upper aerodigestive and lower a/w Little et al. showed in an animal model that acid exposure of 1 minute/d x 8d changed minor tracheal injury  subglottic stenosis Damage can occur with exposure pH>4 (pepsin active at pH of 6.5) GERD vs EERD

7. Epidemiology • GERD • Adults: >75 million in US have GERD, 50% of these also have EER • Pediatrics: 1.8%-22% have GERD • Genetic association to chromosome 13q14 for some • Begins as severe pediatric GERD continues into adulthood • Autosomal-dominant pattern with high penetrance • Genetic link exacerbated by familial dietary and lifestyle habits known to worsen GERD • Tomato sauces, fatty meats, fried food and caffeine • Stress, sedentary, late dinners, large meal b/f exercise

8. Interesting Associations to EERD • Lifestyle and dietary habits associated with other chronic illnesses that also have increasing incidence as EERD • DM • Asthma • Obesity • Mood disorders • Sleep-disordered breathing • Some conditions are exacerbated by EERD • Others may contribute to EERD

9. Clinical Presentation of EERD • In reviewing 235 children with at least 1 positive test for GERD (defined as (+) test on Ba esophagogram, gastric scintiscan, pH probe or esophageal bx), Carr et al. classified EERD into symptom complexes • Gastrointestinal • Airway Symptoms • airway flow and airway irritation • Feeding/Eating • General Ear-Nose-Throat Symptoms • Other

10. Symptoms of EERD:Gastrointestinal • Stomach Aches • Nausea • Frequent emesis (39%) • Regurgitation • Frequent burps • Wet burps (30%) • Heartburn/chest pain (esp. with exercise) • Constipation

11. Chronic cough (51%*) Throat clearing (25%) Recurrent croup Wheezing Cyanotic spells Noisy breathing – stertor/stridor Hiccups Recurrent pneumonia Hoarseness (34%) Tracheotomy issues – stomal granuloma “Gurgly” respirations Symptoms of EERD: Airway

12. Symptoms of EERD: Feeding/Eating • Dysphagia (24%) • Odynophagia • Gagging • Choking • Globus Sensation • Failure to Thrive

13. Nose Nasal obstruction Nasal congestion (45%) Nasal pain Snoring Snorting Post-nasal drip Ear Ear pain Recurrent otorrhea/COM Oral Drooling Oral sores Halitosis Taste/tongue problems Symptoms of EERD: General Ears-Nose-Throat

14. Symptoms of EERD: Other • Sleep disturbances/ frequent arousals • Dental erosion • Headaches • Fatigue/depression • Hyperactivity/academic problems/attention disorders

15. Symptom Complexes for EERD • Carr et al. found that children who present with a certain constellation of airway or feeding symptoms are more likely to have a positive GERD test • < 2yr old: present more with • Airflow: stertor, stridor, cyanotic spells (88% PPV to reflux) • Feeding: dysphagia, FTT, emesis (80% PPV) • >2 yr old: present more with • Airway irritation: cough, recurrent croup, throat clearing (72% PPV)

16. Vocal fold lesions – nodules Laryngo-tracheo-bronchitis Asthma Obstructive or central sleep apnea Non-obstructive sleep disturbances Laryngospasm Paradoxical VC movement Subglottic/tracheal stenosis Chronic laryngitis Laryngeal granuloma Laryngomalacia Chronic bronchitis Recurrent pneumonia Lung fibrosis Recalcitrant RRP Laryngeal carcinoma ENT dx manifestations of EERD:Larynx/Trachea/Lungs

17. Recurrent/chronic rhinosinusitis Chronic nasopharyngitis/ adenoiditis Otalgia Chronic rhinitis OME/COM Chronic pharyngitis Globus pharyngeus Recurrent aphthous ulceration Dental erosion Sialorrhea ENT dx manifestations of EERD:Sinonasal-Oral Cavity-Ears

18. Laryngomalacia and EERD • Matthews et al. • Incidence and frequency of reflux in pts with endoscopically-confirmed laryngomalacia • Based on 24-hr double probe pH test with proximal probe just above cricopharyngeus posterior to larynx • Reported that 24/24 (100%) children with laryngomalacia had pharyngeal reflux • 15 episodes to pharynx in 24h (4s duration, separated by >30s) • Not compared to controls

19. Subglottic Stenosis (SGS) and EERD • Cotton et al. in 1998 • Retrospective review of pts from 1990 to 1996 with SGS who had undergone overnight esophageal pH probe testing • mix of single and double probe • 37/74 had pH of <4 for >5% of test (+ test) at lower probe • 55 had double probe. At upper probe: • 27/55 had pH <4 for >1% of test • 11/55 had pH <4 for >3% of test (normal is <1%) • No correlation with grade of stenosis • SGS may be correlated with GER

20. Recurrent Respiratory Papillomatosis and EERD • Case Series by McKenna et al. in 2005 • 4 cases of RRP whose increase in severity of RRP (3.8 sx/yr) occurred with recognition of symptoms of EERD • Each then had reflux confirmed objectively • RRP improved with treatment of EERD • 2 individuals had complete resolution of RRP • Lapses in compliance with GER in 3 of 4 pts led to rebound worsening in voice quality and endoscopic appearance • Poor evidence but suggests that EER dx/tx should be considered

21. Vocal Cord Nodulesand EERD • Kuhn et al. in 1998 • Compared 11 pts with vocal cord nodules to 11 healthy volunteers • Methods: compared results of barium esophagogram and 3-site pH monitoring • Pharynx: 2cm above UES • Upper esophagus: 10cm distal to pharyngeal lead • Lower esophagus: 5cm above LES • Results: • Pharyngeal reflux: 7/11 VC nodule; 2/11 controls • None of the barium reached the pharynx • Conclusion: GER may have contributory role

22. Asthma and EERD • Strong association mechanically and epidemiologically • 2005 Review in Paediatric Drugs notes trend of treating EERD in pts with difficult to treat asthma • Improved asthma symptoms if pt has documented reflux clinically or diagnostically • Minimal improvement if no reflux

23. Otitis Media and EERD • Tasker et al. in 2002 • At the Triological Society meeting presented that middle ear effusions (MEE) in children with OME requiring tubes had pepsin/pepsinogen levels 1000x higher than serum • Suspected gastric reflux through patent ET • Lieu et al. in 2005 • replicated findings for pepsin/pepsinogen • Reflux symptoms not higher than normal population • Antonelli et al. in 2005 • Did not find elevated pepsin in acute post-tympanostomy otorrhea

24. Otitis Media and EERD • Crapko et al. in Aug 2007 • detected pepsin in 60% of MEE from children receiving tubes for COM • pH was b/w 6.0 – 7.6 so pepsin was inactive, but could be reactivated • Abd El-Fattah in March 2007 • 22/31 children with OME had laryngopharyngeal reflux on dual probe testing • Positive relationship between # of reflux episodes and MEE pepsin levels

25. Diagnostics With clinical history suggesting EER, basic PE is often normal • May have lymphoid hyperplasia, palatal and uvular edema, dental erosions • Laryngoscopy/Bronchoscopy • Barium Swallow • pH monitoring • Scintiscan • Impedance Monitoring • Postcibal Ultrasound • Biopsy • Clinical trial of PPI

26. Diagnostics: Laryngoscopy/Bronchoscopy • According to a review by Cotton et al. in 2001, key signs of reflux laryngitis are: • Posterior glottic edema, hypervascularity and pseudosulcus • Can be present even when pH probe test (-)

27. Diagnostics: Laryngoscopy/Bronchoscopy • Carr et al. in 2000 • Retrospective review of pts with clinical suspicion of EERD who were taken to the OR for laryngoscopy/ bronchoscopy • Scope results were correlated to presence of GERD • defined as least 1 positive test result on upper GI, pH probe, gastric scintiscan or esophageal bx

28. Diagnostics: Laryngoscopy/Bronchoscopy • Results: • 130/155 (84%) had GERD • Of those with GERD, 90% had at least 1 laryngotracheal abnormality • Best sensitivity (75%) and specificity (67%) by combining • Post-glottic, arytenoid and VC edema • 100% PPV by combining post-glottic edema and any VC or ventricular abnormality • Conclusion: • Laryngoscopy/bronchoscopy can have high PPV for GERD • Endoscopy for EERD is a promising tool for diagnosis

29. Diagnostics: Laryngoscopy/Bronchoscopy • Prospective study from Carr et al. in 2001 with 77 consecutive pts comparing endoscopic results to GERD test results

30. Diagnostics:Laryngoscopy/Bronchoscopy Results: • Best correlation to GERD • Severe arytenoid edema, • Post-glottic edema • Enlarged lingual tonsils • Inter-rater reliability = 0.94

31. Diagnostics: Barium Swallow • 60% accurate for GER • Mainly for identifying/ruling out anatomic abnormalities • Esophageal strictures, hiatal hernia, pyloric stenosis, gastric outlet obstruction, webs, malrotation, etc.

32. Single vs double vs multi-probe sensors Positive test: distal esophageal probe is pH<4 for >5% of 24 hr test  Reflux episode identified by pH monitoring as a rapid drop in pH<4 distally longer than proximal Diagnostics: pH Monitoring

33. Diagnostics: pH Monitoring • Double-probe considered gold standard for GERD but… • Laryngeal signs can be present even when double-probe pH test is (-) (50% - Little et al.) • Difficult to interpret • Esophageal acidity varies day-to-day • Mahajan et al. showed reproducibility of test results in peds is poor and recommended repeating the test if results do not correlate with hx • False negative rate = 25% • Control variables difficult to set (esp. in peds) • Detects only acid events, not non-acid events • does not test for pepsin refluxate (active at pH<6.5)

34. Diagnostics: pH Monitoring • Pediatric population tolerance for probe • In 2005, Hochman et al. surveyed pts and parents regarding tolerance for a 48hr probe • 68% pts (avg age 11) reported discomfort • 95% of parents would agree to repeat the test • EERD • Increasing studies showing proximal probe for the double or multi-channel test in hypopharynx • Normative data used in literature though not universally accepted: ? pH<4 for <1% of time • Abnormal with pH<4 for >3% of time

35. Diagnostics: Scintiscan • Records distribution of a radioactive tracer (Tc99) obtained by means of a scanning scintillation counter • Can reveal delayed gastric emptying, reflux and  risk of aspiration pneumonia • Balson et al. found that barium swallow and scintiscan compare poorly with pH probe in diagnosing reflux • Low sensitivity (15%) and moderate specificity (73%) • Fair PPV and NPV compared to pH testing

36. Diagnostics: Impendance Monitoring • Multi-channel intraluminal impedance with pH probe • Answers issue of testing for refluxate that may not have pH<4 • Gives additional information re: non-acid reflux, direction of flow and bolus height • Norms not yet established • Results just beginning to be correlated to EERD • “Correlation of non-acid reflux to persistent respiratory symptoms is high”

37. Diagnostics: Postcibal Ultrasound • Evaluates reflux in relation to gastric emptying • Esophageal reflux (hyperechoic retrograde filling) and gastric emptying (antral areas) are quantified before and after ingestion of a standard formula • Ciaula et al. in 2005 • Measured in 35 untreated pts with recurrent respiratory dx vs 31 controls • Results: • ≥ 8 reflux episodes in 74% of pts vs 3% of controls; • both groups had similar gastric emptying

38. Diagnostics: Biopsy • Esophagoscopy not sufficient • Esophageal biopsy • Esophagitis/eosinophilia indicates need for aggressive tx BUT • Risk for sampling error if uninvolved area biopsied • Pts with upper airway abnormalities from EERD may not have injured esophagus mucosa • 20-80% of pts with EERD have esophagitis on bx • Biopsy indications: failed medical tx, fam hx, ?Barrett’s • Posterior cricoid and inter-arytenoid biopsy highly sensitive for mucosal injury/EERD (Cotton et al) • Basilar hypertrophy, vascular penetration and eosinophils

39. Diagnostics: Clinical Trial of PPI • While GER-related esophagitis is noted to heal with 2 weeks of PPI, most reviews recommend trial of 4-6 weeks or 1-3 months • Ultimately require diagnostic test to confirm diagnosis, especially if refractory to trial or considering surgical intervention

40. Management • Behavioural • Medical • Surgical

41. Management: Behavioural Basic Principles (medical intuition > evidence) • Tx depends on pt age, symptom severity, diet and lifestyle • intra-abdominal pressure • Wt loss, tx of cough and respiratory illness, elimination of pacifier and bottle after 9-12 months old • Alter diet • Address food allergies (especially milk)

42. Management: Behavioural by age Infants: • Modify formula to soy • Mother to avoid refluxogenic foods if nursing • Small, slow and frequent feeds • Feed and keep upright • No or little pressure on infant’s stomach • Ensure diaper not too tight

43. Management: Behavioural by age Aged 2 - 11: • Avoid spicy, acidic, caffeinated and fatty foods • Avoid carbonated drinks that cause bloating • Teach children how to make healthy meal choice in cafeteria and at home to maintain normal weight • Ensure meals are planned (to avoid fast food) with sufficient time to eat • Leave 1 hr after eating before exercise

44. Management: Behavioural by age Adolescents: • Minimize stress • From school, hectic extra-curricular activities, disrupted sleep • Continue to encourage healthy diet and lifestyle • Includes avoidance of alcohol, tobacco • Minimize late meals • Regular physical activity

45. Management: Medical • Antacids • H2-Blockers • Proton Pump Inhibitors • Motility Agents • Tx of H. pylori

46. Recall Stomach Physiology • Acid secretion stimulated by: • Acetylcholine (vagal) • Histamine (enterochromaffin-like/ECL cells) • Gastrin (gastrin-cells) • Cholycystokinin/CCK (endocrine cells of SI) • Acid secretion inhibited by: • Somatostatin (D-cells) • Protons (through D-cells)

47. Management: Medical – Antacids • Mechanism of Action: • Neutralizes acids, binds bile,  prostoglandins • Protective effect on gastric mucosa • Mg-based products  diarrhea • Aluminum-based  hypophosphatemia and constipation • Need q1-2hrs dosing to maintain pH>4 • Not realistic especially for EERD • Does not target refluxate < 4

48. Management: Medical – H2-Blockers • Mechanism of Action • Inhibits histamine stimulation (largest component of parietal stimulation) • pH and  gastric volume • Previously first-line • Falling out of favour compared to PPI • 2º to tachyphylaxis • Tolerance with prolongued use despite dose  • GI community advocate that it can be used for nocturnal breakthrough PRN

49. Management: Medical – Proton Pump Inhibitors • Mechanism of Action: • Binds to cysteine residues on the proton pump directly inhibiting H+ ion exchange • Inactive in circulation, activated by acid exposure • Suppresses acid section to all primary stimulants • No associated tolerance • IV pantoprazole has onset of action <1 hour • 20 minutes after IV bolus  pH and gastric volume remained  for 12h • Transient hypergatrinemia

50. Management: Medical – Proton Pump Inhibitors • Generally (but not completely) accepted as primary medical modality • In a large meta-analysis, Huang et al. found that • PPI x 2wks healed significantly greater % of adults w/ healed erosive esophagitis compared to H2B x 12wks • Considered more effective at keeping pH>4 for longer times including meals compared to H2B • healing and  symptoms • Several studies show faster healing in peds than adults