Pulmonary Complications of Chemotherapy and Other Medications

Nitin Bhatt, M.D.

Fellow, Division of Pulmonary and Critical Care Medicine

 

 

I. Mechanisms

a) Direct cytotoxic effect

b) Oxidative injury

c) Phospholipid deposition with cell dysfunction

d) Immune mediated i.e. hypersensitivity, autoimmune

II. Diagnosis

a) Usually clinical dx of exclusion

b) No specific PE, BAL or CXR/CT findings

(1) Fever, dyspnea, non-productive cough

(2) Exam normal or crackles, clubbing rare

(3) CXR/CT normal, asymmetric interstitial infiltrate, may become diffuse

(4) Lymphadenopathy rare

c) Histologic evidence such as "bizarre" changes in type II pneumocytes, interstitial inflammation not specific, can be seen with malignancy, radiation, oxygen injury

 

III. Cytotoxic Drugs

A. Cytotoxic Antibiotics

1. Bleomycin

a) Incidence approx 10% (2-40%) with mortality approx 1%

b) Present with dyspnea and cough

c) PFTs with decreased DLCO (most sensitive), restrictive pattern

(1)Decreased DLCO may occur without symptoms, CXR findings

(2) Decrease by 20% from baseline considered significant

(3) Reduction in TLC more specific

d) CXR bibasilar reticular pattern, multiple small nodules

e) Acute Hypersensitivity reaction, occ with pleuropericarditis, is a rare complication

(1) Peripheral eosinophilia

f) Progressive interstitial fibrosis most common presentation

g) BOOP that presents as multiple nodules, can cavitate, mimic mets

Requires biopsy for definitive dx

h) Pneumothorax, Pulmonary veno-occlusive disease

i) Risk Factors

(1) Older patients more sensitive

(2) Cumulative Dose greater than 450 total units (10% mortality if >550)

(3) Any exposure in the previous 6 months

(4) Concomitant or prior radiation therapy

(a) Lung injury may not be confined to radiation port

(5) Exposure to high supplemental FiO2 (> 0.25-0.30) can lead to development of ARDS 18-36 hrs after exposure

(6) Combination therapy with cyclophosphamide, G-CSF

(7) Renal failure, longer excretion time

j) Treatment trial of steroids warranted, no studies establish benefit

2. Mitomycin

a) Frequency 3-12%

b) Risk factors

(1) No definite age, sex, cumulative dose effect, synergistic effect with XRT

c) Dyspnea, cough, Chest pain

d) Acute or chronic interstitial pneumonitis

(1) Most begin after after 4th course of tx

e) Association with Micro-Angiopathic Hemolytic Anemia, ARF, non-cardiogenic pulmonary edema (mitomycin + 5-FU)

(1) High mortality (>90%)

f) PFTs with decreased DLCO (but not before symptoms), restriction

g) CXR with reticular pattern, nodules

h) 5% with pleural effusion

i) Mortality up to 50%, improvement in DLCO, symptoms with steroids

 

B. Nitrosureas

1. BCNU (a.k.a. Carmustine, bischlorethyl nitrosurea), CCNU

a) Pulmonary toxicity 20-30%

b)Increased risk in younger, pre-existing lung disease, smokers, or dose above 525 mg/m2 (50% affected at dose >1500)

c) Possible synergy with other drugs (cyclophosphamide), radiation therapy

d) Develop symptoms as soon as 1 mo after tx or up to >10 yrs after

e) Dyspnea, tachypnea, cough

f) End-expiratory crackles on exam

g) CXR bibasilar reticulonodular pattern, often normal

h) Treatment with steroids, 90% mortality

i) Long-term complication with BCNU is development of upper-lobe fibrosis

j) Pneumothorax also seen

C. Anti-Metabolites

1. Methotrexate

a) Frequency approx 7-8%

b) No association with age, total dose, underlying disease

c) Daily/weekly dosing more likely to develop

d) Acute presentation with noncardiogenic pulmonary edema

e) MTX pneumonitis

(1) Dyspnea, cough, f/c usually within wks to 1 yr of starting drug

(2) Hypersensitivity component, eosinophils, poorly-formed granulomas

(3) Usually improve with steroids, discontinuation of drug not always necessary, may be asymptomatic with rechallenge

(4) Diagnostic criteria from Rheum literature (need 1st major or 2nd & 3rd major plus 3 of 5 minor)

Major: HP by pathologic exam, parenchymal abnormalities on CXR,negative cultures

Minor: dyspnea <8 wks, nonproductive cough, sats <90%, DLCO<70% predicted, WBC <15,000

(5) Risk factors are age, other DMARDS, baseline abnormal CXR, low albumin

f) Chronic presentation f/c/malaise, then dyspnea, cough

(1) Decreased DLCO, and restriction

(2) CXR may be normal, more likely has parenchymal infiltrates

(3) May be difficult to differetiate from rheumatoid-related fibrosis, BO

g) Hilar or mediastinal lymphadenopathy can be present in either presentation

h) May present with acute pleuritic chest pain, pleural effusion

 

2. Azathioprine/6-MP

a) Develop acute restrictive lung disease

b) Tx with steroids

3. Cytosine Arabinoside (ara-C)

a) Acute noncardiogenic pulmonary edema

b) May occur up to 1 mo after tx

c) Fever, cough, dyspnea, hypoxemia

d) CXR with interstitial, then alveolar infiltrates. High initial mortality, can resolve after 3-7 days, normalizes in 1 month

 

D. Alkylating agents

1. Busulfan

a) Incidence approx 6%

b) Effects epithelial cells, assoc with secondary Pulmonary Alveolar Proteinosis

c) Risk factors include

(1) Duration of tx (often > 3yrs)

(2) Concomitant radiation therapy

(3) Total dose > 500mg (unless + XRT, other cytotoxic agents)

d) Insidious onset cough, f/c, weight loss

e) Exam with crackles, may club

f) PFTs with decreased DLCO, restriction

g) CXR with alveolar-interstitial pattern

2. Cyclophosphamide

a) Pulmonary toxicity in malignant and non-malignant disease

b) Can be early onset (within wks) or late onset (6 mos-6yrs after tx) pneumonitis

c) Late-onset may have pleural thickening assoc with interstitial infiltrates

d) No association with dose, age, XRT, oxygen

e) Usually develop symptoms within weeks

f) DOE, fevers, crackles

g) CXR with bibasilar reticular pattern, can have diffuse pulmonary edema

h) Treat with steroids, mortality upto 50%

3. Chlorambucil

a) Subacute presentation 6 mos-3yrs after tx

b) Cough, dyspnea, fevers

4. Melphalan

a) Develop 1-4 mos after starting tx

b) Dyspnea, malaise, productive cough

c) CXR with diffuse reticular pattern

E. Others

1. Vinca Alkaloids (vincristine, vinblastine)

a) Toxicity when used in combination with Mitomycin

Usually develop symptoms several hrs after dose of vinca drug

b) Acute respiratory failure, interstitial infiltrates

c) Bronchospasm, obstructive PFTs may also be present

d) Treat with steroids, usually some permanent respiratory impairment

2. All-trans Retinoic Acid

a) ARDS in approx 25% pts not also tx with steroids

(1) Leukocytosis (WBC > 20) and respiratory distress

(2) Occurs within 5-15 days of tx

b) Rare if treated with steroids simultaneously

3. Immunotherapy Agents

a) OKT3

(1) Acute pulmonary edema, especially if pt already fluid overloaded

(2) Also with wheezing, dyspnea, chest pain, f/c

b) IL-2, TNF

(1) Acute noncardiogenic pulmonary edema, reactive airways diseas

IV. Non-Cytotoxic Drugs

A. Antimicrobials

1. Nitrofurantoin

a) Acute hypersensitivity reaction (90% reactions)

(1) F/c, skin rash usually within 1-14d of uninterrupted tx

(2) Most pts have had some type of previous reaction to drug

(3) Elevated ESR, peripheral eosinophilia

(4) Diffuse interstitial/alveolar pattern, may have pleural effusion (eosinophilic)

(5) Tx with drug cessation, steroids, resolves in 24-48 hrs

b) Chronic pneumonitis

(1) Oxidative injury mechanism

(2) Occurs with >2 mos tx (avg is 30 mos)

(3) Insidious onset dyspnea, cough, occ fevers

(4) Can have elevated ANA, LFTs, immunoglobulins

(5) CXR with bibasilar interstitial infiltrates

(6) BAL with lymphocytic reaction

(7) Mortality 10%, most improve with drug discontinuation

2. Sulfasalazine

a) Symptoms within mos of starting drug, dose 1.5-8g/d

b) BOOP

c) Pulmonary infiltrates with eosinophilia

3. TMP/Sulfa

a) Acute pneumonitis

4. Amphotericin B

a) Acute pnuemonitis in patients also receiving blood transfusions or G-CSF

B. Analgesics

1. Aspirin/Salicylates

a) Bronchospasm (asthma, rhinitis/nasal polyps, ASA allergy)

b) Noncardiogenic pulmonary edema usually due to OD, levels >40

c) Pulmonary infiltrates with eosinophilia

d) Psuedosepsis…fever, hypotension, leukocytosis, MOD/ARDS in pts with chronic salicylate use (? Related to IL-6, TNF)

C. Anticonvulsants

1. TCA

a) Noncardiogenic pulmonary edema, usually with OD

2. Phenytoin

a) Hypersensitivity syndrome with fever, rash, leukocytosis with eos, hepatosplenomegaly, lymphadenopathy that may be focal or diffuse

a) Lymph node biopsy reveals hyperplasia, or a lymphoma-like appearance that can resolve with d/c drug…pseudolymphoma or resolve only to recur several mos later as a true lymphoma…pseudopseudolymphoma

a) Increased risk of lymphoma (4-10X) in pts on phenytoin

D. Antiarrythmics

1. Amiodarone

a) Multiple presentations

Interstitial pneumonitis

Mass/Cavitary lesions

BOOP

Hypersensitivity Pneumonitis

Post-op ARDS

DAH

Pleural effusions

Lymphocytic Pneumonitis

CEP

b) 6% of patients on > 400 mg/d for > 2 mos (2-30 wks)

c) Dyspnea, cough, fevers

d) Elevated ESR, no eosinophilia

e) PFTs with decreased DLCO, TLC

f) CT may show dense deposits of radiopaque material

g) BAL usually shows lymphocytosis (decreased TH/Ts), absence of foamy macs in BAL or pleural fluid makes dx unlikely

E. Antirheumatics

1. Penicillamine

a) Pulmonary&endash;renal syndrome

(1) Similar to Goodpasture's with DAH and necrotizing GN

(2) dyspnea, cough, hemoptysis, hematuria

(3) Tx with steroids, immunosuppresssion, pheresis

a) Bronchiolitis Obliterans

(1) 3-14 mos non-productive cough, dyspnea

(2) CXR normal or reticular/alveolar infiltrates

a) Interstitial fibrosis

a) Hypersensitivity Pneumonitis, may be a drug-induced SLE

2. Gold Salts

a) Interstitial pneumonitis

(1) Avg patient >50 y/o, on tx for 15 wks

(2) Dyspnea, peripheral eosinophilia, skin rash, fevers

(3) CXR/CT show non-peripheral infiltrates

(4) BAL with lymphocytosis

a) Bronchiolitis obliterans can be seen with gold tx

F. Drug-induced lupus

1. Procainamide, Hydralazine (daily dose >200mg), INH, methyldopa, chlorpromazine, penicillamine

2. Most common cause of drug-induced pleural effusions, less than 5% have only parenchymal disease

3. Insidious onset f/c, mylagias, arthralgias, pleuritis more common than renal, CNS Symptoms

4. ANA (+), DS-DNA (-), anti-Histone (+), NL complements

G. Opiates

1. Cocaine

a) Noncardiogenic pulmonary edema

b) Hemoptysis, Diffuse alveolar hemorrhage

c) Focal infiltrates, pneumothorax/mediastinum

d) BOOP

2. Heroin

a) Noncardiogenic pulmonary edema

b) Aspiration pneumonia

c) Chronic use associated with bronchiectasis

H. Sympathomimetics

1. Terbutaline

a) Noncardiogenic pulmonary edema

b) DDx cardiomyopathy, aspiration, amniotic fluid embolism, PE

I. Others

1. Dantrolene

a) Chronic pleural effusions without parenchymal disease

(1) Usually unilateral with chest pain after 1 month to yrs of tx

(2) Pleural fluid eosinophilia (12-66%), often with peripheral eos (5-10%)

(3) Pleural biopsy shows nonspecific pleuritis

2. Esophageal Varices Sclerotherapy Agents (Sodium Morrhuate)

a) Not associated with mediastinitis, not clinically significant

(1) Pleural effusions in 25% cases

(2) Mediastinal widening in upto 1/3rd cases

(3) Atelectasis, infiltrates 10 % each

3. Ergot Derivatives

a) Methysergide

(1) Pleural, retroperitoneal, myocardial, valvular fibrosis

(2) Can present with uni/bilateral effusions, progressive dyspnea, pleuritic chest pain, friction rubs

(3) Effusions often loculated, pleura may appear nodular, irregular (similar to mesothelioma, TB, metastatic disease, asbestos exposure)

(4) Improve with d/c drug, some degree of residual fibrosis

b) Ergotamine

(1) Pleural and parenchymal fibrosis

(2) Pleural thickening and chronic effusions, pleural masses

c) Bromocriptine

(1) Pleural thickening/fibrosis, pleuritis in 2-5% patients

(2) Insidious onset cough, dyspnea after 1-2 yrs tx

(3) Uni/bilateral exudative effusion with lymphocytes, eosinophils

(4) Slow resolution with d/c drug

(5) Similar fibrosis with serotonin producing carcinoids

4. Cyclosporin

a) Post-transplant lymphoproliferative disorder (3-5% of all cases)

b) Related to EBV

5. Corticosteroids

a) Mediastinal lipomatosis can mimic mediastinal mass

(1) Patients usually have other Cushing's features

(2) Differentiate by CT/MRI

6. Hydrochlorothiazide

a) Noncardiogenic pulmonary edema

b) Almost always in females, taking HCTZ intermittently for edema

c) Resolves 48-72 hrs

7. Neuroleptics

a) Tardive dyskinesia involving muscles of face, neck

b) May develop respiratory dyskinesia (3-40%)

c) Promethazine, Prochlorperazine, metaclopramide

(1) Usually on drug at least 3 mos, can occur upto 1 yr after drug stopped

d) Irregular breathing pattern, dyspnea, tachypnea, disappear with sleep, worse with anxiety, often mistaken for psychogenic hyperventilation NL PFTs, pO2, low pCO2

8. Dextran

a) Used in hysteroscopic surgery

b) Noncardiogenic pulmonary edema associated with cases > 45min, > 500ml used, excessive endometrial irritation

c) Can develop coagulopathy

 

Updated 3/7/00

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