Drug Induced Lung Disease-Pathologic Patterns

1. Drug Induced Lung Disease-Pathologic Patterns Prof.Dr.E.Handan Zeren Çukurova University ADANA

2. www.pneumotox.com

3. Drug induced lung injury • Many histologic patterns may be noted • Pure patterns • Mixed patterns • Acute injury patterns • Subacute injury patterns • Chronic injury patterns

4. Some pulmonary drug reactions are relatively localized • Can be presented as an acute process in a patient who has been on the drug for a long period of time • Late complications can appear after the therapy ended • E.g. Bischloroethyl nitrosourea (for childhood brain tumors) causes interstitial fibrosis many years after the therapy

5. A lung biopsy may be required to establish the diagnosis • An open or thoracoscopic lung bx is recommended • BAL may be of value and more importantly in ruling out more common causes such as infection and malignancy

6. BAL findings supporting drug-related lung reactions: • 1) Cytotoxic reactions- • atypia (cytomegaly, cytoplasmic eosinophilia, bizzare cell shape, nuclear hyperchromasia, prominent nucleoli, multinucleation), • increased eosinophils, • extracellular lipoproteinaceous debris

7. 2) Pulmonary hemorrage with hemosiderin laden alveolar macrophages • 3) Lymphocytic alveolitis – 40-50% of the cells are lymphocytes • Increased CD8+ cells with a decrease in CD4+ : CD8+ ratio→ suggestive of hypersensitivity reaction • Gold, methotrexate, azathioprine

8. 4) Neutrophilic alveolitis – even ↓ 5% neutrophils, may reflect fibrosis • 5) Eosinophilic alveolitis – even ↓ 5% eosinophils • An acute allergic reaction within a short period of time • 6) Lipoid pneumonia – mineral oil nose drops and laxatives

9. BAL may reveal drug effects without toxicity • Gold therapy – Alveolar macrophages may retain gold for a long period of time without gold induced pneumonitis and chronic rheumatoid lung disease • Amiodarone therapy – Lamellar inclusions in alveolar macrophages show that the patient is taking the drug, do not provide information about the toxicity

10. Amiodarone

11. BAL findings in Amiodarone therapy: • 33% mixed • 26% neutrophilic • 21% lymphocytic • 20% normal

12. Pulmonary edema Alveolar hemorrhage (acute or chronic) DAD Organizing pneumonia UIP-like Dif. cellular inters. infilt. Nonspecific inters. pneumonia Lymphocytic inters. pneumonia Granulomatous inters. pneumonia Eosinophilic pneumonia(acute or chronic) Small vessel angiitis Metastatic calcification Pulmonary arterial hypertension Pulmonary veno-occlusive disease Asthma Constrictive bronchiolitis Bronchiectasis Miliary nodules Emphsema Combination of these patterns Histologic patterns in pulmonary drug toxicity:

13. Many drugs may produce acute and chronic forms of toxicity

14. Nitrofurantoin • An antimicrobial agent mostly used in urinary tract infections • Many cases of pulmonary toxicity have been reported (both acute and chronic) • Different morphological patterns can be noted in the same lung Acute → Subacute → Chronic

15. Nitrofurantoin

16. Nitrofurantoin

17. Nitrofurantoin • Acute reaction pattern may mimic acute eosinophilic pneumonia – and appears within 2 weeks in 90% of the patients • A Type 1 hypersensitivity response and differs from eosinophilic pneumonia • The underlying cause is pulmonary edema • Chronic reaction reveals intersitial inflamation and fibrosis, accompanied by vascular sclerozis

18. Nitrofurantoin • Chronic nitrofurantoin toxicity will recover in most patients when the therapy is terminated

19. Sulfasalazine • Inflammatory bowel disease • Symptoms within 6 months • No relationship between lung toxicity and duration of the therapy, total cumulative dose, daily maintenance dose • Eosinophilic pneumonia • Nonspecific CIP • DIP • OP • DAD and pulmonary thromboemboli

20. Anti-inflammatory drugs- Gold salts • Approximately 1% of patients will develop lung toxicity • 2-6 months after the initiation of the therapy • Organizing DAD, nonspecific CIP, OP patterns that can be interpreted as manifestations of rheumatoid lung disease • Most patients will recover after the termination of gold therapy

21. Gold salts

22. Penicillamine • 18 days to 7 years after the onset of the therapy • Constrictive bronchiolitis- dense mononuclear inflammation and fibrosis around the airways • Epithelial necrosis • In some cases, lymphoid follicles predominate – follicular bronchiolitis • Airway changes – related to the drug? Related to the rheumatoid disease?

23. Penicillamine

24. Other pathologic patterns • Pulmonary – renal syndrome • Diffuse alveolar hemorrhage with no evidence of vasculitis + Glomerulonephritis • DAD

25. Antiarrhythmic drugs- Amiodarone • Between 5-10% of the patients • Daily dose of 400 mg→ increased risk of lung toxicity • Older than 60 yrs. → increased risk of lung toxicity • Many will recover after discontinuation of the drug

26. Amiodarone- reaction patterns • Nonspecific chronic interstitial pneumonia + intraalveolar foam cell accumulation • Lamellar bodies in EM • May also be seen in alveolar epithelium, interstitial and endothelial cells • Pleural inflamation assoc.with pleural effusion • OP pattern • Diffuse alveolar damage (DAD)

27. Amiodarone

28. Amiodarone

29. Antihypertensive drugs • Hexamethonium- is no longer used • After 4-15 months • Acute and organizing DAD • OP pattern • Propranolol • Pulmonary edema • Eosinophilic pneumonia-like syndrome

31. Cytotoxic Drugs • Largest and most important group of drugs associated with lung toxicity • Chemotherapy of malignant diseases • Treatment of some nonneoplastic conditions

32. Alkylating agents: Busulfan • Treatment of CML • First chemotherapeutic agent reported to cause lung toxicity • 4% of patients • Total dose ≥500mg • Latent period 1month to 12 years

33. Busulfan • Organizing DAD associated with bronchiolar and alveolar epithelial cell atypia • Large cells with a high nucleus:cytoplasm ratio • Pleomorphism • Macronucleoli • Intranuclear inclusions with EM • CIP • Pulmonary ossification • Alveolar proteinosis

34. Busulfan

35. Busulfan

36. Alkylating agents: Cyclophosphamide • Malignancies, glomerulonephritis, Wegener`s granulomatosis • Carmustine (BCNU) increases its toxicity • Latent period 2 weeks to 14 years

37. Cyclophosphamide • Organizing DAD • CIP • DIP (desquamative interstitial pneumonia) – like • UIP (Usual interstitial pneumonia) – like • OP • Patchy acute alveolar hemorhage

38. Alkylating agents: Carmustine (BCNU) • Most convincingly proven pulmonary toxic effects as is used as a single agent in primary brain tumors • Relationship between the cumulative dose and toxicity • 20-30 % of patients (almost 50% for the patients who receive ≥1.5 gr/m2 • High mortality rates

39. Carmustine (BCNU) • Acute and organizing DAD – most common • CIP • Delayed toxicity – NSIP • Predominantly upper zones • Subpleural parenchyma • Bilaterally • Pulmonary venoocclusive disease (PVOD) • Pleural disease • Fibrosis of the visceral pleura • Bleb formation - pneumothorax

40. Cytotoxic antibiotics: Bleomycin • Widespread use in treating various malignancies • Dose-limiting toxicity in humans • 3-5% of patients • Risk factors: • ≥400-450 units • >70 yrs. of age • Prior or concomitant thoracic irradiation • Combination chemo. With cyclophosphamide and high dose cisplatin

41. Bleomycin • DAD – Fatal • Eosinophilic pneumonia • OP • PVOD

42. Bleomycin

43. Antimetabolites: Methotrexate • 5-10% of patients • No definite risk factors • No relationship with the cumulative dose • Lower than 10% toxicity

44. Methotrexate • CIP – nodular • Lymphocytes, • Plasma cells, • Histiocytes • Multinucleated giant cells • Eosinophils in 50% • Rare poorly formed granulomas

45. Methotrexate • Hypersensitivity pneumonitis – like • Pt.s receiving low-dose therapy for RA or psoriasis recover rapidly after the termination of the drug • OP – can be in association with poorly formed granulomas • DAD - uncommon • Pulmonary edema –Intrathecal administration • + patchy alveolar hemorrhage

46. Methotrexate

47. Methotrexate

48. Most pulmonary drug reactions are diagnosed clinically and only a minority of patients need a biopsy • The pathologist`s job is to provide the clinician with the data to work with • Should attempt to define the pattern and determine if it is associated with the mentioned drug(s)

49. Drug induced lung disease is a diagnosis of exclusions • Main differential dx includes opportunistic infections – cultures, special stains etc. should be performed • No specific treatment exist for most of the drugs, however, in most cases the drug reaction stops when the therapy is terminated