Accepted Manuscript

Title: Acute and Subacute Chemical-Induced Lung Injuries:

HRCT findings
Author: Masanori Akira Narufumi Suganuma
PII:
DOI:
Reference:

S0720-048X(14)00224-1
http://dx.doi.org/doi:10.1016/j.ejrad.2014.04.024
EURR 6760

To appear in:

European Journal of Radiology

Received date:
Revised date:
Accepted date:

14-1-2014
8-4-2014
19-4-2014

Please cite this article as: Akira M, Suganuma N, Acute and Subacute ChemicalInduced Lung Injuries: HRCT findings, European Journal of Radiology (2014),
http://dx.doi.org/10.1016/j.ejrad.2014.04.024
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Masanori Akira, M.D.1)

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Narufumi Suganuma, M.D.2)

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Acute and Subacute Chemical-Induced Lung InjuriesHRCT findings

Department of Radiology 1), National Hospital Organization Kinki-Chuo Chest Medical

Center, 1180 Nagasone-cho, Kita-ku, Sakai City, Osaka 591-8555, Japan

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Department of Environmental Medicine 2), Kochi Medical School

Corresponding author: Masanori Akira

TEL: +81-072-252-3021

FAX: +81-072-251-1372

E-mail: Akira@kch.hosp.go.jp

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Abstract
Lung injury caused by chemicals includes bronchitis, bronchiolitis, chemical pneumonitis,

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pulmonary edema, acute respiratory distress syndrome, organizing pneumonia, hypersensitivity

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pneumonitis, acute eosinophilic pneumonia, and sarcoid-like granulomatous lung disease.

disease.

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chemical induces variable pathophysiology and the situation resembles to the drug induced lung
The HRCT features are variable and nonspecific, however HRCT may be useful in the

evaluation of the lung injuries and so we should know about HRCT features of lung parenchymal

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abnormalities caused by chemicals.

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Agrichemicals, such as paraquat,

may cause lung injury following ingestion or dermal absorption.

Most commonly, exposure is

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Chemical-induced lung injuries are induced by inhalation.

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Introduction

Household accidents could be underestimated.

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community, either by accident or act of terrorism.

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accidental and occurs in the workplace, although it may also occur in the home or out in the

Many respiratory diseases are caused by exposure to noxious chemicals.

Lung injury caused by

chemicals includes bronchitis, bronchiolitis, chemical pneumonitis, pulmonary edema, acute

respiratory distress syndrome, organizing pneumonia, hypersensitivity pneumonitis, acute

To the best of our

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eosinophilic pneumonia, and sarcoid-like granulomatous lung disease.

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knowledge, HRCT findings of chemical-induced lung injuries have not been well described in the
literature.

The HRCT features are variable and nonspecific. When an individual presents acutely

with an abnormal chest radiograph and acute respiratory distress syndrome (ARDS) or acute lung
injury, chemical-induced lung injury must be considered.

Mechanisms of toxicity
Chemicals that cause lung injury by inhalation appear in the forms of gases, vapors, particles,
and aerosols.

Inhalation injury can produce a wide spectrum of clinical effects, including acute

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lung injury and systemic toxicity (Table 1).

The type of injury caused is a function of the toxin or

The intensity of exposure to an

inhaled toxin is a major determinant of the severity of ensuing damage.

Acute exposure to a high

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duration of exposure, and the host factor status of the individual.

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mix of toxins that constitute the exposure and the physical properties of the toxin, the intensity and

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concentration of toxic fumes causes diffuse alveolar damage, which may result in ARDS [1].

inhalation injury.

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Water solubility plays a significant role in determining the location of the gas or vapor
A highly soluble gas, such as ammonia or sulfur dioxide, is absorbed in the upper

A less soluble gas, such as nitrogen dioxide, is not removed in the upper

sufficiently high doses.

respiratory tract. However, high-solubility gases are also capable of causing lower tract injury at

Gases of intermediate

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passages and reaches the more peripheral areas of the respiratory tree.

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solubility, such as chlorine, may exert irritant effects widely throughout the respiratory tract [2-4].
In addition to water solubility, the particle size of the inhaled substance determines the site and

nature of the injury. All particles with an aerodynamic diameter larger than 10 m are deposited on
the mucous membranes of the nose and pharynx. Particles between 3 and 10 m in diameter can be
deposited throughout the tracheobronchial tree, where they initiate reflex bronchial constriction and
coughing. Particles between 0.1 and 3 m in diameter are mostly deposited within the alveoli.
Particles smaller than 0.1 m are often exhaled [5].

Chemical-induced lung injury may also be

influenced by host factors. Older individuals and individuals with pre-existing lung diseases, such

Page 4 of 49

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as asthma and COPD, may be more susceptible [2].

Bronchitis, bronchiolitis and permeability pulmonary edema without diffuse alveolar damage

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(chemical pneumonitis)

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Toxic fumes or gasses that, because of their physiochemical characteristics (e.g., small particle

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size and low water solubility) or their high inhaled concentration, can reach the peripheral airways
and alveoli will cause injury of the bronchiolar epithelium, alveolar lining cells, vascular
Consequently, diffuse bronchiolar obstruction from edema

endothelium, and airway macrophages.

and inflammatory cell infiltration and alveolar and interstitial edema and hemorrhage may develop

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[2, 3].

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Exposure to a number of irritant substances at high levels may cause bronchiolitis and
pulmonary edema or chemical pneumonitis, depending on the solubility and physicochemical
properties of the substance. The site of injury may be limited around the bronchioles, however they
can be more extensive in the lungs.

The characteristic thin-section CT findings are bronchial wall

thickening, centrilobular nodular areas of ground-glass attenuation and confluent areas of

ground-glass attenuation with peribronchiolar distribution, or extensive ground-glass opacity and
consolidation [6, 7]. As described below, less soluble gases tend to form centrilobular lesions and
high soluble gases tend to form extensive ground glass opacity on CT.

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Ammonia

pungent odor.

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Ammonia is a colorless, highly soluble, extremely irritating alkaline gas with a characteristic
Owing to its high solubility, ammonia causes chemical burns to the eyes, skin,

After severe exposure, radiographs may reveal a

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oropharynx, and upper respiratory tract.

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pulmonary edema pattern (Figure 1). Although most of these patients recover completely, cases of

following inhalation exposure to ammonia gas [8].

Chlorine gas exposure

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bronchiectasis, persistent air-flow obstruction, and bronchiolitis obliterans have been reported

Chlorine is a heavy irritating gas with a characteristic odor. Chlorine is intermediate in

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solubility and affects the lower respiratory tract more often than does ammonia. Acute exposure of

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humans and animals to high concentrations of chlorine gas is known to produce bronchiolar and
alveolar-capillary damage, which is associated with necrotizing bronchiolitis, bronchitis, and
pulmonary edema.

Pulmonary function testing typically demonstrates evidence of air-flow

obstruction with air-trapping, although restrictive changes may also be present [9, 10]. Air-flow
obstruction probably reflects injury to the airway mucosa and bronchoconstriction [4].

Chest

roentgenograms may be normal or show evidence of pulmonary edema with bilateral interstitial
infiltrates. CT shows diffuse nodular opacities consistent with acute small airway injury and patchy
areas of ground-glass attenuation [11]. In our case air-trapping due to air-flow obstruction is

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evident in addition to those findings on CT (Fig. 2).

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Nitrogen dioxide
NO2 (NO2) is a reddish brown gas that is denser than air, relatively insoluble in water, and has

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a characteristic sweet odor. Inhalation of the gases and vapors can be extremely dangerous because

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they do not invoke a violent protective cough reflex such as occurs with chlorine and ammonia [12].

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Silo fillers disease is an acute lung injury caused by inhalation of NO2 in or near an agricultural silo.
Symptoms first appear several hours to days after the exposure episode. The injury comprises
Patients who recover may pass into a latent

diffuse alveolar damage and pulmonary edema [13].

period that lasts from 2 to 6 weeks, during which time they continue to improve and the abnormal

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clinical and radiographic signs disappear, only to relapse suddenly with a second acute episode
It is reported that

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similar to the first without having been re-exposed to the gas (Fig. 3) [10, 14].

the thin-section CT findings of three patients with inhalational lung injury due to NO2 showed
ground-glass attenuation and ill-defined centrilobular nodules distributed predominantly in the innerand middle-lung zones (Fig. 4).

Two of these three patients showed crazy-paving pattern [15].

Fluorocarbon

Fluorocarbons are widely used in industry, and manifestations of inhalation toxicity include
polymer fume fever, reactive airway dysfunction, and bronchospasm [16].

Toxic pneumonitis due

to inhalation of a fluorocarbon used as a waterproofing spray [17] and ARDS after exposure to a

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fluorocarbon resin used as ski wax [18] have also been reported (Fig. 5).

In a previous study,

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approximately 650C) that were contaminated with the powdered polymer [19].

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fluorocarbon-induced pulmonary edema was correlated to smoking cigarettes (temperature of

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Acute respiratory distress syndrome associated with diffuse alveolar damage

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Irritant gas inhalation is a major cause of ARDS. Some of the patients exposed to these
insults progress ARDS, which may develop gradually over a 24-72-hour period after exposure and

Chemical induced ARDS does not differ from ARDS secondary to other causes.

inflammation [1].

even after a deceptive period of initial improvement in the early symptoms of upper airway

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The most striking CT finding in early ARDS is the heterogeneous nature of the lung changes.

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These changes may comprise: 1) normal or near-normal lung regions, most frequently located in the
nondependent lung (ventral in the supine position); 2) ground-glass opacification in the middle lung;
and 3) consolidation in the most dependent lung (dorsal in the supine position) [20, 21].

Prone CT

shows that the dependent opacity due to ARDS decreases in degree (Fig. 6), whereas that due to
pneumonia remains unchanged.

Consolidation is not invariably confined to the dependent lung.

Non-dependent consolidation may be related to the pathophysiology of ARDS or may not be related
to that; infection is a frequent causative agent [20].
Desai et al. [22] described that the differences between ARDS due to pulmonary

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injury and that due to extrapulmonary injury do exist and that a typical CT pattern

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characterized by more extensive dependent intense parenchymal opacification but less

extensive nondependent consolidation and parenchymal cysts, is more frequently seen

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in patients with ARDS due to extrapulmonary injury. Reske et al. [23] found that the most

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striking early CT findings in smoke inhalation injury were infiltrations adjacent to the greater

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airways in the central and ventral regions of the lungs, in addition to substantial bilateral dorsal
atelectasis.

Paraquat

Paraquat is an herbicide that is used widely in agricultural industries around the world.
Paraquat

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Respiratory failure from ARDS is a prominent outcome of paraquat ingestion.

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accumulates rapidly in the lungs, and the consequent lung damage is linked to oxygen radicals that
destroy the cell membranes [24].

A characteristic time course for the CT findings of the lung

related to paraquat poisoning has been described [25, 26].

7 days is areas of ground-glass attenuation.

The predominant finding within the first

The initial areas of ground-glass attenuation are

subsequently transformed into areas of consolidation associated with bronchiectasis and irregular
lines.

The CT pattern 7 days or more after paraquat poisoning is consolidation with irregular lines

and traction bronchiectasis (Fig. 7).

Interestingly, honeycombing in the lung is evident 1 month

after paraquat ingestion (Fig. 8) [25]

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Organizing pneumonia
Organizing pneumonia is a pathologic finding characterized by histological evidence of

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intraluminal polyps of the connective tissue in the distal pulmonary air-spaces, contrasting with

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minor interstitial fibrosis, together with distinctive clinical and radiographic features.

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idiopathic form is called cryptogenic organizing pneumonia (COP) and the predominant finding is
organizing pneumonia with minimal or absent bronchiolitis obliterans [27].

In inhalation lung

has been reported to result from occupational exposure to aerosolized paint

Most of these cases occurred in the Ardystil plant in Alcoy, Spain,

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in the textile industry [28-30].

Organizing pneumonia

injury, different proportions of bronchiolitis obliterans and organizing pneumonia can be found.

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so the disease has been named Ardystil syndrome [31].

polyamide-amine, is considered to be a causative agent.

Acramin FWN, which is a

The prognosis was variable and a sizable

proportion of the patients developed chronic lung fibrosis. The lack of response to steroids or
cyclophosphamide in these cases contrasts with COP.
Very few cases of authentic OP have been related to airborne agents, i.e., single massive

exposure to NO2, chlorine, cocaine or cadmium.

Organizing pneumonia results from the late

organization of pulmonary edema, as described following exposure to Cl2, NO2 or cadmium fumes
[31].

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Eosinophilic pneumonia
An identifiable chemical or drug exposure has rarely been associated with acute eosinophilic

Cases of acute eosinophilic pneumonia induced by inhaled crack cocaine [32],

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pneumonia.

As nickel-associated respiratory disorders, induction of asthma is relatively well known,

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described.

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inhalation of heroin [33], cigarette smoking [34, 35], and smoke from fireworks [36] have been

in addition to pulmonary infiltrates with eosinophilia syndrome [37].

The predominant patterns of acute eosinophilic pneumonia seen at HRCT are bilateral patchy

areas of ground-glass opacity, frequently accompanied by interlobular septal thickening and

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sometimes by consolidation or poorly defined nodules (Fig. 9) [38]. The radiologic features of EP

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due to chemical exposure are sometimes different from those of idiopathic etiology.

We

experienced air-space consolidation which is concentrated in the posterior portion of the lower lung
(Fig. 10).

In part, the predominant distribution of posterior portion may be due to regional

differences in lymphatic function.

Lymph flows centripetally in the center of the lung and

centrifugally in the periphery of the lung; en route to the hilum and clearance of particles is poorest
posteriorly [39].

Granulomatous pneumonitis and hypersensitivity pneumonitis

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Cobalt, titanium, aluminum, copper, talc, and glass fibers have been reported to cause
Organic isocyanates, such as

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granulomatous pneumonitis with sarcoid-like granuloma [40-42].

toluene diisocyanate and diphenylmethane diisocyanate, have been associated with hypersensitivity
The characteristic HRCT features of hypersensitivity pneumonitis are

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pneumonitis [43].

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centrilobular nodules, ground-glass opacities, and mosaic perfusion pattern [44].

Subacute

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hypersensitivity pneumonitis is one of the most common diseases that manifest

centrilobular ground-glass nodules without associated tree-in-bud opacities.

In the

prominent symptomatic period, airspace consolidation and ground-glass opacities are prominent and

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micronodules are fine and ambiguous on CT (Fig. 11).

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Diffuse pulmonary hemorrhage

Trimellitic anhydride (TMA)-induced pulmonary hemosiderosis is the most firmly established

occupationally related diffuse pulmonary hemorrhage syndrome [45-48].

This syndrome is

correlated with high levels of antibodies against trimellityl-human serum albumin (TM-HAS) after
exposure to trimellitic anhydride (TMA) sprayed on a hot metal in poorly ventilated areas. A
causal link between exposure to isocyanates and immunologic hemorrhagic pneumonia has been
identified [47, 48].

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Conclusion

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Lung injury caused by chemicals covers a wide spectrum of diseases, including bronchiolitis,
pulmonary edema, ARDS, sarcoid-like granulomatous lung disease, hypersensitivity pneumonitis,

CT detects abnormalities following exposure, even when the chest

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BOOP, AEP, and so on.

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radiography does not, and CT helps to define the range of severity of the inhalation injury.

HRCT
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demonstrates a more characteristic pattern and distribution of parenchymal opacities.

chemical-induced lung injury, rapid deterioration may occur during the course of the illness, so

careful follow-up is crucial for these patients. We should know about HRCT features of lung

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Figure legends
Figure 1.

Images in a 63-year-old man with ammonia gas exposure (high water-solubility).

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(a) Chest radiograph obtained on the day of exposure shows consolidation with a central distribution

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and sparing of the lung cortex.

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(b) Transverse HRCT scan shows ground-glass opacity with a central distribution and sparing of the
lung cortex. Smooth thickening of interlobular septae (open arrows) and bronchial wall thickening

Images in a 31-year-old man with chlorine gas exposure (moderate water-solubility).

Figure 2.

(arrowheads) are seen.

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(a) Chest radiograph obtained on the day of exposure shows patchy areas of ground-glass opacity in

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both lungs.

(b) Transverse HRCT scan shows centrilobular nodular areas of ground-glass attenuation, confluent
ground-glass opacity in peribronchiolar distribution and bronchial wall thickening (a solid black
arrow).

Multi-panlobular low attenuation areas are also seen in the subpleural region, suggesting

air-trapping (arrows).

(c) Transverse HRCT scan obtained 3 weeks after exposure shows centrilobular nodules throughout
the lungs, which are less severe than those seen in the initial CT scan.
Figure 3.

Images in a 65-year-old man with inhalation of nitrogen dioxide (low water-solubility).

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(a) Chest radiograph taken 8 hours after exposure to nitrogen dioxide shows consolidation in the

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central zone of the right lung.

effusion.

Consolidation is also seen in the central zone of the left lung.

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(b) Transverse CT scan reveals consolidation in the central zone of the right lung and right pleural

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(c) Chest radiograph taken 3 weeks after exposure shows ill-defined nodules and patchy

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consolidation throughout the lung.

(d) Transverse HRCT scan shows centrilobular nodules (open arrows), interlobular septal

Images in a 49-year-old man with inhalation of nitrogen dioxide (low water-solubility).

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Figure 4.

and interlobar pleural effusion are evident.

thickening, patchy areas of ground-glass attenuation, and irregular consolidation. Pleural effusion

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(a) Chest radiograph shows patchy areas of consolidation in both middle lungs.
(b) Chest radiograph taken a few hours later shows increased consolidation in both middle lungs.
(c) Transverse HRCT scan shows centrilobular opacities diffusely distributed throughout the lung.
Figure 5.

Images in a 20-year-old man with inhalation of a fluorocarbon used as a waterproofing

spray.

(a) Chest radiograph shows bilateral air space opacification in peripheral predominant distribution.
(b) Transverse HRCT scan shows patchy areas of ground-glass attenuation. Pleural effusion is
also evident.

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Figure 6. Supine (A) and prone (B) HRCT images in a 64-year-old woman with ARDS.

The

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supine HRCT image shows extensive consolidation in the dorsal lung and consolidation along with
bronchovascular bundles. The prone HRCT image shows a prominent decrease in consolidation in

Post-mortem low-kilovoltage radiograph (a) and HRCT (b) of the inflated and fixed right

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Figure 7.

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the gravity-dependent portion.

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lung obtained from a patient who died within 1 week of ingesting paraquat. Consolidation,
ground-glass opacity, and nodular opacities are evident.

Post-mortem low-kilovoltage radiograph (a) and HRCT (b) of the inflated and fixed right

Figure 8.

Lung abscess presenting as a cavitary lesion is seen in the right middle lobe (arrowhead).

arrows).

Traction bronchiectasis is present (white

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cyst formation are evident.

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lung of a patient who died 1 month after ingesting paraquat. Posterior consolidation, reticulation, and

Figure 9.

Images in a 40-year-old man with acute eosinophilic pneumonia induced by cigarette

smoking.

(a) Chest radiograph shows bilateral pleural effusion and consolidation in the peripheral lungs.
(b) Transverse HRCT scan shows smooth thickening of interlobular septae in the anterior portion of
the lungs (arrows), areas of ground-glass attenuation and consolidation in both the peripheral
and central region.
Figure 10.

Bronchial wall thickening is seen (arrowhead).

Images in a man who inhaled an insecticide.

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(a) Transverse HRCT scan taken 2 days after exposure shows consolidation, which is distributed

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predominantly in the posterior portion of the left lower lung.

(b) Transverse HRCT scan taken 2 weeks after exposure shows consolidation, which is concentrated

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in the posterior portion of the left lower lung.

Figure 11.

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the alveolar spaces, as well as numerous eosinophils.

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(c) Histologic specimen obtained by transbronchial lung biopsy shows fibrinous exudates filled in

Images in a 64-year-old man who had inhaled an insecticide.

The subject suffered

from acute respiratory distress syndrome after inhalation of an insecticide.

(a) Chest radiograph obtained on the day of exposure shows consolidation distributed diffusely

Interlobar pleural effusion is evident in the right lung.

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both upper lungs.

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throughout both lungs, with peripheral predominance. Small nodular-like opacities are seen in

(b) Transverse HRCT scan shows mixture of ground-glass opacity and consolidation, and
interlobular septal thickening.

A few small nodular opacities are evident (arrows).

(c) Histologic specimen obtained by surgical lung biopsy shows noncaseating granuloma
surrounding the terminal bronchiole and its adjacent arteriole.

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Representative Substances of Each Type of Injury

Diffuse alveolar damage:

irritant gas, heated polymers, paraquat, zinc chloride

Non-cardiogenic pulmonary edema:

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Table 1.

irritant gas, heated polymers, metal fume

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Eosinophilic pneumonia:

acramin FWN, NO2, chlorine, cocaine, cadmium

firework smoke, cigarette smoke, cocaine, heroin, scotchguard, nickel,

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Organizing pneumonia:

irritant gas, zinc chloride, petroleum

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Necrotizing bronchitis and bronchiolitis:

acetylene

Granulomatous pneumonitis and extrinsic allergic alveolitis:

cobalt, titanium, aluminum, copper,

trimellitic anhydride, isocyanates

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Diffuse pulmonary hemorrhage:

talc, glass fibers, toluene diisocyanate, diphenylmethane diisocyanate

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All authors do not have any financial and personal relationships with other people or

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organizations that could inappropriately influence (bias) our work.

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Figure 11c

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