Review
Cardiopulmonary Imaging
October 23, 2014

Pulmonary Effects of IV Injection of Crushed Oral Tablets: “Excipient Lung Disease”

Abstract

OBJECTIVE. When crushed oral tablets are injected IV, their filler material (excipient) can induce a potentially fatal foreign-body reaction in pulmonary arterioles, presenting as dyspnea and pulmonary hypertension with centrilobular nodules on CT. We will describe the imaging and pathologic features of “excipient lung disease.”
CONCLUSION. The radiologist has a critical role in recognizing and reporting excipient lung disease because the referring clinician may be unaware of the patient's IV drug abuse.
In 2012, a national survey estimated that 22.2 million persons had substance abuse or dependence, and about 7.3 million used illicit drugs [1]. Prescription pain relievers were second only to marijuana in the rate of abuse, with 2.1 million users, up from 1.4 million in 2004 [1]. Heroin and cocaine are the most commonly injected illicit drugs [2]. Familiar complications of IV drug abuse include endocarditis, septic embolism, and blood-borne infections such as HIV and hepatitis C [2].
IV injection of crushed oral tablets, especially narcotics, surfaced in the 1950s [3] but remains underrecognized today [4]. Tablets contain excipients, which are insoluble inert particulate filler materials that bind and protect the active drug during production as well as shape and lubricate the tablet for easy swallowing [57]. Excipients include talc (hydrated magnesium silicate), microcrystalline cellulose, crospovidone, and starch [6, 811].
Excipient particles lodging in pulmonary arterioles and capillaries can trigger a potentially fatal angiogranulomatous reaction with pulmonary hypertension and shortness of breath [5, 6, 12]. This “excipient lung disease (ELD)” is less familiar to radiologists and clinicians than are the typical complications of IV drug abuse. The imaging features on CT—centrilobular nodules combined with findings of pulmonary hypertension (Figs. 1 and 2)—are often the first clue to the patient's IV drug abuse [12].
Fig. 1A —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
A, Chest radiograph shows diffuse micronodules in both lungs and pulmonary artery enlargement, reflecting pulmonary arterial hypertension.
Fig. 1B —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
B, Axial CT image shows centrilobular nodules.
Fig. 1C —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
C, Axial maximum-intensity-projection (MIP) image better shows tree-in-bud pattern of perivascular nodules.
Fig. 1D —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
D, Coronal MIP image shows uniform distribution of nodules from upper to lower lungs.
Fig. 1E —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
E, Cut gross specimen of lung from postmortem examination shows granular texture from numerous firm micronodules (arrow) with tree-in-bud distribution.
Fig. 1F —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
F, Low-power microscopic view with H and E stain shows perivascular nodules containing microcrystalline cellulose (arrows) branching out from vessel. There is also foreign body granuloma containing another excipient, crospovidone (arrowhead). Crospovidone is deeply basophilic and appears blue-gray in H and E sections.
Fig. 1G —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
G, Higher-power view shows that perivascular nodules are composed of multinucleated giant cells (open arrow) around rodlike crystalline foreign materials (arrowheads). Foreign body giant cell reaction is in vessel wall (solid arrows).
Fig. 1H —42-year-old man with history of IV drug abuse and excipient lung disease from microcrystalline cellulose.
H, Crystalline foreign material (arrows) is strongly birefringent under polarized light, unlike crospovidone.
Fig. 2A —22-year-old woman with acute myeloid leukemia and excipient lung disease from microcrystalline cellulose and starch. She was acutely hypoxic after injecting crushed oxycodone tablets into her central venous catheter. Echocardiogram showed pulmonary arterial hypertension and dilated right ventricle.
A, Chest radiograph 3 months before injection shows clear lungs, normal heart size, and normal pulmonary arteries.
Fig. 2B —22-year-old woman with acute myeloid leukemia and excipient lung disease from microcrystalline cellulose and starch. She was acutely hypoxic after injecting crushed oxycodone tablets into her central venous catheter. Echocardiogram showed pulmonary arterial hypertension and dilated right ventricle.
B, Chest radiograph on admission shortly after injection shows diffuse micronodules and enlarged heart and pulmonary arteries.
Fig. 2C —22-year-old woman with acute myeloid leukemia and excipient lung disease from microcrystalline cellulose and starch. She was acutely hypoxic after injecting crushed oxycodone tablets into her central venous catheter. Echocardiogram showed pulmonary arterial hypertension and dilated right ventricle.
C, Axial CT image obtained at admission shows enlarged right heart chambers with straightening of interventricular septum.
Fig. 2D —22-year-old woman with acute myeloid leukemia and excipient lung disease from microcrystalline cellulose and starch. She was acutely hypoxic after injecting crushed oxycodone tablets into her central venous catheter. Echocardiogram showed pulmonary arterial hypertension and dilated right ventricle.
D, Axial maximum-intensity-projection (MIP) image obtained at higher level than C shows diffuse micronodules with tree-in-bud pattern.
Fig. 2E —22-year-old woman with acute myeloid leukemia and excipient lung disease from microcrystalline cellulose and starch. She was acutely hypoxic after injecting crushed oxycodone tablets into her central venous catheter. Echocardiogram showed pulmonary arterial hypertension and dilated right ventricle.
E, Chest radiograph obtained 3 weeks later shows regression of micronodules and decreased heart size compared with B.
Fig. 2F —22-year-old woman with acute myeloid leukemia and excipient lung disease from microcrystalline cellulose and starch. She was acutely hypoxic after injecting crushed oxycodone tablets into her central venous catheter. Echocardiogram showed pulmonary arterial hypertension and dilated right ventricle.
F, Axial MIP obtained 1 year later shows substantial clearing of nodules, likely reflecting regression of acute excipient lung disease secondary to rapid clearance of cornstarch emboli; heart size and pulmonary artery dilation also decreased.
The angiogranulomatous reaction to the excipient has many names, including pulmonary mainline granulomatosis, pulmonary angiothrombotic granulomatosis, pulmonary granulomatous vasculitis, and pulmonary foreign body angiogranulomatosis as well as microcrystalline cellulose embolization, cellulose granulomatosis, talc granulomatosis, intravascular talcosis, and talcosis [4, 6, 8, 9, 13, 14]. Because the excipient is the critical element, we will use the term “ELD.” To understand the imaging findings of ELD, we will first describe its background, clinical manifestations, pathophysiology, and histopathology.

Background

The initial cases of ELD involved heroin addicts on methadone [14]. Addicts found they got a more intense effect by injecting methadone tablets (containing talc) [14]. Injection of tablets expanded to other medications, particularly analgesics, stimulants, and even antihistamines, which are injected with the analgesic to decrease nausea [6, 14]. Other injected talc-containing tablets include barbiturates, methylphenidate, pentazocine, tripelennamine, propoxyphene, phenmetrazine, and amphetamine [11, 15, 16].
“Ritalin lung” is the term for the basal-predominant panlobular emphysema caused by injecting talc-containing methylphenidate (Ritalin, Novartis Pharmaceuticals) tablets [7, 17] (Fig. 3). We will discuss Ritalin lung later in this article.
Fig. 3A —50-year-old woman with Ritalin (methylphenidate; Novartis Pharmaceuticals) lung.
A, Coronal CT image shows severe basal-predominant panlobular emphysema.
Fig. 3B —50-year-old woman with Ritalin (methylphenidate; Novartis Pharmaceuticals) lung.
B, Brightfield low-magnification image (B) shows severe panlobular emphysema with perivascular interstitial micronodules (arrows). Same field photographed under crossed polarizers (C) shows birefringent talc deposits (white) within micronodules (arrows). In B and C each image corresponds to field 4 mm wide; each micronodule is less than 0.2 mm in diameter. Talc granulomas seen on histopathology are not visible on CT, probably reflecting their small size.
Fig. 3C —50-year-old woman with Ritalin (methylphenidate; Novartis Pharmaceuticals) lung.
C, Brightfield low-magnification image (B) shows severe panlobular emphysema with perivascular interstitial micronodules (arrows). Same field photographed under crossed polarizers (C) shows birefringent talc deposits (white) within micronodules (arrows). In B and C each image corresponds to field 4 mm wide; each micronodule is less than 0.2 mm in diameter. Talc granulomas seen on histopathology are not visible on CT, probably reflecting their small size.
More recently, ELD has involved injection of codeine and hydrocodone tablets, in which the excipient is microcrystalline cellulose rather than talc [8, 12]. Crospovidone and starch may be combined with other excipients to promote breakup of the tablet in an aqueous environment [9, 11]. Opiate solutions intended for IV administration do not cause ELD because they do not contain insoluble particulate material [15].
The term “talcosis” refers to talc deposition from inhalation as well as from injection. Whereas injection leads to ELD, inhalation leads to pneumoconiosis. Workers may inhale talc in mining or in manufacturing cosmetics, textiles, rubber, and insecticides [14, 18]. Inhaled talc is usually accompanied by other dusts, such as silica or asbestos, and these other dusts may predominate in causing pneumoconiosis and the radiographic findings [14, 16]. Inhaled talc particles, which are typically less than 5 μm, deposit in distal bronchioles and alveolar ducts, whereas injected talc particles, which are usually larger than 10 μm, deposit in arterioles and perivascular tissues [14]. Finding excipient particles in the retina or spleen suggests IV injection because inhaled particles are less likely to get into the systemic circulation [4]. Excipient particles reaching systemic sites tend to be smaller than those that are trapped in pulmonary arterioles [4].

Clinical Features

Before injection, the tablets are crushed and the powder is suspended in water or another solvent and sometimes heated [5, 7, 8, 14]. Infection can result from the lack of sterile technique [8]. Patients with ELD may have no symptoms or only nonspecific ones, the most common being shortness of breath [14]. An abrupt onset of pulmonary arterial hypertension, cor pulmonale, or even sudden death raises the question of ELD [6] once acute pulmonary embolism has been excluded. A patient may have experienced recurrent episodes of respiratory decompensation or fever [12, 13], reflecting rounds of injection. Some patients may have needle tracks or a history of IV drug abuse [4, 5, 13, 19], but because most users deny drug abuse, the examining physician needs a high index of suspicion [20].
One suggestive setting is a history of chronic pain or illness, such as malignancy, multiple sclerosis, migraine headaches, or psychiatric illness, for which narcotics may have been prescribed [12, 13]. Health care workers are also susceptible to ELD because of medical knowledge and easy access to analgesic tablets [21]. Other risks are inadequate pain control after surgery and intolerance to oral medications [8]. A patient with an indwelling vascular catheter in place for chemotherapy, transfusion, or nutrition is particularly susceptible to ELD, given the easy route for injection [6, 8].
Clinical examination rarely detects ELD [14]. However, funduscopy may show excipient crystals in retinal arterioles [14, 19] (Fig. 4). Talc retinopathy may eventually develop from long-term injection [14], with severity reflecting the number of tablets injected [19].
Fig. 4A —70-year-old man with excipient lung disease from talc. Patient admitted to injecting crushed methylphenidate tablets for many years more than two decades ago.
A, Funduscopic image of retina shows talc crystals (arrowheads) adjacent to retinal arterioles. Talc retinopathy is from long-term injection of crushed oral tablets. (Courtesy of Takasugi JE, VA Puget Sound Health Care System, Seattle, WA)
Fig. 4B —70-year-old man with excipient lung disease from talc. Patient admitted to injecting crushed methylphenidate tablets for many years more than two decades ago.
B, Chest radiograph shows bilateral apical scarring with dense perihilar masses and right apical bulla.
Fig. 4C —70-year-old man with excipient lung disease from talc. Patient admitted to injecting crushed methylphenidate tablets for many years more than two decades ago.
C, Coronal CT image better shows bilateral apical scarring and right perihilar conglomerate mass, resembling progressive massive fibrosis from silicosis or coal worker's pneumoconiosis. Conglomerate masses are late finding in “excipient lung disease.” (Clinical details and other images from this case have been published in Chest by Bastawrous S and Hirschmann JV [33].)
Echocardiography may show pulmonary hypertension up to 70 mm Hg along with dilated right heart chambers [4]. Pulmonary function tests may be normal or may show decreased diffusing capacity, decreased flow, and increased residual volume [2224]. Patients who injected pentazocine and tripelennamine tablets had worse pulmonary symptoms and lower diffusing capacity than did heroin users, reflecting vascular obstruction [23]. Laboratory tests are usually unhelpful and diagnosis may ultimately require lung biopsy [5, 14, 25].
Lung fibrosis and pulmonary hypertension may progress over months and years, with increasing dyspnea, respiratory failure, and even death [24]. At 10-year follow-up of six patients who had stopped injecting talc-containing tablets, three patients had died of respiratory failure and the other three had severe respiratory symptoms [24]. Pulmonary function tests usually showed progressive obstruction [24]. Thus, ELD can lead to respiratory failure even years after injection has ended. However, because pulmonary impairment reflects the number of tablets injected, stopping exposure is the most important treatment [24]. Lung transplantation is effective unless the patient resumes injecting [14, 26].

Pathogenesis and Histopathologic Features

In general, the injected excipient particles trigger pulmonary foreign body angiogranulomatosis. Some other features vary depending on the particular excipient.

Talc

Lung sections show birefringent talc crystals associated with foreign body giant cells, usually concentrated in perivascular rather than intravascular tissue [4] (Fig. 3). Talc is carried out of the intravascular space by hydrostatic pressure and by macrophages that engulf the particles and migrate to form perivascular foreign body giant cells and granulomas [4]. Occlusion of pulmonary arterioles by talc granulomas causes pulmonary hypertension [4], which is worse when granulomas are concentrated intravascularly [15]. Granulomas in the interstitium may promote lung fibrosis [15].
Granulomas and fibrosis progressively replace normal lung tissue [4, 15]. Depending on the degree of talc exposure, fibrosis ranges from focal to massive and is concentrated around the hila and in the upper lungs [15, 24]. Talc particles are fine enough to pass through capillaries to pulmonary veins and lodge in the retina, spleen, liver, kidneys, lymph nodes, bone marrow, and spinal cord [10, 13, 19, 27].

Microcrystalline Cellulose

Microcrystalline cellulose, like talc, forms granulomas. Pathologic findings include occluded and recanalized pulmonary arterioles, intravascular and perivascular foreign body granulomas and foreign body giant cells, disrupted arteriolar elastic lamina and smooth muscle leading to aneurysms, and architectural distortion by granulomas and fibrosis [8, 12, 28, 29] (Fig. 1). Microcrystalline cellulose appears as refractile pale crystals in the granulomas [12].
Compared with talc, microcrystalline cellulose particles are larger and less likely to pass through the lungs to other organs [10]. However, extrapulmonary embolization has been found on autopsy [13], possibly via recruitable arteriovenous shunts, which can pass particles up to 50 μm [30].

Starch

Starch is quickly removed from the lung and provokes less reaction than other excipients [11]. Animal experiments show rapid clearance (90% in 24 hours) of cornstarch emboli, explaining the minimal foreign body response [11]. Rapid clearance also means that any starch detected on biopsy or autopsy indicates recent drug injection [11]. Injecting a large amount of starch can cause overwhelming vascular occlusion and even death [11].

Crospovidone

Crospovidone is a polymer of N-vinyl-2-pyrrolidone [9]. Like other excipients, it causes thrombosis, foreign body granulomatosis, and ensuing vascular damage [9] (Fig. 1).

Identification at Histopathology

The excipients, except crospovidone, appear as clear or weakly staining birefringent crystals on H and E stains [6, 31] (Figs. 1 and 3). They can be distinguished by size and structure [6]. Talc particles are almost colorless to pale yellow on H and E staining [10]. Under polarized light, they are strongly birefringent needlelike or platelike crystals ranging from 5 to 15 μm [6, 10] (Fig. 3). Microcrystalline cellulose crystals are translucent and colorless or pale blue-gray on H and E staining; they are birefringent rodlike crystals, ranging from 20 to 200 μm [6, 32] (Fig. 1). Starch granules are typically round, with a Maltese cross pattern under polarized light [10]. Crospovidone has a unique appearance with a deeply basophilic irregular coral-like structure up to 100 μm long on H and E staining; it is not birefringent [9] (Fig. 1).
Sometimes additional pathologic studies are needed to identify the excipient [31]. Infrared spectroscopy can help but is time-consuming and expensive [31]. Histochemistry is available, quick, and economical and is thus the mainstay for identification [31]. Table 1 summarizes the characteristics of these excipients, including size, polarization, and histochemistry [6, 9, 10, 31, 32].
TABLE 1: Characterization of Various Excipients on Basis of Size, Polarization, and Histochemical Staining Features [6, 9, 10, 31, 32]
CharacteristicExcipient
TalcMicrocrystalline CelluloseStarchCrospovidone
Size (μm)5–1520–2008–12≤ 100
PolarizationNeedlelike or platelike crystalsRodlikeMaltese cross patternNonbirefringent
Histochemistry    
 Congo redNo stainingOrange Red-brown
 Grocott methenamine silverNo stainingGray to blackGray to blackBrown to gray, weak or equivocal staining
 Modified Russell Movat pentachromeLight-blue, weak or equivocal stainingYellow, positive stainingNo stainingYellow-orange to blue-green, positive staining
 Mucicarmine   Red, positive staining
 Oil red O (72 h)Pink, weak or equivocal stainingNo stainingNo stainingNo staining
 Periodic acid Schiff (PAS) with diastaseNo stainingViolet, weak or equivocal staining Blue-gray, positive staining
 Sirius red for amyloidNo stainingRed, positive staining  

Imaging Features

On radiography, the typical findings of ELD are innumerable micronodules (up to 2 mm in diameter) in the lungs, corresponding to perivascular granulomas [5, 19, 25] (Figs. 1 and 2). The micronodules are better depicted by CT [5] (Figs. 1 and 5), especially by maximum-intensity-projection (MIP) images (Figs. 1 and 2). The nodules are distributed along pulmonary arterioles, which are centrilobular [12]. Thus, the micronodules largely spare the lobular septa, fissures, and subpleural interstitium [5, 12, 14] (Figs. 1, 2, and 5).
Fig. 5 —43-year-old man with excipient lung disease from injection of pentazocine (Talwin, Sterling-Winthrop) tablets. Axial CT image of right lung base shows innumerable centrilobular nodules. Patient had injected pentazocine tablets in early 1970s before naloxone was added to tablets to discourage recreational drug use. Transbronchial biopsy showed crystalloid talc foreign-body inclusions within fibrous nodules and foreign-body giant cells. Echocardiogram showed severe pulmonary hypertension.
Although centrilobular nodules usually reflect bronchiolar disease, in the setting of ELD, they reflect arteriolar disease [12]. Centrilobular periarteriolar micronodules can even create a tree-in-bud pattern, further mimicking bronchiolar disease [12] (Figs. 1 and 2). In most cases, the centrilobular micronodules are uniformly distributed throughout the lung zones [7, 12, 14] (Figs. 1 and 2), but they can concentrate in the middle [5] and lower zones [25], probably reflecting the greater blood flow to the bases.
Other findings include enlargement of pulmonary arteries from pulmonary hypertension [12] (Figs. 1 and 2) and signs of right ventricular strain, such as dilation of the right ventricle and flattening or bowing of the intraventricular septum (Fig. 2).
Thus, the combination of centrilobular nodules and acute pulmonary hypertension should raise concern for ELD [12]. Imaging does not reveal which excipient is causing the centrilobular nodules; thus biopsy may be required [5, 25].
In some cases, the centrilobular nodules and pulmonary hypertension appear to regress on early repeat imaging (Fig. 2), possibly because one contributing agent, such as starch, rapidly clears and the acute granulomatosis subsides to some degree [11]. However, the other excipients (such as talc or microcrystalline cellulose) remain and vascular destruction continues. Ground-glass opacities can be present, probably reflecting confluent micronodules [7]. Hilar and mediastinal lymphadenopathy [14, 16] are not major findings [14]. Calcification of nodes is uncommon [14].
Over time, talc micronodules may coalesce into perihilar conglomerate masses (Fig. 4), resembling progressive massive fibrosis from silicosis or coal worker's pneumoconiosis [7, 14, 33]. The conglomerate masses in ELD may contain high-attenuation material, likely talc or calcium [7, 14, 33].
As mentioned earlier, the other minerals, typically silica or asbestos, inhaled along with talc usually determine the radiologic features, including upper lung micronodules, conglomerate masses, fibrosis, calcified lymph nodes, and pleural thickening and calcification [14, 16]. The micronodules and conglomerate masses in pneumoconiosis may be indistinguishable from ELD caused by injected talc.

Differential Diagnosis

Many diseases cause micronodules on CT. Because the nodules in ELD are typically centrilobular, the first step in the differential diagnosis is to determine whether the distribution of micronodules is random, perilymphatic, or centrilobular. MIP images can help depict the distribution. A random distribution suggests metastasis, miliary tuberculosis, or fungal infection. A perilymphatic distribution suggests sarcoidosis or lymphangitic carcinomatosis. A centrilobular distribution suggests bronchiolar or arteriolar disease (including ELD).
Centrilobular micronodules are more commonly caused by bronchiolar than arteriolar disease. Bronchiolar causes include acute bronchiolitis, mycobacterial infection, hypersensitivity pneumonitis, and respiratory bronchiolitis. Bronchiolitis usually presents with signs of infection and cough and is not associated with acute pulmonary hypertension. Imaging findings include bronchial wall thickening, bronchiectasis, consolidation, lymphadenopathy, and air trapping [34]. Mycobacterial infection is subacute or chronic. The usual CT findings of Mycobacterium avium-intracellulare complex infection include centrilobular nodules with tree-in-bud pattern, bronchiectasis, and consolidation [35]. Hypersensitivity pneumonitis usually presents with subacute or chronic dyspnea without pulmonary hypertension [36]. In sub-acute hypersensitivity pneumonitis, the centrilobular nodules are less well defined than those of ELD [36, 37]. Other CT findings are ground-glass opacities and air trapping [36]. Respiratory bronchiolitis is usually caused by cigarette smoking [38, 39]. CT findings are upper lobe–predominant centrilobular ground-glass opacities, bronchial wall thickening, and centrilobular emphysema [38].
Arteriolar causes of centrilobular nodules besides ELD include granulomatosis with polyangiitis, plexogenic arteriopathy, and pulmonary capillary hemangiomatosis (PCH). Nodules in granulomatosis with polyangiitis are usually large and cavitary and only rarely small and centrilobular [40]. Thus, plexogenic arteriopathy and PCH are the most important differential considerations because both combine centrilobular nodules with pulmonary hypertension [4143].
Plexogenic arteriopathy occurs in chronic pulmonary hypertension [41, 44]. Capillary-like channels form in and around the walls of dilated centrilobular arterioles [44]. CT findings include centrilobular ground-glass nodules (Fig. 6) with signs of chronic pulmonary hypertension, including mosaic lung attenuation; sometimes there are small corkscrew-like peripheral arteries [41], which are not found in ELD.
Fig. 6 —25-year-old woman with plexogenic arteriopathy from long-standing primary pulmonary hypertension. Axial CT image shows diffuse ill-defined, centrilobular nodules, reflecting proliferation of vascular channels. Dilated pulmonary arteries reflect pulmonary hypertension. Note different appearance of nodules in plexogenic arteriopathy, which is more poorly defined, resembling ground-glass opacities compared with well-defined nodules in “excipient lung disease.”
PCH is a rare cause of rapidly progressive pulmonary hypertension [42, 43]. Its histologic feature is proliferation of capillary channels in alveolar septa that are visible on CT as centrilobular ground-glass nodules (Fig. 7), with signs of pulmonary hypertension [42, 43]. The ground-glass nodules are usually larger and less well defined than those in ELD.
Fig. 7 —17-year-old boy with pulmonary capillary hemangiomatosis. Axial CT image shows centrilobular nodules, reflecting dilated capillaries in alveolar walls. Patient had severe pulmonary hypertension (not shown).

Ritalin Lung

Ritalin lung is the basal-predominant panlobular emphysema caused by injection of methylphenidate (Ritalin) tablets, which contain talc [7, 14, 17] (Fig. 3). Basal emphysema is much less common when other talc-containing tablets, such as methadone, are injected [24, 45], and it is not associated with other excipients. Centrilobular micronodules are uncommon CT findings in Ritalin lung [7], probably because the talc granulomas found on histology (Fig. 3) are too small.
The cause of emphysema in Ritalin lung is not clear. One theory is that talc granulomatosis causes ischemic necrosis that destroys alveolar walls [24]. Infection has been considered because endotoxin releases elastases but infection in other kinds of IV drug abuse does not cause basal emphysema [24].
Elastases released by macrophages and neutrophils reacting to talc particles may be the explanation [45] given the similar emphysema caused by α-1 antitrypsin (AAT)
deficiency, in which elastases produced by neutrophils and macrophages are inadequately controlled, permitting digestion and destruction of alveolar walls [46].
Basal-predominant emphysema is far more common from injected methylpheni-date tablets than from other talc-containing tablets [7], suggesting that methylphenidate itself may be elastolytic and contribute to emphysema [7, 17, 22].
The differential diagnosis of Ritalin lung is AAT deficiency [7, 14, 17] (Fig. 8). Centrilobular nodules are not typical in either condition; thus, the CT findings are usually identical [17]. Distinguishing Ritalin lung from AAT deficiency is therefore based on history of tablet injection, serum AAT levels, and pathologic detection of talc granulomas in the lung [14, 17].
Fig. 8 —51-year-old man with α-1 antitrypsin deficiency. Coronal CT image shows severe basal-predominant panlobular emphysema, indistinguishable from Ritalin (methylphenidate; Novartis Pharmaceuticals) lung.

Conclusion

Clinical diagnosis and radiologic interpretation of ELD require a high index of suspicion and familiarity with the imaging findings. Clinical manifestations range from no symptoms to fulminant respiratory failure and pulmonary hypertension. The imaging findings include diffuse centrilobular micronodules and arterial dilatation from pulmonary hypertension. Pathologic findings include pulmonary foreign-body angiogranulomatosis with pulmonary arterial inflammation, fibrosis, distortion, and obstruction. It is vital for radiologists to be aware of the imaging findings of ELD to alert the clinician to this diagnostic possibility given its nonspecific signs and symptoms and the reluctance of most patients to admit to drug abuse.

Acknowledgment

We thank Julie E. Takasugi for providing funduscopic images of excipient lung disease.

Footnotes

Based on a presentation at the Radiological Society of North America 2012 annual meeting, Chicago, IL.
WEB
This is a web exclusive article.

References

1.
Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: summary of national findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013
2.
Wolff AJ, O'Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med 2004; 25:203–216
3.
Spain DM. Patterns of pulmonary fibrosis as related to pulmonary function. Ann Intern Med 1950; 33:1150–1163
4.
Griffith CC, Raval JS, Nichols L. Intravascular talcosis due to intravenous drug use is an under-recognized cause of pulmonary hypertension. Pulm Med 2012; 2012:617531
5.
Diaz-Ruiz MJ, Gallardo X, Castaner E, Mata JM, Catala J, Ferreres JC. Cellulose granulomatosis of the lungs. Eur Radiol 1999; 9:1203–1204
6.
Tomashefski JF, Felo JA. The pulmonary pathology of illicit drug and substance abuse. Curr Diagn Pathol 2004; 10:413–426
7.
Ward S, Heyneman LE, Reittner P, Kazerooni EA, Godwin JD, Muller NL. Talcosis associated with IV abuse of oral medications: CT findings. AJR 2000; 174:789–793
8.
Fields TA, McCall SJ, Reams BD, Roggli VL, Palmer SM, Howell DN. Pulmonary embolization of microcrystalline cellulose in a lung transplant recipient. J Heart Lung Transplant 2005; 24:624–627
9.
Ganesan S, Felo J, Saldana M, Kalasinsky VF, Lewin-Smith MR, Tomashefski JF. Jr Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol 2003; 16:286–292
10.
Kringsholm B, Christoffersen P. The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Forensic Sci Int 1987; 34:53–62
11.
Lamb D, Roberts G. Starch and talc emboli in drug addicts’ lungs. J Clin Pathol 1972; 25:876–881
12.
Bendeck SE, Leung AN, Berry GJ, Daniel D, Ruoss SJ. Cellulose granulomatosis presenting as centrilobular nodules: CT and histologic findings. AJR 2001; 177:1151–1153
13.
Chute DJ, Rawley J, Cox J, Bready RJ, Reiber K. Angiocentric systemic granulomatosis. Am J Forensic Med Pathol 2010; 31:146–150
14.
Marchiori E, Lourenco S, Gasparetto TD, Zanetti G, Mano CM, Nobre LF. Pulmonary talcosis: imaging findings. Lung 2010; 188:165–171
15.
Arnett EN, Battle WE, Russo JV, Roberts WC. Intravenous injection of talc-containing drugs intended for oral use: a cause of pulmonary granulomatosis and pulmonary hypertension. Am J Med 1976; 60:711–718
16.
Feigin DS. Talc: understanding its manifestations in the chest. AJR 1986; 146:295–301
17.
Stern EJ, Frank MS, Schmutz JF, Glenny RW, Schmidt RA, Godwin JD. Panlobular pulmonary emphysema caused by IV injection of methylphenidate (Ritalin): findings on chest radiographs and CT scans. AJR 1994; 162:555–560
18.
Akira M, Kozuka T, Yamamoto S, Sakatani M, Morinaga K. Inhalational talc pneumoconiosis: radiographic and CT findings in 14 patients. AJR 2007; 188:326–333
19.
Paré JA, Fraser RG, Hogg JC, Howlett JG, Murphy SB. Pulmonary ‘mainline’ granulomatosis: talcosis of intravenous methadone abuse. Medicine (Baltimore) 1979; 58:229–239
20.
Mouchantaf FG, Campagna AC, Lamb CR. Foreign body granulomatosis in a patient with a factitious disorder. J Bronchology Interv Pulmonol 2011; 18:179–180
21.
Volkow P, Tellez O, Allende S, Vazquez C. Drug abuse through a long-indwelling catheter cared for by an intravenous team. (letter) Am J Infect Control 1999; 27:459
22.
Sherman CB, Hudson LD, Pierson DJ. Severe precocious emphysema in intravenous methylpheni-date (Ritalin) abusers. Chest 1987; 92:1085–1087
23.
Itkonen J, Schnoll S, Daghestani A, Glassroth J. Accelerated development of pulmonary complications due to illicit intravenous use of pentazocine and tripelennamine. Am J Med 1984; 76:617–622
24.
Paré JP, Cote G, Fraser RS. Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis 1989; 139:233–241
25.
Giuliano V, Velez-Rivera C, Carlone D. Cellulose granulomatosis of the lungs: CT findings. AJR 1994; 163:220–221
26.
Shlomi D, Shitrit D, Bendayan D, Sahar G, Shechtman Y, Kramer MR. Successful lung transplantation for talcosis secondary to intravenous abuse of oral drug. Int J Chron Obstruct Pulmon Dis 2008; 3:327–330
27.
Mizutani T, Lewis RA, Gonatas NK. Medial medullary syndrome in a drug abuser. Arch Neurol 1980; 37:425–428
28.
Tomashefski JF Jr, Hirsch CS, Jolly PN. Microcrystalline cellulose pulmonary embolism and granulomatosis: a complication of illicit intravenous injections of pentazocine tablets. Arch Pathol Lab Med 1981; 105:89–93
29.
Zeltner TB, Nussbaumer U, Rudin O, Zimmermann A. Unusual pulmonary vascular lesions after intravenous injections of microcrystalline cellulose: a complication of pentazocine tablet abuse. Virchows Arch A Pathol Anat Histol 1982; 395:207–216
30.
Lovering AT, Stickland MK, Kelso AJ, Eldridge MW. Direct demonstration of 25- and 50-microm arteriovenous pathways in healthy human and baboon lungs. Am J Physiol Heart Circ Physiol 2007; 292:H1777–H1781
31.
Lewin-Smith MR, Kalasinsky VF, Mullick FG. Histochemical identification of microcrystalline cellulose, calcium oxalate, and talc in tissue sections. (letter) Arch Pathol Lab Med 2011; 135:963, author reply 963–964
32.
Sigdel S, Gemind JT, Tomashefski JF Jr. The Movat pentachrome stain as a means of identifying microcrystalline cellulose among other particulates found in lung tissue. Arch Pathol Lab Med 2011; 135:249–254
33.
Bastawrous S, Hirschmann JV. A man in his early 70s with progressive dyspnea and abnormal fundoscopic examination. Chest 2014; 145:178–181
34.
Rossi SE, Franquet T, Volpacchio M, Gimenez A, Aguilar G. Tree-in-bud pattern at thin-section CT of the lungs: radiologic-pathologic overview. RadioGraphics 2005; 25:789–801
35.
Song JW, Koh WJ, Lee KS, et al. High-resolution CT findings of Mycobacterium avium-intracellulare complex pulmonary disease: correlation with pulmonary function test results. AJR 2008; 191:[web]W160–W166
36.
Hirschmann JV, Pipavath SN, Godwin JD. Hypersensitivity pneumonitis: a historical, clinical, and radiologic review. RadioGraphics 2009; 29:1921–1938
37.
Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR 2007; 188:334–344
38.
Park JS, Brown KK, Tuder RM, Hale VA, King TE Jr, Lynch DA. Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic correlation. J Comput Assist Tomogr 2002; 26:13–20
39.
Woo OH, Yong HS, Oh YW, Lee SY, Kim HK, Kang EY. Respiratory bronchiolitis-associated interstitial lung disease in a nonsmoker: radiologic and pathologic findings. AJR 2007; 188:[web]W412–W414
40.
Ananthakrishnan L, Sharma N, Kanne JP. Wegener's granulomatosis in the chest: high-resolution CT findings. AJR 2009; 192:676–682
41.
Grosse C, Grosse A. CT findings in diseases associated with pulmonary hypertension: a current review. RadioGraphics 2010; 30:1753–1777
42.
Frazier AA, Franks TJ, Mohammed TL, Ozbudak IH, Galvin JR. From the Archives of the AFIP: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. RadioGraphics 2007; 27:867–882
43.
Lawler LP, Askin FB. Pulmonary capillary hemangiomatosis: multidetector row CT findings and clinico-pathologic correlation. J Thorac Imaging 2005; 20:61–63
44.
Wagenvoort CA. Plexogenic arteriopathy. Thorax 1994; 49(suppl):S39–S45
45.
Weisbrod GL, Rahman M, Chamberlain D, Herman SJ. Precocious emphysema in intravenous drug abusers. J Thorac Imaging 1993; 8:233–240
46.
Meyer CA, White CS, Sherman KE. Diseases of the hepatopulmonary axis. RadioGraphics 2000; 20:687–698

Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: W506 - W515
PubMed: 25341165

History

Submitted: January 30, 2014
Accepted: March 30, 2014

Keywords

  1. centrilobular nodules
  2. drug abuse
  3. excipient
  4. microcrystalline cellulose
  5. oral tablet
  6. pulmonary arterial hypertension
  7. talc

Authors

Affiliations

Vicky T. Nguyen
Department of Radiology, University of Washington, 1959 NE Pacific St, Box 357115, Seattle, WA 98195.
Elaine S. Chan
Department of Pathology, University of Washington, Seattle, WA.
Present address: Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Shinn-Huey S. Chou
Department of Radiology, University of Washington, 1959 NE Pacific St, Box 357115, Seattle, WA 98195.
J. David Godwin
Department of Radiology, University of Washington, 1959 NE Pacific St, Box 357115, Seattle, WA 98195.
Corinne L. Fligner
Department of Pathology, University of Washington, Seattle, WA.
Rodney A. Schmidt
Department of Pathology, University of Washington, Seattle, WA.
Sudhakar N. J. Pipavath
Department of Radiology, University of Washington, 1959 NE Pacific St, Box 357115, Seattle, WA 98195.

Notes

Address correspondence to V. T. Nguyen ([email protected]).

Metrics & Citations

Metrics

Citations

Export Citations

To download the citation to this article, select your reference manager software.

Articles citing this article

View Options

View options

PDF

View PDF

PDF Download

Download PDF

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media