Foreign body granulomatosis

INTRODUCTION — Pulmonary foreign body granulomatosis is caused by intravenous injection of pulverized pharmaceutical tablets or, rarely, by nasal inhalation of drugs cut with insoluble binding agents. Several terms have been used to describe this condition, including self-induced pulmonary granulomatosis, pulmonary angiothrombotic granulomatosis, pulmonary mainline granulomatosis, and angiocentric (or angiothrombotic) systemic granulomatosis [1,2].

Tablets intended for oral use typically contain insoluble binding agents, such as talc (hydrated magnesium silicate), microcrystalline cellulose, crospovidone, potato starch, and cornstarch [3]. Medications abused in this manner (either alone or in combination) include methylphenidate (Ritalin), oral opiates (methadone, pentazocine, and meperidine), and antihistamines.

Pulmonary foreign body granulomatosis will be reviewed here. The recognition and management of drug abusers and pulmonary disease in injection drug users are discussed separately. (See "Substance use disorders: Clinical assessment" and "Overview of pulmonary disease in people who inject drugs".)

PATHOPHYSIOLOGY — The pathophysiology of lung disease caused by injection of pulverized tablets varies based on the agent injected and the route of exposure. The most information comes from studies of talc granulomatosis.

Talc — Talc (hydrous magnesium silicate) is used in tablets (eg, methadone, pentazocine, methylphenidate, amphetamine) as a filler and lubricant [3]. Pulmonary granulomatosis has also been associated with inhaled cosmetic talc [4].

Experimental injection of crushed pentazocine tablets or an equivalent amount of talc in dogs revealed similar changes in pulmonary artery pressures and lymph flow with the two agents [5]. Talc embolization causes an initial arteritis, which is associated with the rapid influx of neutrophils around the intravascular foreign body. This influx may in part be mediated by endothelial cell production of a neutrophil chemoattractant factor [6]. Increased levels of immunoglobulins and products of lymphocyte activation (eg, tumor necrosis factor, interleukins) are also present. Areas of thrombosis in the pulmonary arteries have been described in autopsy series of patients who died following acute injection [2,3,7].

The initial arteritis is followed by the development of foreign body granulomas, as talc particles migrate through the vessel wall to the surrounding perivascular and pulmonary interstitial tissue and are phagocytized by macrophages and giant cells [8]. Over time, development of discrete small nodules occurs, resulting in replacement of normal lung tissue by mononuclear cells and multinucleated giant cells. This granulomatous inflammation leads to nodules that may coalesce into progressive massive fibrosis, diffuse interstitial fibrosis, and arteritis, depending on the intensity of exposure [9,10]. These changes occur predominately in a perihilar and upper lobe distribution.

In addition, after repetitive intravenous exposure to talc, emphysema may develop, usually distributed in the lower lobes [11-13]. It is thought that the emphysematous changes are caused by occlusion of small blood vessels due to intra and perivascular deposition of talc particles, leading to ischemia with alveolar wall necrosis [11,12]. Macrophage and leukocyte production of elastin-degrading enzymes may also contribute [10]. As this pattern is reported after chronic injection of methylphenidate, it is also possible that the drug itself contributed to the pattern [13]. Areas of low attenuation are sometimes seen with inhalational exposure to talc, but are not basilar predominant.

Autopsy series of intravenous drug abusers have demonstrated talc material in a variety of other organs, including the spleen (76 percent), liver (55 percent), portal lymph nodes (39 percent), bone marrow (24 percent), heart, and kidney [14]. These extrapulmonary deposits generally produce little functional damage [14].

Nasal inhalation of talc-containing methamphetamine or cocaine can also cause pulmonary foreign body granulomatosis; however, this appears to be unusual [15,16]. When the talc is nasally inhaled, the foreign body granulomas and crystalline particles are typically found in the bronchial walls, rather than in and around the arterial walls.

Microcrystalline cellulose — Microcrystalline cellulose when injected intravenously as part of a pulverized tablet causes a similar pathologic process to talc with perivascular foreign body granulomatosis and angiothrombosis [14,17-20].

The larger size of cellulose particles makes them less likely to embolize to other organs, compared with talc, although embolization does occur [1,14]. At least one case of cerebral vascular embolization of microcrystalline cellulose with granuloma formation has been reported in association with a clinical syndrome similar to multiple sclerosis [1]. The mechanism for systemic embolization despite the large particle size was thought to be recruitment of arteriovenous shunts due to extensive distortion of the normal alveolar architecture.

Crospovidone — Crospovidone (polyvinylpyrrolidone, also known as povidone) is used as a binder in pharmaceutical tablets. This product is different from the povidone-iodine complex used as an antiseptic agent [1,18,21].

Crospovidone injection results in pulmonary angiothrombosis, destruction of the pulmonary arterial wall, and an intravascular and perivascular foreign body giant cell reaction [21].

Cotton-wool fibers — After tablets are pulverized, they are frequently heated and then filtered through materials such as cotton-wool before injection. The injected material often contains residual cotton-wool fragments that are embolized when the material is injected intravenously. Embolized cotton-wool fragments cause a granulomatous reaction in a rat model and in humans [22].

Cornstarch and soluble sugars — Cornstarch and soluble sugars including lactose, which are often "cut" into injectable illicit narcotics, generally cause only a transient foreign body reaction [9]. However, the amount of starch injected may be considerable and result in sudden death due to vascular occlusion [17]. Injected cornstarch and potato starch are rapidly removed from the lung and do not cause the type of chronic progressive changes seen with talc and cellulose. In rats injected with cornstarch, an early foreign body reaction in the lungs is followed by the disappearance of the starch particles within seven days [17].

Needle fragments — Embolization of needle fragments can complicate intravenous injection of drugs. In general, needle fragments migrate centrally and lodge in the lung parenchyma or pericardial fat and do not lead to significant pulmonary pathology [23].

CLINICAL FEATURES

Clinical presentation — Patients with pulmonary foreign body granulomatosis usually present with nonspecific complaints such as dyspnea, cough, or an increase in sputum production. However, some patients will be asymptomatic, despite abnormalities on chest radiography, pulmonary function testing, or exercise testing. Night sweats, weight loss, and hemoptysis are less commonly reported [24,25]. (See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'History'.)

Other clinical presentations include [9,10,26-28]:

●Acute pulmonary hypertension due to pulmonary arterial occlusion

●Chronic pulmonary hypertension and cor pulmonale

●Panlobular emphysema

●Spontaneous secondary pneumothorax [29]

●Progressive massive fibrosis (see "Silicosis", section on 'Imaging')

●Acute respiratory distress syndrome (ARDS)

ARDS may also be caused by opiates in the injected tablets or aspiration of gastric contents. However, the occurrence of ARDS in some patients undergoing talc pleurodesis suggests that injected talc can cause this syndrome. (See "Chemical pleurodesis for the prevention of recurrent pleural effusion".)

Additional symptoms, such as altered mental status, may be caused by symptoms related to the drug that was injected. (See "Acute opioid intoxication in adults", section on 'Clinical features of overdose'.)

Physical examination — The lung examination is generally within normal limits, although bibasilar end-inspiratory crackles may be present [16,28]. When patients present with more advanced disease, evidence of pulmonary hypertension may be apparent with augmentation of the second heart sound, a right ventricular heave, or peripheral edema. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations' and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

When pulmonary foreign body granulomatosis is caused by talc, irregularly-shaped, glistening crystals may be observed on funduscopic examination in the retinal microvasculature, either concentrated in the maculae or diffusely distributed [30-33].

Patients will often have other stigmata of injection drug abuse, such as needle "track" marks, cutaneous abscesses, and hyperpigmented scars at the site of previous injections [34]. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment", section on 'Physical examination' and "Substance use disorders: Clinical assessment", section on 'Physical examination and medical history'.)

DIFFERENTIAL DIAGNOSIS — Pulmonary disease due to the intravenous injection of pulverized pharmaceutical tablets must be distinguished from other forms of pulmonary vascular compromise, emphysema, interstitial lung disease (eg, lymphangitic carcinomatosis, pneumoconioses), and granulomatous lung disease (eg, sarcoidosis, berylliosis, miliary tuberculosis). (See "Evaluation of diffuse lung disease by conventional chest radiography", section on 'Basic patterns' and "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Causes of ILD'.)

Acute pulmonary vascular occlusion by injected particulates has a similar clinical presentation to acute pulmonary thromboembolism, septic embolism from tricuspid valve endocarditis, and tumor emboli [24]. The chronic pulmonary hypertension that develops in patients with repeated injection of pulverized tablets should be differentiated from other forms of pulmonary hypertension. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults", section on 'Clinical presentation, evaluation, and diagnosis' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Although many patients who self-inject tablets also abuse tobacco, the extensive emphysema seen in patients with foreign body granulomatosis is often out of proportion to that expected from cigarette use alone and should be differentiated from alpha-1-antitrypsin deficiency. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Overview of pulmonary disease in people who inject drugs".)

Infectious causes of diffuse nodular or reticular opacities among injection drug abusers include Pneumocystis jirovecii pneumonia, miliary tuberculosis, and fungal infections [35-37]. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Diagnostic evaluation of the incidental pulmonary nodule".)

The appearance of foreign body granulomatosis on chest radiograph and CT scan can mimic sarcoidosis, chronic beryllium exposure, healed varicella pneumonia, lymphangitic carcinomatosis, and other types of granulomatosis lung disease. Typically, the nodules seen in these diseases are slightly larger, up to 1 cm in diameter, than those of foreign body granulomatosis. However, as coalescence of individual micronodules of foreign body granulomatosis occurs, the radiograph may resemble the even larger nodules of silicosis or coal workers' pneumoconiosis. The presence of hilar and mediastinal adenopathy would favor a diagnosis of sarcoidosis or berylliosis. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Chronic beryllium disease (berylliosis)" and "Bronchocentric granulomatosis" and "Silicosis".)

DIAGNOSTIC EVALUATION — The evaluation of a patient with a history of intravenous injection of pulverized pharmaceutical tablets generally includes a chest radiograph and assessment of oxygenation and pulmonary function. In some patients, the clinical history and radiographic findings are highly suggestive of foreign body granulomatosis and further diagnostic evaluation is unnecessary, as long as the clinical course is stable. When patients present with an acute onset of dyspnea, fever, weight loss, or hemoptysis, evaluation for possible infection, malignancy, or other causes of interstitial lung disease is indicated. Depending on the severity of gas transfer abnormalities and the clinical suspicion of pulmonary hypertension, an echocardiogram and right heart catheterization may be indicated. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

As noted above, the diagnosis of talc granulomatosis can sometimes be suggested by funduscopic examination, when irregularly-shaped, glistening crystals indicative of talc-induced vascular disease are noted [30]. (See 'Physical examination' above.) Biopsy of organs other than the lungs, such as the liver, is usually not helpful as the likelihood of finding foreign body granulomas is less and extrapulmonary lesions are unlikely to be clinically significant.

Laboratory testing — Routine laboratory tests are usually normal or nonspecific. The value of assays for D-dimer in differentiating acute pulmonary compromise due to injected intravenous particles from an acute pulmonary embolism is not known.

An elevated serum angiotensin converting enzyme level has been reported in a large percentage of patients with a history of foreign body granulomatosis, but this test is neither sensitive nor specific and is not recommended [38-40]. Hypercalcemia rarely occurs, presumably via mechanisms similar to those observed in other granulomatous diseases [41]. (See "Hypercalcemia in granulomatous diseases" and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Proposed activity tests, including angiotensin converting enzyme (ACE) level'.)

Serologic testing for HIV infection should be considered given the increased incidence of HIV exposure in intravenous drug users [42,43]. (See "Screening and diagnostic testing for HIV infection".)

Unless the patient is entirely asymptomatic, blood cultures are usually indicated to exclude septic emboli or bacterial endocarditis, due to the nonsterile preparation and injection techniques used by these patients.

An alpha-1 antitrypsin level is obtained when emphysema is noted on chest imaging. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis'.)

Pulmonary function tests — Pulmonary function tests (PFTs), including pulse oximetry or arterial blood gas analysis, are performed to evaluate dyspnea, cough, or an abnormal chest radiograph. (See "Overview of pulmonary function testing in adults".)

PFT abnormalities may be limited to a reduction in the diffusing capacity for carbon monoxide (DLCO) [38]. More advanced disease is associated with a restrictive or obstructive pattern on spirometry and decreased or normal lung volumes [9].

One question is whether injection of pulverized tablets is more damaging to the lungs than intravenous heroin abuse. This question was addressed in a study that compared patients with a history of intravenous pentazocine and pyribenzamine tablet abuse with intravenous heroin abuse [44]. Those who injected tablets had a lower DLCO, a lower arterial oxygen tension, and greater dead space ventilation. In addition, a more rapid decline in pulmonary function was associated with injection of tablets, suggesting that the tablet excipients or the particular medications in the tablets were more injurious to the lungs than heroin. (See "Acute opioid intoxication in adults", section on 'Lung injury and ARDS'.)

Imaging — The chest radiograph in foreign body granulomatosis typically shows widespread, small 2 to 3 mm well-defined micronodules, often occurring in the midlung zones [7]. In advanced disease, the nodules may coalesce and massive fibrosis may be seen. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

High-resolution computed tomography (CT) is typically performed to evaluate chest radiographic abnormalities or hypoxemia not explained by findings on the chest radiograph. The high-resolution CT findings in foreign body granulomatosis include nodular opacities, a diffuse ground glass pattern, adenopathy (rare), and severe, lower lobe predominant, panacinar emphysema (image 1) [18,24,45,46].

Intravenous injection of talc-containing tablets is associated with widespread ground glass opacities, panacinar emphysema, fine nodular opacities, and confluent masses containing areas of high attenuation consistent with talc deposits, while microcrystalline cellulose granulomatosis has been described as having a "fibrous appearance" and centrilobular distribution [18,19,47,48].

Right upper lobe collapse was noted on chest CT in a patient with a long history of cosmetic talc inhalation; endobronchial foreign body granulomatosis was found on biopsy of the right upper lobe bronchus stricture [49].

CT pulmonary angiogram is performed to exclude thromboembolic disease when the clinical presentation suggests acute pulmonary embolism or an echocardiogram is suggestive of pulmonary hypertension [24].

Gallium-67 scanning is not helpful in the evaluation of foreign body granulomatosis. Although diffuse pulmonary uptake has been described, this finding does not correlate with clinical symptoms or radiographic abnormalities [38,39].

Echocardiography — Echocardiography with estimation of pulmonary artery pressures is typically performed when the patient reports dyspnea on exertion, oxygen desaturation is noted during exertion, or the DLCO is reduced. As patients who inject pulverized tablets have an increased risk of endocarditis, the valves are also inspected. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

Right heart catheterization — When the echocardiogram suggests elevated pulmonary artery pressures or right ventricular dysfunction, right heart catheterization is necessary to confirm the diagnosis of pulmonary hypertension (PH), assess its severity, and ensure that it is not due to a primary cardiac cause such as diastolic or systolic dysfunction. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

If pulmonary hypertension is confirmed by right heart catheterization, assessment of vasoreactivity may be considered during the right heart catheterization. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Bronchoalveolar lavage — When the diagnosis is unclear or the patient presents with acute onset of cough, fever, or weight loss, flexible bronchoscopy is performed with bronchoalveolar lavage (BAL). The main purpose is to exclude other processes, such as infection or malignancy. BAL fluid is sent for cell counts, cytologic examination, and microbiologic cultures. Depending on the patient's occupational history, fluid may also be sent for beryllium lymphocyte transformation testing. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Basic principles and technique of bronchoalveolar lavage".)

Reports of cell counts of BAL fluid from patients with foreign body granulomatosis vary from a marked lymphocytosis and a predominance of CD8+ lymphocytes to a low lymphocyte count [38,50]. The finding of a CD8+ lymphocytosis on BAL would be evidence against sarcoidosis, which typically has a CD4+ lymphocytosis.

Examination of BAL fluid under polarized light may reveal crystalline material [39].

Lung biopsy — When the chest CT scan shows diffuse interstitial disease (without significant emphysematous changes) and the diagnosis is unclear, transbronchial biopsy is typically performed at the time of flexible bronchoscopy (in the absence of contraindications). Specimens are sent for microbiologic cultures and histopathologic examination. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible bronchoscopy in adults: Indications and contraindications", section on 'Contraindications' and "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

Fine-needle aspiration of pulmonary masses to obtain samples for histopathologic examination has been described when nodules have coalesced into a mass large enough for fine needle aspiration, although the diagnostic yield is likely to be lower than with an open lung biopsy. (See "Silicosis", section on 'Chronic silicosis'.)

Video-assisted thoracoscopic or open lung biopsy is performed, when the diagnosis remains unclear after the above evaluation and the patient's lung function is deteriorating or severely impaired. Generally, an echocardiogram is performed prior to either of these procedures to exclude the possibility that pulmonary hypertension is the cause of dyspnea or hypoxemia. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Histopathology — Lung biopsy specimens typically reveal perivascular fibrosis and aggregates of multinucleated giant cells and granulomas [14]. Polarizable material may be seen within the granulomas and giant cells, or extracellularly in the vessel wall [51]. The vessel lumen may be occluded by the foreign material, intravascular thrombosis, and compression by the inflammatory reaction in the vessel wall [25].

The appearance under polarizing light and staining characteristics of particles in biopsy specimens may help identify the injected substances [14].

●Talc crystals are described as needle-shaped or plate-like and birefringent under polarizing light [3]. The crystals are typically smaller in size (mean of 3.7 microns) when the agent is nasally inhaled, compared with intravenously injected (mean of 14.2 microns) [15,16,52].

●Microcrystalline cellulose crystals are long, polarizable, and stain with periodic acid-Schiff, methenamine silver, and Congo red stains.

●Cornstarch particles are round and have a distinctive Maltese cross birefringence under polarizing light [3,17].

●Crospovidone causes deeply basophilic annular or coral-like deposits that resemble calcification [1,18,21].

●Cotton fibers stain positively with Congo red [25]. Cotton fibers are birefringent under a polarizing lens.

Crystals may be further analyzed by energy dispersive x-ray film analysis, although this analysis is generally reserved for research purposes.

Other findings include angiothrombosis and medial muscular hypertrophy of the small and medium sized arteries without evidence of thrombosis. Cellulose appears more likely to result in thrombosis than other the additives. Additional parenchymal abnormalities include panacinar emphysema with focal formation of bullae.

In long-standing disease from injection of talc-containing medications, the nodules may coalesce, producing large foci of consolidation associated with progressive fibrosis, resembling the progressive massive fibrosis seen in pneumoconioses like silicosis [24].

MANAGEMENT — There are no clearly established treatments for pulmonary foreign body granulomatosis. Our approach to management depends on the pattern of disease and the severity of symptoms and respiratory impairment.

Cessation of smoking and intravenous drug abuse is paramount.

Asymptomatic radiographic changes — Patients with asymptomatic radiographic changes undergo periodic reassessment for disease progression, but do not require specific therapy.

Acute onset — For patients with an acute onset of dyspnea, improvement in symptoms and gas transfer may occur over days to weeks with supportive care alone, presumably due to resolution of thrombi and clearance of injected material from the pulmonary circulation. After resolution of the acute episode, periodic reassessment is appropriate.

Chronic progressive disease — For patients with chronic progressive dyspnea and respiratory impairment, the ideal treatment is unknown.

Treatment with systemic glucocorticoids has been suggested to inhibit or clear the granulomatous inflammation. However, data supporting glucocorticoid therapy is sparse, and we do not generally use glucocorticoids in such patients [53]. A single case report describes a patient with intravenous talc-induced lung disease who had a rapid radiographic and symptomatic response following 60 mg of prednisone daily [54]. Systemic glucocorticoids are reported to be initially beneficial in a related disease, accelerated or acute silicosis, although the benefit appears to wane with time. If a trial of glucocorticoids is contemplated, a superimposed infectious process must be excluded prior to initiation of therapy. (See "Silicosis", section on 'Treatment'.)

The successful use of inhaled glucocorticoids in a symptomatic patient has been reported [55]. However, trials of this approach are lacking, and the rationale is unclear as the granulomatous inflammation seen on biopsy is predominantly perivascular.

Immunomodulating agents have been used with some success in animal models of foreign body granuloma formation and in other human granulomatous diseases such as sarcoidosis, but use of these agents for foreign body granulomatosis in humans has not been reported [56]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

It is not known whether bronchodilator therapy is of benefit in those patients those who have a radiographic pattern suggestive of emphysema, but a trial of bronchodilator therapy is reasonable, particularly when spirometry shows an obstructive pattern. (See 'Pulmonary function tests' above.)

Pulmonary hypertension — When pulmonary hypertension is the cause of dyspnea and impaired oxygenation, the initial approach is to optimize general supportive care. General supportive therapy for pulmonary artery hypertension includes supplemental oxygen for resting or exercise-related hypoxemia, cautious diuretic therapy for fluid retention, and exercise training. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

Although not well-studied, pulmonary hypertension associated with talc granulomatosis may be responsive to vasodilator therapy. In the only reported study, hydralazine was administered to six patients with foreign body granulomatosis [57]. The increases in pulmonary artery pressure and pulmonary vascular resistance due to exercise were ameliorated and exercise tolerance was improved. Studies with short-acting agents (eg, epoprostenol, adenosine, inhaled nitric oxide) are needed to determine vasoreactivity of this etiology of pulmonary hypertension. The efficacy of currently available pulmonary specific vasodilators for pulmonary hypertension due to foreign body granulomatosis also needs to be determined. If vasodilator testing is undertaken for such patients, it should only be performed in an experienced center. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'.)

PROGNOSIS — Foreign body granulomatosis is associated with a poor outcome due to the complications of angiothrombosis, severe emphysema, pulmonary hypertension, hypoxia, and progressive interstitial lung disease [9]. Individuals who have injected fewer pills may have a better outcome than those with a higher number of injected pills, although there is no clear correlation between the amount of material injected and the degree of pulmonary pathology. A few individuals whose pulmonary function improved or stabilized after cessation of intravenous or inhaled talc exposure have been reported; however, most experience a progressive decline in pulmonary function.

Another reason for the poor prognosis of foreign body granulomatosis is that patients often succumb to drug overdose, as evidenced by the many reports of the diagnosis being made postmortem [1,3,17,27].

LUNG TRANSPLANTATION — Lung transplantation has been performed in patients with advanced pulmonary hypertension secondary to foreign body granulomatosis [58-60]. In a case series of 19 patients with talc granulomatosis who underwent lung transplantation after a careful selection process that required six months of abstinence from intravenous drug abuse and exclusion of HIV infection, but allowed previously treated hepatitis C infection [60]. Survival at one and five years was comparable to that of the 393 other lung transplants performed at the same institution. However, recurrent disease in the allograft has been reported in a separate report of a patient who had resumed intravenous drug abuse despite a seven year hiatus prior to transplantation [58]. Current guidelines suggest that patients must be free of substance abuse for at least six months to be eligible for transplantation. (See "Lung transplantation: General guidelines for recipient selection".)

SUMMARY AND RECOMMENDATIONS

●Etiology – Pulmonary foreign body granulomatosis, also known as angiocentric systemic granulomatosis or pulmonary angiothrombotic granulomatosis, is caused by intravenous injection of pulverized oral medication tablets or, rarely, by nasal inhalation of drugs cut with insoluble binding agents. (See 'Introduction' above.)

●Pathophysiology – The pathophysiology of foreign body granulomatosis varies with the responsible agent. Talc and microcrystalline cellulose, the most widely used insoluble binding agents (or "fillers"), cause significant pulmonary damage, including granuloma formation. In contrast, cornstarch and soluble sugars (eg, lactose), which are often "cut" into injectable illicit narcotics, generally cause only a transient foreign body reaction. (See 'Pathophysiology' above.)

●Clinical features – A variety of presentations of pulmonary foreign body granulomatosis have been described, including asymptomatic radiographic changes, acute onset of dyspnea, progressive respiratory insufficiency with nodular opacities and emphysematous scarring of the lungs, and pulmonary hypertension. (See 'Clinical features' above.)

●Diagnostic evaluation – The clinical history and radiographic findings are often highly suggestive of foreign body granulomatosis and further diagnostic evaluation is unnecessary, as long as the clinical course is stable. (See 'Diagnostic evaluation' above.)

When patients present with an acute onset of symptoms (eg, dyspnea, fever, weight loss, or hemoptysis) or chronic progressive dyspnea, evaluation for possible infection, malignancy, thromboembolism, or other causes of interstitial lung disease is indicated. (See 'Diagnostic evaluation' above.)

When the diagnosis is unclear or the patient presents with acute onset of cough, fever, or weight loss, flexible bronchoscopy is performed with bronchoalveolar lavage (BAL). When technically possible, transbronchial lung biopsy should be obtained at the time of bronchoscopy. Lung biopsy via video-assisted thoracoscopic surgery (VATS) is performed when the diagnosis is unclear, pulmonary hypertension has been excluded, and other treatable diseases are still included in the differential diagnosis. (See 'Bronchoalveolar lavage' above and 'Lung biopsy' above.)

●Management – There are no clearly established treatments for pulmonary foreign body granulomatosis. Cessation of smoking and intravenous drug use is paramount in these patients. (See 'Management' above.)

•General measures – For patients with pulmonary hypertension due to foreign body granulomatosis, general supportive measures typically include supplemental oxygen for resting or exercise-related hypoxemia, cautious diuretic therapy for fluid retention, and exercise training. (See 'Pulmonary hypertension' above and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

•Patients with symptomatic pulmonary hypertension despite general measures – Limited data suggest that vasodilator therapy may be beneficial in selected patients with pulmonary hypertension due to foreign body granulomatosis, but further study is needed before specific recommendations can be made. Referral to a center with expertise in pulmonary hypertension is appropriate. (See 'Pulmonary hypertension' above.)