25y

1. 25y/o hypoxic female smoker with significant interstitial lung disease and a restrictive pattern on spirometry

2. Diseases Resulting in Interstitial Infiltrates Sarcoidosis Hypersensitivity Pneumonitis IPF and other interstitial pneumonias (DIP, NSIP, etc.) TB & other mycobacteria Fungal Aspiration CVDz, Cancer (classically broncho-alveolar & lymphangitic spread) Eosinophilic granuloma (Langerhans Cell Histiocytosis) Drugs & Dusts Amiodarone, MTX, bleomycin, nitrofurantoin Silica, asbestos, beryllium

3. Another scheme to classify Interstitial Lung diseases Primary/Idiopathic IPF, etc. Sarcoidosis BAC LCH Secondary CVD-associated SLE, Sjogren’s, scleroderma, polymyositis Drugs Lymphangitic mets Infectious TB & mycobacteria Fungi Viruses P. carinii Inhalational HP Dusts Aspiration

4. Questions to ask History of malignancy Exposure history Occupational Environmental Hobbies Pets TB risk factors Sexual history/HIV status CTD symptoms Infectious/”B” symptoms

5. A second look

6. Symmetric interstitial/reticulonodular infiltrate Normal or increased lung volumes Cystic fibrosis Hypersensitivity pneumonitis (chronic) Langerhans cell histiocytosis Coexistent emphysema and fibrotic lung disease LAM Sarcoidosis

7. Pt is lost to follow-up Turns out, she went north for a second opinion Had a spontaneous tension pneumothorax while at Mayo, VATS pleurodesis and biopsy.

8. Paul Langerhans b. July 25, 1847 German-born, pathologist by training Described clusters/islands of cells in the pancreas that secreted insulin Found dendritic cells in skin (although he thought they were neurons) Contracted TB in 1874 Died of progressive uremia and renal failure in 1888

9. Langerhans’-Cell Histiocytosis The disease formerly known as eosinophilic granuloma, Histiocytosis X, Letterer-Siwe disease, Hand-Schüller-Christian disease Primary pathology is associated with the proliferation of, and organ infiltration by, Langerhans’ cells The lung is by far the most common organ involved, but can also affect bone, skin, pituitary, and any organs that contain lymphatic tissue

10. Table 1. Simplified System of Classification of Langerhans'-Cell Histiocytosis in Adults.Table 1. Simplified System of Classification of Langerhans'-Cell Histiocytosis in Adults.

11. LCH Epidemiology Precise incidence not known One study identified 5% of lung biopsies with interstitial lung disease as LCH (probably an exaggeration) Only one case of a familial clustering has been reported (father and son) No sex predilection, and it is primarily seen in whites

12. Table 1. Characteristics at the Time of the Diagnosis of Pulmonary Langerhans'-Cell Histiocytosis in 102 Adults.Table 1. Characteristics at the Time of the Diagnosis of Pulmonary Langerhans'-Cell Histiocytosis in 102 Adults.

13. Smoking is the only identified risk factor for developing LCH >90% of pt’s have a history of smoking Exactly how cigarette smoke induces the disease has not been delineated A mouse model exists for LCH secondary to tobacco smoke exposure

14. Monoclonal proliferation of Langerhans cells has been demonstrated in multi-organ disease, but not in the pulmonary form of disease Lung disease is considered a reactive rather than a true neoplastic process

15. Pathology Routine stains reveal large collections of nodules rich in Langerhans’ cells These lesions may be hypercellular, cavitating, or entirely fibrotic and devoid of all cells in later stages Nodules often connect with one another to produce a distinctive honeycomb appearance Progressive disease may result in cystic and bullous lung lesions

16. Presentation Up to 25% are asymptomatic (?!) Most common presenting symptom is non-productive cough and dyspnea “B symptoms” occur in up to 1/3 Chest pain and pleurisy are also relatively common Spontaneous pneumothoraces can also occur

17. Physiology Spirometry is variable and no single abnormality is consistently seen with the exception of a loss of diffusing capacity Hypoxia is common in later stages of disease

18. Table 2. Pulmonary Function at Diagnosis.Table 2. Pulmonary Function at Diagnosis.

19. Diagnosis Although tissue samples are not mandatory to diagnose LCH, most cases are diagnosed by lung biopsy specimens or BAL cytology The typical clinical syndrome (smoker <60yrs old with decreased DLCO) in association with typical radiographic features can be enough to establish a diagnosis of LCH

20. Figure 8. Suggested Diagnostic Algorithm for the Workup of Patients with Suspected Pulmonary Langerhans'-Cell Histiocytosis.Figure 8. Suggested Diagnostic Algorithm for the Workup of Patients with Suspected Pulmonary Langerhans'-Cell Histiocytosis.

21. Treatment of LCH Smoking cessation!! However, it has never been proven whether smoking cessation actually improves progression or survival Corticosteroids may be of benefit in symptomatic patients, but again, no studies to actually prove efficacy Salvage chemotherapy is reserved for relentless disease Lung transplantation is an option, although there are no formal guidelines specific to LCH

22. Figure 1. Kaplan-Meier Analysis of Expected and Observed Survival among 102 Adults with Pulmonary Langerhans'-Cell Histiocytosis. The expected survival was defined as that for age- and sex-matched members of the general U.S. population.Figure 1. Kaplan-Meier Analysis of Expected and Observed Survival among 102 Adults with Pulmonary Langerhans'-Cell Histiocytosis. The expected survival was defined as that for age- and sex-matched members of the general U.S. population.

23. Median survival after diagnosis: 12.5yrs

24. Back to our patient She returns to clinic, this time for evaluation for lung transplant Over the past 3 years she has been treated with corticosteroids and chemotherapy (cladribine) with no benefit, and has been on supplemental oxygen at home continuously for the past several months Pulmonary function tests have shown progressive decline in lung function, DLCO is now 22% of predicted

25. Back to our patient EKG CT scan

26. Back to our patient Echocardiogram Normal LV size and function Marked R atrial enlargement Marked RV enlargement and hypokinesis with diastolic and systolic flattening of IV septum c/w pressure and volume overload Agitated saline bubble study + for PFO Estimated PA pressure: 56mmHg

27. Learning Points How to approach a hypoxemic patient A sweet mnemonic for interstitial lung disease A focused differential for mid-upper lung interstitial dz LCH and smoking do not mix

28. References N Engl J Med 342:1969, June 29, 2000 Review Article http://content.nejm.org/cgi/reprint/342/26/1969.pdf N Engl J Med 346:484, February 14, 2002 Original Article http://content.nejm.org/cgi/reprint/346/7/484.pdf KPS

29. FVC 2.4L (59%) FEV1 2.0L (58%) FEV1/FVC: 86% TLC: 4.3L (81%) RV: 154% DLCO: 43%

30. Interstitial diseases that often spare the bases Sarcoidosis Silicosis Hypersensitivity Pneumonitis LCH