Rare and Emergent Drug-Induced and Iatrogenic Respiratory Conditions: A Guide to Their Recognition and Management


Pattern of DI involvement

Typical timing to onset

Develops in

Typical drugs or compoundsa

Main complications

Angioedema and UAO

Immediate-to-late

min-h

ACEI, ARB

UAO, throat closure, locked airway, asphyxia

Anaphylaxis

Immediate

min

Drugs, biologics, RCM, latex

Bronchoconstriction, shock, pulmonary edema

Laryngospasm

Immediate

sec
 
Asphyxia, NPPE

Sudden catastrophic bronchospasm

Immediate

min

ß-blockers, NSAID, aspirin, muscle relaxants, abused drugs

Locked airway, ARF, hypoxia, brain death

Acute intraoperative DI respiratory problem

Intraoperative, immediate

sec-min

See specific table

Anaphylaxis, acute bronchospasm, death

Flash pulmonary edema

min

min

Adrenaline, abused drugs, chemo, RCM

Hypoxemia, ARDS

Noncardiac pulmonary edema

min-h up to (months with oral drugs)

min-h

Chemo, hydrochlorothiazide, salicylate (dose-related)

Hypoxemia, ARDS

ARDS-DAD

d-y

h-d

Amiodarone, bleomycin, blood, chemo agents, paraquat

Hypoxemic ARF

TKI, oxygen, radiation therapy

May evolve to pulmonary fibrosis

Alveolar hemorrhage

d-mo

h-d

All anticoagulants, platelets inhibitors, cocaine, PTU

ARDS, clotting in central airway

Dense acute interstitial lung disease

w-y

h-d

Methotrexate

Hypoxemic ARF/ARDS

Acute amiodarone pulmonary toxicity

d-y

h-d

Amiodarone

Hypoxemic ARF/ARDS. Late pulmonary fibrosis

Acute eosinophilic pneumonia

d-mo

h-d

Minocycline, cocaine, venlafaxine, tobacco/marijuana smoke

Hypoxemic ARF/ARDS

Acute radiation-induced lung injury

w

d-w

Radiation therapy to the chest

Hypoxemic ARF/ARDS

Catastrophic pulmonary hypertension

Intraoperative, immediate

min

Protamine

Acute RVF, hypoxemia

Acute foreign body embolism

h-d

h-d

Lipids, silicone, hyaluronate, acrylate cement

Acute RVF/ARF/ARDS

Opportunistic infection

w-y

d

Corticosteroids, immunosuppressants, anti-TNF

ARF/ARDS (undistinguishable from DIRD)

Massive pleural/pericardial effusion/bleeding

w-y

h-d

Dantrolene, lupus-inducing drugs, all anticoagulants

Compression/tamponade

Acute methemoglobinemia

h-d

min-h

Benzocaine, dapsone, nitrites, oxidizing/occupational agents

Tissue hypoxia, pulmonary edema, brain damage

Ventilatory arrest

Immediate

sec

Opiates, colimycin

Tissue hypoxia

Neuromuscular failure

h-d

min-h

Aminosides, curares, dantrolene, narcotics

Hypoxemic ARF

Acute left ventricular failure

h-d

h-d

Doxurubicin, fluorouracil

Pulmonary edema

Multiple organ dysfunction syndrome

w-mo

d

Drugs that induce DRESS

Multi-organ dysfunction/failure


Abbreviations: ACEI ACE inhibitors, ARDS adult respiratory distress syndrome, ARF acute respiratory failure, DAD diffuse alveolar damage, DAH diffuse alveolar hemorrhage, DI drug-induced, DIRD drug-induced respiratory disease, DRESS drug rash eosinophilia and systemic symptoms, NCPE noncardiac pulmonary edema, NPPE negative pressure pulmonary edema, NSAID nonsteroidal antiinflammatory drug, NSIP nonspecific interstitial pneumonia, PTU propythiouracil, RCM radiocontrast media, RILI radiation-induced lung injury, RVF right ventricular failure, TKI tyrosine kinase inhibitor, UAO acute airway obstruction, y years, h hours, d days, w weeks, mo months, min minutes, sec seconds

aComplete list of offenders see pneumotox.com



Drug-induced adverse reactions occur unexpectedly in a few individuals who are predisposed often without a clear reason for it, who receive the drug at normal dosage. There are usually little or no annunciating symptoms. Strictly speaking, drug overdosing is outside the province of drug-induced adverse effects, although overdoses of drugs can cause pulmonary edema, acute respiratory failure, the adult respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH) and death. In addition, the limit between normal and above-normal dosage is blurred for such drugs as oral anticoagulants, thrombolytic agents, amiodarone, cyclophosphamide, bleomycin, nitrosoureas, salicylate and drugs of abuse, and for practical reasons respiratory injury associated with drug overdose will be covered here inasmuch as aging, impaired hepatic or renal function, drug interactions and/or variability in drug metabolism and clearance may alter drug disposition. Drug abuse and misuse (e.g. intravenous injection of crushed tablets intended for oral use) and chemical-induced respiratory injury are also covered here and in Pneumotox. Other complications from drugs include drug withdrawal-induced flare of the underlying condition, as shown by relapse of amiodarone pulmonary toxicity (APT) upon corticosteroids withdrawal, rebound respiratory failure following naloxone reversal of opioid intoxication [4], rebound pulmonary hypertension (PHT) following inadvertent cessation of pulmonary vasodilator therapy [5], or the recently-described ruxolitinib withdrawal syndrome [6].

Reports on drug-induced respiratory disease (DIRD) appeared as early as the late nineteenth century. The topic grew in the 1950s–1970s, and in 1973 about 120 drugs were known to injure the respiratory system [7]. This figure was propelled since the 1990s to 950 iatrogenic offenders at large, 15 main and 200 subpatterns. Classic offenders such as angiotensin-converting enzyme inhibitors (ACEI), amiodarone, anticoagulants, beta-blockers, bleomycin, cyclophosphamide, nitrosoureas and other chemo agents, blood transfusions, ergots, irradiation, methotrexate, minocycline, nitrofurantoin, nonsteroidal antiinflammatory drugs (NSAIDs) and salicylate still cause a persistent background of DIRD, although the current literature may not reflect it well as these adverse effects get rarely published nowadays. Drug-induced respiratory disease has garnered further interest as amiodarone, and novel biologicals and targeted agents such as tyrosine (TKI) or proteine kinase inhibitors (e.g. BCR-ABL), TNF-alpha antagonists, anti-CD20 (rituximab), inhibitors of the mTOR pathway, of platelet glycoprotein IIB/IIIA receptors, and direct antithrombin anticoagulants and reverse transcriptase inhibitors are now available to treat coronary artery disease, solid and hematologic malignancies, rheumatoid arthritis and other connective tissue disease (CTD), and systemic vasculitis. Targeted agents may cause on- and off-target adverse effects including but not limited to opportunistic infections [8, 9]. Exposure to these agents has been temporally related to the development of ILD, rapidly-progressive ILD, organizing pneumonia, eosinophilic pneumonia, sarcoidosis-like condition, diffuse alveolar hemorrhage (DAH), hypersensitivity, and anaphylaxis. Drugs, abused drugs, biologicals and silicone may also cause autoimmunity or autoimmune conditions [10, 11] with possible lung or serosal involvement including but not limited to lupus erythematosus, ANCA-related granulomatosis and polyangiitis (formerly known as Wegener’s), PR3- or MPO-antineutrophil cytoplamsic antibody (ANCA)-related vasculitis [12], eosinophilic vasculitis (Churg-Strauss’), Goodpasture-like pneumorenal syndrome, inflammatory myopathy and the anti-phospholipid syndrome. Drug-induced systemic conditions may manifest in the chest exactly as they do when they occur idiopathically in the form of ILD, DAH, eosinophilic pneumonia, lung nodules, lymphadenopathy, pleuropericardial effusion, systemic myositis or pulmonary thromboembolism. Biologicals used to treat rheumatoid arthritis also interfere with TNF signaling pathway causing opportunistic pulmonary or and/or systemic infections including reactivation of latent tuberculosis infection (LTBI) [13].

The possibility of exposure to illicit drugs should also be raised in patients presenting with acute pulmonary edema, diffuse alveolar hemorrhage, upper airway injury/burns, ILD, acute eosinophilic pneumonia, organizing pneumonia, pulmonary granulomatosis, foreign body reaction, talcosis, acute bronchospasm, pneumothorax, pneumomediastinum, pulmonary hypertension, pleuritic chest pain and blackened material in the alveolar lavage fluid [14, 15]. History taking of exposure to abused drugs often is challenging.



Epidemiology


Amiodarone, methotrexate-, nitrofurantoin-, chemotherapy agents and radiation cause lung injury with a significant incidence rate (nitrofurantoin: 0.2 %; amiodarone 2–4 % per year). Incidence with most other drugs is low to very low, fitting the numerical definition for orphan diseases of <1/2,000 patients affected. The base of evidence for drug causality is heterogenous as many reports date back several years and few specific tests were or are available. In a few phase I or II combination chemotherapy regimens where bleomycin, CCNU, gemcitabine, or dasatinib were given concomitantly with irradiation, the incidence of DIRD could be as high as 50 % or more [16].

Drugs are a significant contributor for pulmonary diseases accounting for 3–5 % of all ILD cases [17], 10 % of ARDS [18], 11–18 % of DAH [19] or eosinophilic pneumonia and 30 % of organizing pneumonia cases. Four percent of all DIRD are fatal and about 8 % are preventable although risk evaluation and prevention are still in their infancy.

Drugs cause DIRD after variable times on the medication, from a few seconds for flash pulmonary edema [20], catastrophic bronchospasm or anaphylaxis [21], to months or years into treatment for many ILD, or even after termination of treatment for iatrogenic fibrotic conditions [22]. DIRD may develop regardless of route of administration of drugs, although the oral and parenteral routes are foremost. Drugs given via topical instillation (transdermal, ophtalmic, gingival, intra-uterine, endomyometrial, subcutaneously, or in the vertebral body, pleura, urinary bladder or intrathecally), via inhalation or aspiration may also cause substantial lung injury [2].

Clinically, DIRD may manifest with involvement of the lung, central or peripheral airways, pleural and/or pericardial surface, circulation, mediastinum, neuromuscular system, heart or hemoglobin [2]. Although drugs or drug families may cause stereotyped patterns of adverse effects (Table 34.2), drugs generally may cause more than one pattern of involvement depending on the patient, with amiodarone outdoing any other drug with over 20 possible patterns [2].


Table 34.2
Main drug families capable of causing respiratory damage
























































































































































































































































































































































































































































































Drug or family
 
Incidence

Involvement

Comment

Abused drugs/substances

Heroin, cocaine, crack, cannabis

*****

Thermal airway injury

Crack cocaine
     
Catastrophic bronchospasm

Snorted/insufflated heroin
     
Pulmonary edema

Heroin overdose
     
DAH

Cocaine or levamisole toxicity
     
Pneumothorax/pyopneumothorax

Injection of drug in subclavian/jugular vein by mate
     
Cutaneous necrotic plaques

Cocaine-levamisole toxicity
     
Endocarditis

Intravenous drug use

ACE inhibitors

Captopri, enalapril, ramipril…

*****

Cough

Chronic. Abates with drug avoidance
   
****

Angioedema

Underdiagnosed. Ay lead to asphyxia. Relapses upon rechallenge
       
Sartans not entirely safe
     
PIE

Rare

Aphetamine-like anorexigens

Aminorex, fenfluramine, benfluorex

***

PHT/Valvular heart disease

Drugs were discontinued

Antibiotics

Minocycline, sulfasalazine, penicillin

****

Anaphylaxis

Can cause ARF, shock, and death
     
AEP

Can cause ARF. Good prognosis

Anticonvulsants

Carbamazepine, phenytoin, lamotrigine

****

DRESS

Rash, end-organ involvement, PIE in about 10 %

Anticoagulants (oral)

Coumadin, warfarin, brodifacoum

***

Bland DAH

Risk increases with the INR
 
New direct anticoagulants (DOA)

**

Laryngeal tongue hematoma

May cause acute UAO

Anticoagulants and thrombolytic agents

Heparin, SK, UK, alteplase

**

Bland DAH
 
     
Hemothorax

Can cause tamponade and CV collapse

Antidepressants

Sertraline, venlafaxine
 
AEP
 
     
DRESS
 

Antithyroid drugs

Propylthiouracil, benzylthiouracil

***

Capillaritis, DAH, systemic vasculitis

p- or c-ANCA present, often anti-HNE at high titers
       
Renal involvement possible

Angiotensin receptor blockers

Sartans

**

Angioedema

Risk 1/10 1/20 compared to risk of ACEI

Beta agonists (parenteral tocolytics)

Salbutamol, terbutaline, isoxuprine

***

NCPE

Mostly in parturients. Fatal in 5 %

Beta-blockers

Most ß-blocking drugs

***

Catastrophic bronchospasm

Can be fatal
   
**

Lupus syndrome

Pleural/pleuropericardial effusion and a positive ANA titers
   
*

ILD/OP

Low evidence for causality

Biologics

Anti-TNF agents, rituximab, omalizumab

**

Hypersensitivity, anaphylaxis
 
   
**

Acute ILD

More common with rituximab or infliximab
   
**

Pulmonary granulomatosis

More common with etanercept
   
**

Lupus syndrome

Serositis and high ANA and at times anti-ds-DNA

Blood, blood products

Blood, blood components, FFP

****

TRALI

Onset in 6–8 h of transfusion

Curares

Pancuronium, tubocurarine

***

Severe bronchospasm
 
   
**

Anaphylaxis
 

Cytotoxic agents

Bleomycin, busulfan, cyclophosphamide gemcitabine, nitrosoureas, taxanes

***

Transient pulmonary infiltrates

Caution as rechallenge may cause full-blown NCPE/ARDS
   
****

NCPE, DAH, ARDS

May relapse on rechallenge
     
Pulmonary fibrosis

Some will benefit corticosteroid therapy
 
Oxaliplatin

**

Anaphylaxis

Can be fatal

DMARDs

NSAIDs

****

Acute asthma. PIE

Class effect
 
Methotrexate

****

Acute cellular NSIP-like

Needs be separated from an infection and Pneumocystis pneumonia
 
Leflunomide

**

Cellular NSIP-like

Described mostly in Japanese RA patients
 
Tacrolimus

*

‘ILD’

Described almost exclusively in Japanese RA patients
 
Biologics

****

ILD/SLE/DAH

See under TNF-alpha inhibitors

Ergots

Bromocriptine, cabergoline ergotamine, DHE, methysergide nicergoline, pergolide

****

Pleural effusion
 
     
Pleural thickening
 
   
***

Acquired valvular heart disease

Anorexigens produced similar valvular changes

Interferon alfa/beta
 
***

Cellular NSIP-like ILD

New drugs to treat viral hepatitis C infection may decrease the incidence
     
OP
 
     
Sarcoid-like disease
 

Leukotriene receptor antagonists

Montelukast, pranlukast, zafirlukast

**

Eosinophilic granulomatosis polyangiitis

Causal relationship needs be examined in each case

Lipids (aspirated/inhaled) hydrocarbon

Paraffin, naphtha, kerosene

*****

Exogenous lipoid pneumonia, HCP

Free lipids in sputum, BAL or tissue

Lipids (infused)

Parenteral nutrition, excipients

**

Fat embolism
 

m-TOR inhibitors

Everolimus, sirolimus, temsirolimus

****

Cellular NSIP-like, OP, DAH

Dose-related. Abates dose with reduction or discontinuance
     
Rare PAP pattern
 

NSAIDs, aspirin

ASA, ibuprofen, indomethacin naproxen, piroxicam

****

Severe bronchospasm

Relapses on rechallenge
   
**

PIE

Relapses on rechallenge
 
Aspirin

***

NCPE

Anion gap, metabolic acidosis, high salicylate levels in blood

Platelet GPIIb/IIIA inhibitors

Abciximab, clopidogrel, eptifibatide, ticlodipine, tirofiban

***

DAH
 

Radiation therapy

Lung

****

Radiation-induced lung injury

Localizes along radiation beam
 
Lung

***

Stereotactic radiation therapy

Nodule/Mass. Whorled appearance. Can be tracer-avid on PET scan
 
Mediastinum

**

Mediastinal fibrosis

Compression of pulmonary vein
 
Trachea

**

Stenosis
 
 
Endobronchial

**

Dehiscence

Fatal hemoptysis
 
Breast

***

OP

Corticosteroid may be indicated
 
Liver

**

ARDS

131-I (radioiodine)

Statins

Fluvastatin, pravastatin, simvastatin

***

Cellular NSIP-like

Ground-glass on HRCT
     
OP

Fixed or migrating alveolar opacities
     
ARDS

Statin myopathy can be present in association

TKI inhibitors

Erlotinib, gefitinib

***

DAD/ARDS

Difficult to separate from underlying disease or from an infection
       
Baseline ILD may increase risk of developing the condition
 
Imatinib

**

Cellular NSIP-like

Class effect of these medications
 
Dasatinib

**

Pleural exudate, chylous effusion
 

TNF alpha-antibody therapy

Etanercept, infliximab, adalimumab

***

Accelerated ILD

May mimic an infection or exacerbation of underlying rheumatoid lung
     
Pulmonary granulomatosis

May mimic sarcoidosis
     
Opportunistic infections incl. TB

Pretherapy evaluation as regards latent TB indicated using TST and IGRA


Boldface: potentially life threatening conditions

Abbreviations: ACEI angiotensin converting enzyme inhibitors, AEP acute eosinophilic pneumonia, ANA antinuclear antibody, Ds-ANA anti double strand antibody, ANCA antineutrophil cytoplasmic antibodyantibodies, ARDS adult respiratory distress syndrome, ARF acute respiratory failure, ASA acetylsalicylate, CV cardiovascular, DAD diffuse alveolar damage, DAH diffuse alveolar hemorrhage, DHE dihydroergotamine, DRESS drug rash with eosinophilia and systemic symptoms, HCP hydrocarbon pneumonitis, ILD interstitial lung disease, INR international normalized ratio, NCPE noncardiac pulmonary edema, NSIP nonspecific interstitial pneumonia, OP organizing pneumonia, PAP pulmonary alveolar proteinosis, PHT pulmonary hypertension, PIE pulmonary infiltrates and eosinophilia, RA rheumatoid arthritis, SLE systemic lupus erythematosus, TB tuberculosis, UAO upper airway obstruction

Illicit/abused drugs including alcohol (also harbored in Pneumotox) are relevant DIRD providers [2]. In the past 40 years, the death toll from opioids in the US increased nine-fold, due to ventilatory depression, falls, and aspiration [23]. Subversion of drug use, herbals, dietary supplements, incense and chemical concoctions obtained through the Internet emerge as a cause of life-threatening respiratory disease [24, 25]. The new trend of ‘Met-Labs’ may cause life-threatening injuries to the manufacturer, family, law enforcement officers, firefighters and forensic personnel [26]. Other forms of DIRD include occupational asthma in pharmaceutical industry workers, and lung injury in pets and other animals, which closely resemble those seen in humans [2729].


Diagnosis


To raise the possibility that a new respiratory problem is caused by the administration of a drug, a combination of drugs and/or radiation therapy can be important for the patient: further/irreversible damage can be prevented if use of the harmful drug is stopped (although the underlying illness needs be managed using other medications so that the patient is not exposed to a flare of the underlying disease), patients may be spared unnecessary invasive evaluation (e.g. a lung biopsy and/or empiric corticosteroid therapy) pending the result of a drug holiday which can be diagnostic, and unnecessary readministration of the causal drug can be avoided. A high index of suspicion for drugs or chemicals as the possible cause for any new respiratory problem is warranted regardless of age as DIRD can occur in children or in newborns, gender though a few DIRD are female- or male-specific or are unique to the pregnancy state and underlying condition. Altered sensorium and inability of the patient to communicate in the emergency setting may complexify history taking, which may then rest on relatives, family physician or pharmacist. A urine drug screen and blood levels of the suspect drug or chemical (e.g. paraquat, brodifacoum) are indicated as early as possible after admission, so as the compound has not cleared to insignificant levels [30]. Analysis of the time course of symptoms vs. exposure is indicated as both drugs and patterns differ in this respect. Literature should confirm that the observed pattern (symptoms, imaging, laboratory findings, BAL, pathology, outcome) is appropriate for the specific drug. Pneumotox was designed to expedite this search [2]. Diligent exclusion of other possible causes is required as drug-induced pneumonitis and infectious pneumonia may present similarly. The expanse of differential diagnosis varies according to drug, basic disease, clinical context, presentation, pattern of injury and whether the patient was being exposed to one or several drugs or immunosuppressive agents. Abatement or resolution of symptoms should follow drug discontinuance, preferably without adjunctive corticosteroid therapy otherwise drug dechallenge is more difficult to interpret. Hyperacute drug-induced cellular ILD, pulmonary edema, alveolar hemorrhage, ARDS and systemic reactions may not improve upon simple drug withdrawal and corticosteroid therapy is indicated in such case and can be life-saving. Absence of recurrence of symptoms within an appropriate observational period off the drug will support the drug etiology. Relapse after inadvertent or deliberate rechallenge with the drug is undisputable evidence for drug causality, but this test often is not available as rechallenge can be hazardous or cause patient’s demise. Rechallenging the patient can be considered only if the drug is vital, there is no substitute for it, safe rechallenge has been described in the literature (e.g. imatinib, dasatinib, m-TOR inhibitors), and/or a prococol for rechallenge or induction of tolerance is available. Overall, 1.4 % of all DIRD cases have been rechallenged, leading to death of 7 % of those so managed. Lung pathology is rarely available in DIRD, being described in 3.8 % of all DIRD reports. Tissue abnormalities in drug-induced lung disease may be ‘consistent with’, ‘suggestive of’ or rarely ‘diagnostic of’ the drug etiology, which limits the contribution of this test. Table 34.3 lists the pathology patterns and whether BAL can be used as a surrogate test. The lung biopsy may have an important exclusionary role, whereby other illnesses or an infection can be ruled out with greater certainty. The recently described cryobiopsy technique is being currently evaluated [31]. Diagnostic criteria are summarized on Table 34.4. Overall, only a few cases can be definitely ascribed to drugs, namely those with a distinctive pathology or positive rechallenge. In a fraction, drugs can be ruled out, and the vast majority is labled possible or probable, with all uncertainty left to such wording [32]. Classic papers by Hill [33] and the Naranjo scoring system [34] still are valuable resources. The topic of counterfeit drugs [35] and the recent issue of fake journals [36] is a further challenge in evaluation the materiality of DIRD; continued vigilance is necessary.


Table 34.3
Drug-induced respiratory disease: pathology consistent with: pathology shows nonspecific findings and cannot support the diagnosis Suggestive: pathology shows distinctive findings that are distinctive enough to support the diagnosis specific: changes almost pathognomonic













































































































































































































































































































































































































Histopathologic pattern

Typical drug or drugs causing the pattern

Frequency

BAL surrogate?

Consistent with

Suggestive

Specific

Cellular ILD, NSIP-cellular-like

Methotrexate, nitrofurantoin, sirolimus

Common

Y if lymphocytic

X
   

Eosinophilic pneumonia

Minocycline, NSAIDs

Common

Y
 
X
 

Organizing pneumonia (OP pattern)

Amiodarone, interferon

Common
 
X
   

Acute Fibrinous Organizing Pneumonia AFOP

Amiodarone

Uncommon
       

ILD with a granulomatous component

BCG, interferon, methotrexate

Common
 
X
   

ILD with a necrotizing granulomatous component

BCG, marijuana, methotrexate

Uncommon
       

Diffuse alveolar damage DAD

Chemotherapy, irradiation

Common
 
X

X
 

A reactive epithelium, pneumocyte atypia

Alkylating chemotherapy, irradiation

Common

Y

X

X
 

Diffuse alveolar hemorrhage DAH

Anticoagulants, platelet aggregation inhibitors

Quite common

Y

X
   

Pulmonary fibrosis, NSIP-fibrotic

Chemotherapeutic drugs

Common
       

Pleuroparenchymal fibroelastosis

Cyclophosphamide

Rare
       

UIP pattern

Chemotherapeutic drugs

Common
       

DIP pattern

Amiodarone, nitrofurantoin, sirolimus

Unusual
 
X
   

GIP pattern

Nitrofurantoin

Rare
 
X
   

LIP pattern. Lymphoid hyperplasia

Amiodarone

Unusual
 
X
   

PAP pattern – secondary PAP

Busulfan, sirolimus

Rare

Y
     

Endogenous lipoid pneumonia – phospholipidosis

Amiodarone

Very common

Y/N
 
X

X

Changes in amiodarone pulmonary toxicity can be very suggestive

Or nearly so

Exogenous lipoid pneumonia

Paraffin, mineral oil

Common

Y
   
X
         
Lipid staining diagnostic

Interstitial foreign body granuloma

Abused drugs, talc

Uncommon

Y
   
X

Smudged parenchymal necrosis

Amiodarone

Uncommon
   
X

X

Pneumoconiosis, talcosis

Abused drugs, talc

Uncommon

Y
   
X

Amyloid deposits

Insulin

Rare
       

Crystal storage disease

Clofazimine

Rare
       

Diffuse pulmonary calcification

Calcium replacement

Rare
 
X
 
X

Bland pulmonary edema

Chemotherapy, salicylate

Common
 
X
   

Subacute/acute cellular bronchiolitis

Aspirated food, tobacco smoke, talc

Uncommon
   
X

X (if demonstrable food particulate matters in tissue)

RB-ILD

Tobacco smoke

Common

Y?
 
X (if pigmented macrophages present)
 

Constrictive obliterative bronchiolitis

?Penicillamine ?Gold. Sauropus androgynus

Rare
     

Foreign body bronchiolitis

Talc

Uncommon

Y
   
X

Pulmonary capillaritis

ATRA, PTU

Rare
 
X
   

Pulmonary vasculitis other than capillaritis

Hydralazine, tryptophan

Rare
 
X
   

Eosinophilic vasculitis

Tryptophan

Uncommon

Y
 
X
 

Fat/marrow embolism

Parenteral nutrition, propofol, vertebroplasty

Uncommon

Y
 
X
 

Silicone embolism

Fluid silicone

Uncommon
     
X

Foreign body vasculopathy

Talc, excipients

Uncommon
     
X

Elemental mercury embolism

Liquid mercury

Rare
     
X

Cement embolism

Acrylate cement

Uncommon
     
X

Crystal pulmonary embolism

i.v. lipids

Rare
   
X
 

Venoocclusive disease

Antineoplastic chemotherapy

Uncommon
 
X
   

Pulmonary hypertension

Anorexigens

Quite commona
 
X
   

Pleuritis

Radiation therapy, drug lupus

Common
 
X
   

Eosinophilic pleuritis

Propylthiouracil PTU

Uncommon
 
X
   

Pleural fibrosis

Amiodarone, ergots, drug-induced lupus

Common
   
X
 

Fire eater’s lung

Kerdane, petrolatum

Uncommon
   
X
 

Kayexalate lung

Kayexalate

Uncommon
     
X

Alveolar carbonaceous deposits

Crack cocaine

Uncommon

Y
   
X


Where BAL can reasonably be used as a substitute or surrogate, consider deferring the lung biopsy, pending the results of BAL and drug withdrawal or dechallenge test

The results of the transbronchial lung biopsy may not match those of the open lung biopsy

Watching the progress of cryolung biopsy is indicated

Blank/void cell indicates absence of data

aDrug has been recalled



Table 34.4
Check list for diagnosing drug-induced respiratory disease



































No evidence for pulmonary disease prior to therapy with the drug

Event unlikely in the course of the specific disease state

Confirmed exposure

Eligible drug

Drug singularity

Absence of prodromal signs and symptoms prior to exposure to the drug

Appropriate timing (latency time, onset) relative to taking the medication

Pattern appropriate for the drug under scrutiny

Confirmatory literature (qualitative: consistency, quantitative: magnitude)

Supportive imaging, laboratory, BAL, pathological features

Laboratory evidence including blood levels

Reasonable exclusion of other causes including an infection and the effects of other drugs

Abatement or resolution with discontinuation of drug, preferably without corticosteroid therapy

Lack of recurrence is patient not rechallenged

Relapse following rechallenge with the drug


Rare Drug-Induced Respiratory Disease


The orphan patient is the one presenting with DIRD in whom the diagnosis is not raised and drug dechallenge is not attempted. A list of common inducers and the corresponding clinical-imaging-pathologic patterns of involvement is given in Table 34.5. Being supported by a wealthy and persistently fueled literature, involvement from these drugs is not reviewed here in great detail although atypical respiratory presentations from some of these compounds is reviewed later in this text.


Table 34.5
Drug-induced respiratory disease: common inducers and patterns of involvement



















































































































































































































































































































 
Typical clinical imaging pattern

Incidence/RR

Practical risk factors

Clinical presentation

Onset

Management

Comment

ACEI

Cough

RR 2.5

Varies with ACEI

Chronic dry cough

w-y

DW

Resolves in all
 
Angioedema

0.1–0.4 % – RR 7.7

Dark-skinned people

Acute UAO/Asphyxia

w-y

DW

Fatal in 5 %

Amiodarone

ILD, endogenous lipid PNA

Up to 4 %

Dosage, time on drug, O2

Dyspnea, cough

d-y

Corticosteroids

Can leave residual fibrosis

Anticoagulants, oral

DAH. Airway hematoma

Rare

INR-dependent

Acute dyspnea & anemia

w-y

DW vitK FFP

BAL diagnostic

Anticonvulsants

DRESS syndrome

Up to 1/1,000

Familial incidence

Skin, deep-seated involvement

mo-y

DW

Mortality ca. 5 %

Aspirin/salicylate

Pulmonary edema

45 % of those poisoned

Elderly

NCPE, M metabolic acidosis

h-mo

DW, alkalinization dialysis

Mortality up to 15 %

ATRA

Pulmonary edema, DAH

6–27 %. Less if CS given

Leukocytosis

Pulmonary edema ARDS DAH

d

Supportive + corticosteroids

Mortality up to 13 %

Beta-blockers

Bronchospasm

Common

Asthma, atopy

Acute bronchospasm

min

Supportive + DW

25 % fatal

Bleomycin

Pulm infiltrates ARDS

About 10 %, up to 22 %

Retreatment, age, smoking, dose, O2

Basilar/diffuse infiltrates

w-mo

Supportive + DW + steroids

Up to 24 %

Chemo agents

Pulm infiltrates ARDS

Usually about 5 %

Dose, oxygen, ? CSF

Basilar/diffuse infiltrates

w-y

DW + corticosteroids

Fatality in DAD

Cyclophosphamide

Pulm infiltrates ARDS fibrosis

Up to 12 %

Dose, oxygen

Basilar/diffuse infiltrates

w-y

DW + corticosteroids

Up to 40 % mortality

Drugs of abuse

Pulm infiltrates, ARDS, EoP

Difficult to evaluate

Dose

Infiltrates pneumothorax burns

min-y

DW (corticosteroids)

Panoply of AEs

PHTn
 
Injection of crushed tablets

PHTn

y

Treat PHT, consider Tx

UDS indicated

Ergolines

Pleural thickening

Unknown

None identified

Restrictive lung dysfunction

y

DW corticosteroids rarely indicated

No fatalities. May leave residual

Gemcitabile

Pulmonary infiltrates NCPE

0.03–2 %

Concomitant bleomycin or irradiation

NCPE, ARDS

Within 2 mo

DW corticosteroid therapy

Mortality 20 %

HUS

2.2 %
 
NCPE, DAH, renal failure
     

Gold

Acute NSIP

Unknown

None identified

Diffuse infiltrates

w-y

DW + corticosteroids

Drug out of favor

Lipid (p.o.)

Exogenous lipoid pneumonia

15 % of institutionalized patients

Chronic aspiration

Basilar infiltrates

mo-y

DW. Corticosteroids ?

A disease of the elderly or with achalasia

Methotrexate

Acute NSIP

0.9–3 %

? previously diagnosed ILD

Diffuse infiltrates

w-y

DW. Corticosteroids

Common in RA

Minocycline

Acute eosinophilic pneumonia

Unknown

? Atopy

Peripheral or diffuse infiltrates

w-mo

DW. Corticosteroids

Distinctive pattern

Autoimmune ANA/ANCA disease

Unknown
 
Pleuropulmonary reaction
 
DW. Steroids. IS. Plasma exchange

When assayed ANA in 45 %; ANCA in 7 %

Some patients developed PAN

m-TOR inhibitors

Pulmonary infiltrates

Up to 35 %

Somewhat dose-related

Basilar pulmonary infiltrates. DAH

w-mo

Dose reduction. DW. Corticosteroids

Fatal cases among DAH

ILD may equate efficacy in RCC

Diagnostic challenge in lung Tx recipient

Nitrofurantoin

Acute pleuropulmonary reaction

1/5,000

None indentified

Acute dyspnea + chest pain

d-w

DW. Corticosteroids

Some patients have ANA

Chronic ILD or fibrosis

1/15,000–45,000

None indentified

Chronic dyspnea

mo-y

DW. Corticosteroids
 

NSAIDs

Asthma, anaphylaxis

Clinical: 3 %

Atopy

Acute bronchospasm

min

O2, corticosteroids, MV

Cross reaction among COX1 inhibitor drugs

Eosinophilic pneumonia

Higher on airway challenge

None identified

Bilateral infiltrates

mo

DW. Corticosteroids

Induction of tolerance possible

Nitrosoureas

Acute lung injury, ARDS

3–5 % overall

Dose, young age

Basilar or diffuse infiltrates

w-mo

DW. Corticosteroids

A fraction will respond to steroids

Pulmonary fibrosis

Basilar or diffuse infiltrates

mo

DW. Corticosteroids

Can be devastating

Phenytoin

DRESS syndrome

1/1,000–1/10,000

Family history

Multiorgan

W

DW ?Corticosteroids

Other anticonvulsants may cross-react

Radiocontrast media

Anaphylaxis

02/100.000 PY – 1.2/million doses

Atopy

CV collapse, arrest, angioedema, shock

min

Withdrawal
 

Sulfasalazine

Eosinophilic pneumonia
   
Basilar or diffuse infiltrates and eosinophilia

mo

DW. Corticosteroids

Needs be separated from effect of IBD on lung

TKI

DAD-ARDS

1–5 % in Japan0.3 % outside Japan

Prior ILD

Basilar or diffuse infiltrates

d-w

DW. Corticosteroids

Fatality rate up to 40 %


C condition, CSF colony-stimulating factors, DRESS the syndrome of drug rash, eosinophilia and systemic symptoms, DW drug withdrawal or dechallenge test, HUS hemolytic and uremic syndrome, LVDF left ventricular dysfunction or failur, PAN polyarteritis nodosa, RCC renal cell carcinoma, RR risk ratio of developing the condition vs. untreated subjects (when data available), TKI tyrosine kinase inhibitors, y years, h hours, d days, w weeks, mo months, min minutes


Adverse Respiratory Reactions with Indeterminate Evidence for Causality


About half the 950 drugs and agents censored in Pneumotox at this time cause ILD with a low to very low incidence rate (<10 reports overall despite many years on the market), indicating circumstantial evidence for causality. Reports are heterogenous [37], often date back many years, details were not given, patients were managed empirically with drug withdrawal and corticosteroid therapy making retrospective assessment difficult. The issue of causation vs. chance association is an unresolved one at this time and may remain so in the foreseable future. These drugs appear in Pneumotox with a 0–1 frequency [2].


Drugs Recalled or Fallen Out of Favor


Mecamylamine, hexamethonium, aminorex, tryptophan, fenfluramine, dex fenfluramine and benfluorex have all been recalled. We keep them in Pneumotox though, as any drug may regain popularity in light of a new indication as is the case with thalidomide, or because related congeners may reproduce DIRD similar to those of the parent compound.

The antneoplastic antibiotic mitomycin-C is now less commonly used than it once was. Mitomycin pneumonitis developed in about 5–10 % of the patients in the form of acute lung injury and DAD followed, in some patients by irreversible pulmonary fibrosis [38]. Corticosteroids have been effective in reversing early cases [39]. Mitomycin-associated hemolytic uremic syndrome is a rare (incidence 0.015 %) dreadful dose-related complication of mitomycin, gemcitabine and other chemotherapy regimens [4042]. The syndrome is characterized by any association of hemolytic anemia, circulating schizocytes, thrombocytopenia, reticulocytosis, hyper- or hypotension, renal failure central nervous system symptoms, renal failure, pulmonary edema, alveolar hemorrhage, ARDS and/or pulmonary hypertension. Blood transfusions can trigger the onset of or aggravate the syndrome. Pathologic appearance is with intravascular pulmonary fibrin thrombi, pulmonary edema, hemorrhage and/or DAD. Management includes plasmapheresis, renal replacement therapy and high-dose corticosteroids. Serial monitoring of renal function and urinalysis may indicate those patients with early impending toxicity [43].

The once popular antirheumatoid drugs gold and penicillamine have mostly fallen into disuse since the advent of methotrexate, leflunomide and TNF-alfa antagonists. Severe gold-induced NSIP-like disease, obliterative bronchiolitis and Goodpasture like disease from penicillamine are for now diseases of the past [2].

Amphetamine-like anorectics (aminorex in the 1960s, fenfluramine-dexfenfluramine in the 1990s, benfluorex in the 2000s,) were recalled on the basis of acquired pulmonary hypertension (PHT) or valvular heart disease. As early as 1977, Widgren et al. reported on plexiform arterial lesions in the pulmonary circulation of young ladies who had used the anorectic aminorex [44]. In the series by Gurtner [45] prior to the advent of new therapies for PHT, death was mainly from right ventricular failure after an average of 3.5 years. Patients with higher grades of pulmonary artery pressures had worse outcomes. However, the prognosis was not as severe as that of primary PHT. Pathologically, aminorex vasculopathy is similar to primary PHT and similar findings have been reported with the use of other anorexigens [46, 47]. The aminorex epidemic peaked in the 1960s and declined in the early 1970s concomitant with aminorex discontinuation. Although household manufacture of aminorex has been responsible for sporadic PHT cases [48], most of the concern with aminorex now resides in its precursor levamisole, a veterinary antihelminthic agent that is widely used since the early 2000s to cut street cocaine [49]. Levamisole is bioconverted to aminorex in mammals [50]. One PHT case has been documented following cocaine-levamisole abuse [51], and the topic is closely monitored. Accordingly, history of exposure to cocaine and other PHT inducers is indicated in any PHT case [52]. On the other hand, levamisole can produce a distinctive p-ANCA (with dual anti-PR3 and -MPO specificity) cutaneous vasculopathy mainly involving the face, earlobes and limbs, which is covered in more detail below [12].

The potent 5-HT2B receptor antagonist anorexigen fenfluramine and its dextro-isomer dexfenfluramine have also caused a PHT epidemic with a 6.3-fold increase in risk compared to nonusers [53]. Current data from the UK and Ireland Registry indicates a 1.7 % prevalence of antecedent anorexigen use among PHT cases [54]. In addition, fenfluramine caused valvular heart disease in the form of mainly left-sided valvular retraction with regurgitation or stenosis [55]. Fenfluramine and its dextro-isomer were recalled for that reason in the late 1990s. Benfluorex was promoted as an antidiabetic drug while in fact this is a fenfluramine prodrug. Vast numbers of valvular heart disease [56] and a few PHT cases developed in France following longterm indiscriminate exposure to the drug [57]. The drug was recalled in 2009.

Illicit amphetamines remain of concern as regards ‘primary’ PHT. An undeniably strong association between stimulant use (amphetamine, methamphetamine, cocaine) and ‘idiopathic’ PHT cases has been noted in western USA [58]. Chin et al. found a history of stimulant use in 28.9 % of their ‘idiopathic’ pulmonary hypertension cases, ten-fold that in nonidiopathic PHT [58].

Several members of the thiazolinedione (glitazones) family were discontinued in some countries owing to their propensity to cause capillary leak, pleural effusions and at times irreversible heart failure [2].

L-tryptophan once was a popular neutraceutical. The compound has produced an epidemic of ‘eosinophilia-myalgia syndrome’ [59]. Blood eosinophils were increased, about half of affected patients presented with small irregular or dense radiographic opacities and pleural effusion. An ARDS picture was noted in a few [2]. Minute amounts of contaminants (denoted peak and a suffix) formed during the bioengineered-driven synthesis of tryptophan at the Showa Denko plant were blamed as the cause for the syndrome. Incident cases diminished sharply after l-tryptophan was recalled. Only rare sporadic cases are now being reported [60].


Potentially Life-Threatening Emergencies


Pulmonologists, anesthesiologists, emergency physicians, intensive care and ENT specialists, dental and other surgeons can be confronted with acute life-threatening drug-induced respiratory and/or systemic emergencies. These reactions can affect (by decreasing order of frequency) the lung, upper or lower airways, pulmonary circulation, pleura or they are systemic in nature with pulmonary involvement in association. Clinical presentations are in the form of diffuse white-out of the lung corresponding to several forms or acute lung injury or airway emergencies. The causal relationship with administration of a drug is deduced from the brief time-to-onset of the reaction upon exposure, which can be of seconds. Some reactions develop electively during the intra- or perioperative period, causing difficult diagnostic and management issues. Recognition of the drug etiology is paramount and can be life-saving.


White-Out and the Adult Respiratory Distress Syndrome (Table 34.6 and Fig. 34.1)





Table 34.6
Acute life-threatening reactions potentially causing ARDS
















































































































































































































































































Clinical pathological diagnosis

Subpattern

Pathology

Typical drugs/agents

Time to onset

Tempo

BAL

Imaging (may predominate in LL)

Diagnosis

N drugs

1. Pulmonary edema

Pulmonary edema

Pulmonary edema & alveolar flooding

Chemo, ARA-C, HCT, ß2+

Short

Acute
 
GGO + pleural effusion

Normal heart, short tempo

170

Flash PE

?Pulmonary edema ?DAD

Adrenaline, RCM

Ultrashort <5 min

Hyperacute
 
Haze, GGO, lobular thickening

Tempo, foam at mouth

9

Transient pulmonary infiltrates

Pulmonary edema, DAD, vaculitis

Paclitaxel, ATG

Short

Acute
 
Slight haze, GGO, lobular thickening

Short-lived; relapse on rechalleng

6

Pulmonary edema & shock

Pulmonary edema

Hydrochlorothiazide

Short

Acute-to-hyperacute

N

Alveolar shad ± pleural eff.

Tempo, shock, relapse on rechallenge

2

Salicylate pulmonary edema

Pulmonary edema, DAD

Salicylate

Variable

Subacute

N

Alveolar shadowing ± pleural eff.

Salicylemia, metabolic acidosis, anion gap

1

TRALI

Pulmonary edema, DAD, DAH

Blood, blood componenta, plasma

Within 8 h

Acute

N

Bilateral infiltrates or whiteout

Tempo – Relevant antibody in donor

6

2. Acute ILD

Chemotherapy lung

Pulmonary edema, NSIP, DAD, reactive pneumocytes

Chemo agents

Days-Weeks

Acute/Subacute

N + reactive cella

Haze, GGO, consolidation, whiteout
 
50

Acute ILD

Dense NSIP w/wo pulmonary edema or DAD

Methotrexate, nitrofurantoin, mTOR inhibitors

Variable

cute

L/N

Bilateral infiltrates

Exclusion/BAL:Pathology in selected cases

81

Acute granulomtous ILD

Acute granulomatous ILD

BCG, fludarabine, IFN, MTX

Variable

Acute

L

Bilateral infiltrates

Pathology

24

Acute foreign body reaction

Foreign body granuloma

Talc, crospovidone, food

Subacute

Subacute


Bilateral infiltrates

BAL, pathology

9

Acute eosinophilic pneumonia

AEP

Minocycline

Weeks

Acute

E

Bilateral infiltrates

Eos blood/BAL

28

Acute OP/AFOP

OP/AFOP w/wo foam cells

Amiodarone, statins

Variable

Acute

M

Bilateral infiltrates

Pathology

7

Accelerated pulmonary fibrosis

Dense interstitial fibrosis

Bleomycin, nitrosoureas, anti-TNF, paraquat

Days to weeks

Subacute

N

Bilateral infiltrates

Pathology

17

Acute amiodarone lung

NSIP w/wo a DIP pattern

Amiodarone

Weeks-months

Acute

M

Bilateral infiltrates

BAL/Pathology

1

Acute postoperative APT

DAD + foam cells

Amiodarone

Acute

Acute

M

Bilateral infiltrates

BAL/Pathology

1

3. DAH

Bland DAH

DAH

All anticoagulants, antiplatelet

Variable

Acute

RBC

Bilateral infiltrates

BAL

102

ANA-related DAH

DAH

Hydralazine, PTU, anti TNF

Variable

Acute

RBC

Bilateral infiltrates

BAL + Ab

3

ANCA-related

DAH w/wo capillaritis

PTU, cocaine levamisole

Variable

Acute

RBC

Bilateral infiltrates

BAL + Ab

7

Secondary DAH

DAH and silicone or hyaluronate

Silicone, hyaluronate

Short

Subacute

RBC

Bilateral infiltrates

BAL, silicone, hyaluronate

2

4. Exacerbation of preexisting IPF

Subacute

NSIP/OP + fibrosis

Any drug causing ILD

Variable

Acute

L/E/N

Aggravated bilateral infiltrates

?BAL

Many

Precipitous

DAD + PF

Amiodarone, anti TNF, chemo

Variable

Acute

N

Bilateral infiltrates


24

5. Acute vasculopathy

Fat embolism syndrome

Fat embolism

Amphotericin, propofol

Short

Acute

AMa

Bilateral infiltrates

BAL

10

Silicone embolism sd

Silicone embolism

Subcutaneous silicone injections

Hrs-days

Subacute/Acute

AMa

Bilateral infiltrates

BAL/Pathology

1

6. RILI

Outside the radiation field

DAD

Irradiation (chemo aggravate)

Weeks

Subacute

L

Haze, GGO

BAL, imaging



Abbreviations: see text

aAM: macrophages containing foreign inclusions


A300193_1_En_34_Fig1_HTML.gif


Fig. 34.1
Cellular ILD: methotrexate lung (chest tube present on lef post lung biopsy)

The Adult Respiratory Distress Syndrome (ARDS) is defined by the triad of pulmonary infiltrates in the absence of cardiac failure and a ratio of partial pressure of arterial oxygen to FIO2 of less than 300 [61]. Although this classification is relevant to the stratification of disturbances in gas exchange, it does not reflect lung pathology well. Notwithstanding the common lack of tissue available for review, the lesional pattern-based classification used by pathologists is appropriate to disentangle the group of ARDS as defined clinically and on gas exchange and has practical implications as regards the recognition, understanding and assessment of drug causality and patients’ management. Pathologically, the majority of ARDS cases show the features of diffuse alveolar damage (DAD) [62, 63]. A smaller proportion corresponds to pulmonary edema, acute- NSIP or granulomatous ILD, -eosinophilic pneumonia (AEP), organizing (OP) or -fibrinous organizing pneumonia (AFOP), or diffuse alveolar hemorrhage (DAH) with or without circulating autoantibodies (ANCA, ANA) (Table 34.6). Although pathologically distinctive, the above patterns are rarely specific for the drug etiology (Table 34.3). Diagnosis is best approached noninvasively using literature holdings, imaging features, BAL, exclusion of another cause particularly an infection and response to drug therapy withdrawal and corticosteroid therapy. Imaging is a relevant adjunct for diagnosing drug-induced lung disease and separating it from other conditions to which DILD may resemble [15, 6474]. The chest radiograph is examined as regards vascularity, septal lines, the vascular pedicle, heart, fissures, haze, and pleural/pericardial effusion [75]. Features of interest on HRCT include haze, ground-glass, inter- or intra-lobular septal thickening, crazy-paving, pleural effusion, zonal consolidation, micronodules, lymphadenopathy, increased attenuation of lung and liver tissue, and parenchymal calcification. Data in Table 34.6 may help establish a likely diagnosis for ARDS and from this analysis, to deduce an appropriate management strategy.

Acute pulmonary edema (Fig. 34.2) can develop quickly following inadvertent or deliberate overdoses of drugs or chemicals [2] including carbamates, calcium channel blockers (nicardipine, nifedipine, verapamil), tricyclic antidepressants, abused drugs including heroin, cocaine, amphetamine and salicylate [66, 7682]. The naloxone test and urine drug screen may be indicated in patients suspect of being overdosed with opiates. Monitoring of blood levels should be ordered in salicylate intoxicated patients since dialysis may be indicated in severely poisoned acidotic patients with salicylate levels above 100 mg/dL [30]. Drug-induced pulmonary edema (DIPE) is defined by the subacute-to-rapid onset of pulmonary infiltrates coexisting with hypoxemia and a normal cardiac function, heart ultrasound and pulmonary capillary wedge pressure if measured, in a patient receiving one of the 171 compatible drugs taken at normal dosages in the absence of other explanation. DIPE may develop following oral, parenteral or topical administration of such drugs as epinephrine, treninoin (ATRA), arsenic trioxide (As203), salicylate, CSF, hydrochlorothiazide, nafazoline, opiates, propofol (a drug with potential for addiction) [83], i.v. ß2 agonists when used as tocolytic agents near term, the chemo agents gemcitabine, methotrexate, mitomycin C or taxanes, and radiocontrast agents. Pulmonary edema can also be a complication of drug-induced anaphylaxis. Hydrochlorothiazide- and salicylate-induced pulmonary edema is diagnosed suboptimally [30, 84, 85]. The edema may develop with intake of as little as one tablet of the causal drug and the diagnosis is sometimes raised by patient or family. Abrupt onset in minutes or a few hours following exposure and rapid clearing in a few hours or days upon drug stoppage are characteristic features of DIPE. In one case, pulmonary edema developed as a consequence of radiocontrast material (RCM) administration during HRCT examination, lobular pulmonary shadowing and septal lines denoting edema were noted 25 s following drug administration [20]. Such episodes are labeled ‘flash pulmonary edema’ to reflect the extreme shortness of onset [86]. Some DIPE cases may evolve to full-blown ARDS picture after stepwise increases in edema severity with each administration of the causal drug. Severe pulmonary edema classically but exclusively so in drug abusers may be heralded by a plume of protein-rich frothy sputum at the mouth (with a protein to plasma fluid ratio >0.7) [87]. Fever, hypotension, shock and hemoconcentration concomitant with the appearance of pulmonary infiltrates characterize hydrochlorothiazide-induced pulmonary edema [88]. Instances of pulmonary infiltrates waning in a few hours have been noted after exposure to crack cocaine, hydrochlorothiazide, nitrofurantoin and anti-thymocyte globulin [2] may also correspond to drug-induced pulmonary edema for lack of better fit, although pathology is rarely available.
Sep 20, 2016 | Posted by in CARDIOLOGY | Comments Off on Rare and Emergent Drug-Induced and Iatrogenic Respiratory Conditions: A Guide to Their Recognition and Management
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