1. What your test results mean to you and your doctor Emily Gilbert, MD Assistant Professor, Dept of Medicine Div of Pulmonary & Critical Care Loyola University Medical Center

2. Case 35 year old Caucasian female with eight years of worsening shortness of breath She was diagnosed with asthma but feels no relief from inhalers Further testing is ordered – Chest X-Ray – CT scan of chest – Pulmonary function tests

3. Chest X-Ray

4. Pneumothorax

5. Chest X-Ray Pleural effusion

6. Chylous pleural effusion Chlye

7. Chest X-Ray

8. Chest CT - LAM

9. Chest CT - Emphysema

12. Why get Pulmonary Function Tests? Obtain baseline of lung function Assess disease progression Assess response to medications Determine prognosis and need for lung transplantation

14. “Breathe normally” “Breathe in as deeply as you can” “Breathe out as hard as you can”

15. Cleveland Clinic Jnl of Med 2003; 70: 866-881 Volume of air expelled during the entire forced exhalation Volume of air expelled during the first second of the forced exhalation Maximum Inhalation Maximum Exhalation

16. Spirometry Measures the exhaled volume and flow of air vs time Tidal Volume: volume of air moved during normal breathing FVC (forced vital capacity): – volume of air expelled during the entire forced exhalation (measured in liters) FEV 1 (forced expiratory volume in 1 second): – volume of air expelled during the first second of the forced exhalation (measured in liters) FEV 1 /FVC: % of air expelled in the first second

17. Cleveland Clinic Jnl of Med 2003; 70: 866-881 Volume of air expelled during the entire forced exhalation Volume of air expelled during the first second of the forced exhalation

18. FEV 1 /FVC 70-75% of volume expelled during forced expiration should be exhaled during the 1 st second FEV 1 /FVC ratio<70% indicates obstructive lung disease – Asthma – Emphysema – LAM

19. Spirometry in LAM Smooth muscle cells proliferate and surround airways Narrowing of airways  Air flow decreased  Decreased FEV 1

20. Normal Spirometry Values Reference value based on: – Age – Height – Ethnicity – Gender Reference value, measured value (L) and % of predicted value are reported % predicted = patient’s value reference value X 100

21. Severity Reduced FEV 1 /FVC ratio – FEV 1 /FVC ratio<70% = obstruction FEV1 is decreased due to obstruction of flow Severity of obstruction is based on FEV 1 – FEV 1 80-100% predicted = normal – FEV 1 60-80% predicted = mild obstruction – FEV 1 40-60% predicted = moderate obstruction – FEV 1 <40% predicted = severe obstruction

23. <70% = obstruction 50% = Moderate

25. Hypothesis for cyst formation

26. Bronchodilator Response Bronchodilators (e.g., Albuterol) relax muscles around the airway Spirometry is performed before and after administration of a bronchodilator Positive bronchodilator response: – 200mL increase in FEV 1 and – 12% change

28. Average LAM Spirometry Values Average FEV 1 /FVC = 64.5% Average FEV 1 = 70% of predicted – Mild disease Patients with TSC-LAM have more mild disease at the time of presentation Ryu et al. NHLBI LAM registry. AJRCCM 2006; 173:105-111

30. Pulmonary Diffusing Capacity Diffusing capacity of the lungs for carbon monoxide (D L CO) Measures the transmission of the CO molecule from alveolar gas to hemoglobin in the pulmonary capillary blood

31. Pulmonary Diffusing Capacity 1.Patient exhales completely 2.Breathes in the test gas (10% helium, 0.3% CO + oxygen and nitrogen) to maximum inspiration 3.Breath hold x 10 seconds CO has very high affinity for hemoglobin so crosses membrane and binds quickly to red blood cell 4.Patient exhales quickly and exhaled gas is collected

32. D L CO D L CO is adjusted for hemoglobin D L CO 80-100% = normal diffusion capacity D L CO 60-80% = mildly decreased diffusion capacity D L CO 40-60% = moderately decreased diffusion capacity D L CO <40% = severely decreased diffusion capacity Ryu et al. NHLBI LAM registry. AJRCCM 2006; 173:105-111

35. Cleveland Clinic Jnl of Med 2003; 70: 866-881 Volume of air left in lungs at end of maximum exhalation Total volume of air in the lungs at maximum inhalation

36. Obstruction Air Trapping Increased RV or TLC (>120% predicted) = Air trapping

37. Restriction Decreased TLC (<80% predicted) = Restriction Causes of restriction: – Pleural effusion – Pleurodesis for recurrent pneumothorax

39. Moderate obstruction + bronchodilator response Mild air trapping Severe defect in gas diffusion

40. The diagnosis of LAM is suspected based on Chest CT findings A serum Vascular Endothelial Growth Factor D (VEGF-D) level is drawn

42. VEGF-D Serum VEGF-D level of >800pg/mL in female with typical lung cystic changes on CT is specific for S-LAM Higher levels indicate more severe disease Her level returns at 935 pg/mL Based on her CT scan and VEGF-D level, she is given a diagnosis of LAM

43. Other testing… MRI brain – To look for evidence of tuberous sclerosis complex (TSC) Abdominal CT scan – To assess for evidence of angiomyolipoma Desaturation screen

44. 88% oxygen saturation

45. Results No evidence of Tuberous Sclerosis on her MRI of the brain No angiomyolipoma on CT of abdomen She desaturates to 84% on room air while ambulating and requires 2L of oxygen to keep saturations >88%

46. Next steps She is started on oxygen to keep oxygen saturation >88% while ambulating Given her symptoms and moderate obstruction on spirometry, Rapamycin is started

47. Follow-up appointments Rapamycin trough Cholesterol level VEGF-D level CT chest – Every few years – Very slowly progressing disease Pulmonary function tests – Every 6-12 months

48. Average lung function decline Nonsmokers without lung disease lose 30ml/year of lung function after age 35

49. Lung function decline in LAM PremenopausalPostmenopausal Decline FEV 1, % predicted 2.2% per year0.9% per year Decline FEV 1, mL 90 mL/year55 mL/year Decline D L CO, % predicted 2.8% per year1.9% per year Decline D L CO, mL/mmHg/min 0.78 per year0.58 per year CHEST 2004; 126:1867–1874

50. MILES trial N Engl J Med 2011; 364:1595-1606 Rate of change of FEV 1 was primary outcome in the MILES trial Placebo group had an observed FEV 1 decline of 134mL over one year Sirolimus group had improvement in FEV 1 of 19mL over one year

51. Value at time of enrollment Value at 12 months Placebo Sirolimus Change from baseline Placebo Sirolimus FEV1 (mL)1367mL (48%) 1272mL1383mL-134mL+19mL FVC (mL)2791mL (79% pred) 2843mL2780mL-129mL+97mL MILES trial N Engl J Med 2011; 364:1595-1606

52. Value at time of enrollment Value at 12 months Placebo Rapamycin Change from baseline Placebo Rapamycin FEV1 (mL)1367mL (48%) 1272mL1383mL-134mL+19mL FVC (mL)2791mL (79% pred) 2843mL2780mL-129mL+97mL Serum VEGF-D (pg/mL) 2029pg/mL2444pg/mL862pg/mL-14.8pg/mL-1032pg/mL MILES trial N Engl J Med 2011; 364:1595-1606

53. Despite being on Rapamycin, our patient has continued progression of her disease with worsening shortness of breath and increasing oxygen requirements 2010 Value% Predicted FVC3.51105% FEV11.4150% FEV1/FVC40% DLCO7.334

54. Despite being on Rapamycin, our patient has continued progression of her disease with worsening shortness of breath and increasing oxygen requirements 20102014 Value% PredictedValue% Predicted FVC3.51105%3.2098% FEV11.4150%0.7925% FEV1/FVC40%25% DLCO7.334%6.930%

55. Lung Transplantation Pulmonary function tests help predict when one should be listed for lung transplant Guidelines for lung transplant in LAM: – Severe life-limiting shortness of breath – Uncontrollable, recurrent pneumothorax – Use of oxygen Average lung function of LAM patients at time of transplant: – FEV 1 25% of predicted – D L CO 27% of predicted

56. Summary CXR, CT chest can help lead to diagnosis Pulmonary Function tests obtained at baseline and every 6-12 months FEV 1 /FVC ratio <70% indicates obstruction – Severity of obstruction is based on FEV 1 – Rule of 20s to determine severity VEGF-D level can help make diagnosis without biopsy and may decrease with Rapamycin Lung transplant is an option if disease progresses despite therapy

57. References Fletcher C. The natural history of chronic airflow obstruction. British Medical Journal 1977;1:1645-1648. Taveira-DaSilva AM et al. Reversible Airflow Obstruction, Proliferation of abnormal smooth muscle cells and impairment of gas exchange as predictors of outcome in LAM. AJRCCM 2001; 164: 1072-1076. Taveira-DaSilva AM et al. Decline in Lung Function in Patients with Lymphangioleiomyomatosis Treated with or without Progesterone. Chest 2004; 126:1867-1874. Orens JB, et al. International Guidelines for the selection of Lung Trasplant Candidates: 2006 update. Jnl of Heart and Lung Transplant 2006; 7: 745-755. McCormack FX. Lymphangioleiomyomatosis: A Clinical Update. Chest 2008; 133:507-516. Taveira-DaSilva AM et al. Reversible Airflow Obstruction in LAM. Chest 2009: 136; 1596-1603. Clements D et al. Lymphangioleiomyomatosis. Eur Respi Mon 2009; 46:176-207. McCormack FX et al. Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis. N Engl J Med 2011; 364:1595-1606 Henske, EP, McCormack FX. Lymphangioleiomyomatosis – a wolf in sheep’s clothing. JCI 2012;122(11):3807-3816.