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Drug Induced Lung Disease-Pathologic Patterns. Prof.Dr.E.Handan Zeren Çukurova University ADANA. www.pneumotox.com. Drug induced lung injury. Many histologic patterns may be noted Pure patterns Mixed patterns Acute injury patterns Subacute injury patterns Chronic injury patterns.
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Drug Induced Lung Disease-Pathologic Patterns Prof.Dr.E.Handan Zeren Çukurova University ADANA
Drug induced lung injury • Many histologic patterns may be noted • Pure patterns • Mixed patterns • Acute injury patterns • Subacute injury patterns • Chronic injury patterns
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
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
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
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
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
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
BAL findings in Amiodarone therapy: • 33% mixed • 26% neutrophilic • 21% lymphocytic • 20% normal
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:
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
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
Nitrofurantoin • Chronic nitrofurantoin toxicity will recover in most patients when the therapy is terminated
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
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
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?
Other pathologic patterns • Pulmonary – renal syndrome • Diffuse alveolar hemorrhage with no evidence of vasculitis + Glomerulonephritis • DAD
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
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)
Antihypertensive drugs • Hexamethonium- is no longer used • After 4-15 months • Acute and organizing DAD • OP pattern • Propranolol • Pulmonary edema • Eosinophilic pneumonia-like syndrome
Cytotoxic Drugs • Largest and most important group of drugs associated with lung toxicity • Chemotherapy of malignant diseases • Treatment of some nonneoplastic conditions
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
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
Alkylating agents: Cyclophosphamide • Malignancies, glomerulonephritis, Wegener`s granulomatosis • Carmustine (BCNU) increases its toxicity • Latent period 2 weeks to 14 years
Cyclophosphamide • Organizing DAD • CIP • DIP (desquamative interstitial pneumonia) – like • UIP (Usual interstitial pneumonia) – like • OP • Patchy acute alveolar hemorhage
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
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
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
Bleomycin • DAD – Fatal • Eosinophilic pneumonia • OP • PVOD
Antimetabolites: Methotrexate • 5-10% of patients • No definite risk factors • No relationship with the cumulative dose • Lower than 10% toxicity
Methotrexate • CIP – nodular • Lymphocytes, • Plasma cells, • Histiocytes • Multinucleated giant cells • Eosinophils in 50% • Rare poorly formed granulomas
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
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)
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