Case 3 -
Pulmonary Foreign Body Embolism and Granulomatosis Associated with Injection of Pharmaceutical Tablets
Joseph F. Tomashefski, Jr.
MetroHealth Medical Center and
Case Western Reserve University
Cleveland, Ohio, U.S.A.
Click on each slide thumbnail image for an enlarged view
A 40-year old African-American woman with sickle cell disease and frequent sickle cell crises died 2
weeks after hospitalization for Enterococcus cloacae sepsis. Her hospital
course included respiratory failure requiring supplemental oxygen and mechanical ventilation.
Echocardiogram revealed an elevated pulmonary artery pressure of 69 mm Hg. The patient was taking
hydromorphone and methadone, as well as multiple other medications for pain control, and was on a
patient-controlled anesthesia pump.
Case 3 - Figure 4 - Mucicarmine stain (left panel), Movat stain (right panel)(40X magnification, both panels)
Case 3 - Figure 5 - Congo red stain, intermediate magnification
Case 3 - Figure 6 - Gomorri methenamine silver stain (left panel), Movat stain (right panel) 40X magnification, both panels)
Pulmonary Foreign Body Embolism and Granulomatosis Associated with Injection of Pharmaceutical Tablets
Foreign body embolism and granulomatosis is an important pulmonary vascular complication of
intravenous drug abuse
. Although a small amount of insoluble material such as talc or cotton
fibers may embolize to the lung following the intravenous injection of processed narcotics, the most
important cause of foreign body emboli is the intravenous injection of aqueous suspensions of
pharmaceutical tablets intended for oral consumption
. Patients with indwelling venous access
devices are particularly susceptible to this practice. Drugs frequently used in this manner include
methadone, methylphenidate, pentazocine and hydromorphone
. Antihistamine tablets, including
tripelennamine and diphenhydramine, may be injected concurrently to decrease nausea induced by the
Pharmaceutical tablets contain abundant inert, insoluble, filler substances which impart bulk and
physical properties to the tablet
. These filler materials act as lubricants, binders and
disintegrants which, respectively, facilitate the smooth production of tablets, promote tablet
cohesiveness, and allow for rapid dispersal of the tablets when ingested. The most important materials
likely to be encountered in the lung are talc, cornstarch, microcrystalline cellulose, and crospovidone
Table 1. Tablet Filler Substances*
|Filler ||Shape ||Size ||Polarization ||Histochemistry|
|8-12цm ||Maltese Cross ||PAS/D, GMS|
|Unstained (H&E) |
Movat (weakly blue)
|GMS, PAS, Congo Red|
|100цm ||Non-polarized ||H&E, Mucicarmine|
Movat (orange or green-blue)
|Magnesium stearate ||Irregular rounded ||5-10цm ||Positive ||Negative|
|Siliciumoxid (silica)||Elongate ||10-20цm ||Positive ||Negative|
* Reference 9
Tablet excipients may have distinctive histochemical staining properties and/or a characteristic
birefringence when viewed under polarized light, which facilitates their recognition in tissue sections
(Table 1). Talc particles appear as brightly birefringent crystals having a needle-like or "stacked
. Talc consistently appears light blue-green with Movat pentachrome stain.
Microcrystalline cellulose particles are large, brightly birefringent, rod-like ("matchstick-like"), and
often have a stacked appearance. Microcrystalline cellulose stains well with GMS (gray to black),
Congo-red (orange}, and Movat (yellow}, but stains variably with PAS
. Starch granules are
polyhedral and brightly birefringent with a central "Maltese-cross" pattern. Starch particles stain
brilliantly with PAS and are jet black with GMS (resembling large fungal yeast forms). While most inert
particles persist within the lung, starch may be metabolized and disappear over time, and has therefore
been considered to be a marker of recent drug injection . Crospovidone, a polymer of vinyl
pyrrolidone, is non-birefringent, deeply basophilic when stained with hematoxylin and eosin, and has a
convoluted, coral-like structure . Crospovidone is also well demonstrated by mucicarmine and
Inert particles induce thrombosis, intravascular inflammation, foreign body reaction, and granuloma
formation . Migration of foreign material and granulomas through the vascular wall occurs over time
. Angiocentric foreign body granulomasimpart a macroscopically
granular texture and appearance to the parenchyma
. Histologically, vascular remodeling includes
recanalized arteries, eccentric intimalfibrosis, and web
lesions admixed with foreign material . Plexiform-like and angiomatoid lesions may be seen
with severe pulmonary hypertension
. Infrequently, plexiform lesions occur in the absence of,
or with only minimal, embolized foreign material . In such instances, other causes of pulmonary
hypertension like primary pulmonary hypertension, hepatic cirrhosis, HIV infection, or collagen vascular
disease should be carefully excluded. Small particles which escape the lung's filtration and pass
through its capillary bed may be incidentally detected at autopsy in solid viscera or observed clinically
as pinpoint bright reflections on funduscopic examination
A unique form of panacinar emphysema afflicts intravenous drug users who chronically inject
talc-containing pharmaceutical tablets
. Histologically, numerous brightly birefringent
interstitial talc particles are associated with perivascular fibrosis and panacinar emphysema
Individuals with talc-induced emphysema progress from predominantly restrictive to severe obstructive
lung disease. The mechanism by which foreign-body microemboli induce emphysema may relate to repeated
episodes of intracapillary neutrophil sequestration and release of inflammatory mediators and proteases
Another uncommon parenchymal response to embolized foreign material is progressive massive fibrosis,
resembling that seen in mineral dust pneumoconiosis
The differential diagnosis of injectional foreign body granulomatosis includes incidental foreign body
emboli associated with indwelling lines or intravascular prosthetic devices, inhalation exposures,
crystallized hyperalimentation fluid, endogenous crystals and aspiration. Injectional talcosis is
histologically distinguished from inhalational talcosis by the intravascular and perivascular location of
talc particles as well as their size distribution. Compared to inhaled talc, pulmonary talc particles in
injectional talcosis tend to be larger ( > 5ųm vs < 5ųm)
. Rarely, inhaled mineral
additives such as silica may contribute to interstitial fibrosis in alkaloidal cocaine smokers
Intravascular birefringent calcium phosphate crystals have been reported in patients on
. These crystals can be distinguished from tablet additives by histochemical
stains or elemental analysis. Endogenous birefringent calcium particles in sarcoidal granulomas tend to
be more amorphous than talc or cellulose and can be removed from the histologic section by acid digestion
. When tablet preparations are aspirated, filler materials reside within distal airspaces and are
associated with acute and organizing pneumonia. Aspirated crospovidone may be confused with foci of
dystrophic calcification or with the potassium binding polystyrene resin, Kayexalate . Compared to
crospovidone, Kayexalate has a smooth surface and is sharply angulated .
When necessary, the elemental composition of mineral particles can be determined by electron
microscopy and energy dispersive x-ray analysis, in conjunction with characteristic ultrastructural
features . Raman laser and infrared spectroscopy have also been used to identify crospovidone and/or
microcrystalline cellulose in tissue sections
- Glassroth J, Adams GD, Schnoll S. The impact of substance abuse on the respiratory system. Chest 1987; 91:596-602.
- Radow SK, Nachamkin I, Morrow C, et al. Foreign body granulomatosis: Clinical and immunologic findings. Am Rev Respir Dis 1983; 127:575-80.
- Tomashefski JF Jr, and Hirsch CS. The pulmonary vascular lesions of intravenous drug abuse. Hum Pathol 1980; 11:133-45.
- Tomashefski JF Jr, Felo JA. The pulmonary pathology of illicit drug and substance abuse. Current Diagnostic Pathology 2004; 10:413-426.
- Pare JAP, Fraser RG, Hogg JC, Howlett JG, Murphy SB. Pulmonary 'Mainline' Granulomatosis: talcosis of intravenous methadone abuse. Medicine 1979; 58:229-39.
- 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.
- Waller BF, Brownlee WJ, Roberts WC. Self-induced pulmonary granulomatosis. A consequence of intravenous injections of drugs intended for oral use. Chest; 1980; 78:90-94.
- Rowe RC, Sheskey PJ, Weller PJ (ed). Handbook of pharmaceutical excipients 4th ed. Pharmaceutical Press, London, 2003.
- Kringsholm B, Christoffersen P. The nature and the occurrence of birefringent material in different organs in fatal drug addiction. Forensic Sci Intern 1987; 34:53-62
- 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.
- Lamb D, Roberts G. Starch and talc emboli in drug addicts' lungs. J Clin Path 1972;25: 876-881.
- Zeltner TB, Nussbaumer U, Rudin O, Zimmermann A. Unusual pulmonary vascular lesions after intravenous injections of microcrystalline cellulose. Virch Arch (Pathol Anat) 1982; 395:207-216.
- 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(4):286-292.
- Houck RJ, Bailey GL, Daroca PJ Jr, Brazda F, Johnson FB and Klein RC. Pentazocine abuse – report of a case with pulmonary arterial cellulose granulomas and pulmonary hypertension. Chest 1980; 77:2:227-230.
- Puro HE, Wolf PL, Skirgaudas J and Vazquez J. Experimental production of human "blue velvet" and "red devil" lesions. JAMA, 1966; 197(13):152-154.
- Liu YC, Tomashefski J Jr, McMahon JT, Petrelli, M. Mineral-associated hepatic injury: A report of seven cases with x-ray microanalysis. Hum Pathol 1991; 22:1120-1127.
- Pare JP, Cote G, Fraser RS. Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis 1989; 139:233-241.
- Schmidt RA, Glenny RW, Godwin JD, Hampson NB, Cantino ME, Reichenbach D. Panlobular emphysema in young intravenous Ritalin abusers. Am Rev Respir Dis 1991; 143:649-656.
- Farber HW, Fairman RP, Millan JE, Rounds S, Glauser FL. Pulmonary response to foreign body microemboli in dogs: Release of neutrophil chemoattractant activity by vascular endothelial cells. Am J Respir Cell Molec Biol 1989; 1:27 -35.
- Crouch E, Churg A. Progressive massive fibrosis of lung secondary to intravenous injection of talc. A pathologic and mineralogic analysis. Am J Clin Pathol 1983; 80:520-526.
- Sienkiewicz DJ, Nidecker AC. Conglomerate pulmonary disease: a form of talcosis in intravenous methadone abusers. AJR 1980; 135:697-702.
- Abraham JL, Brambilla C. Particle size for differentiation between inhalation and injection pulmonary talcosis. Environ Res 1980; 21:94-96.
- O'Donnell AE, Mappin FG, Sebo TJ, Tazelaar H. Interstitial pneumonitis associated with crack cocaine abuse. Chest 1991; 100:1155-7.
- Dicpinigaitis PV, Jones JG, Frymus MM, Folkert VW. "Crack" cocaine-induced syndrome mimicking sarcoidosis. Am J Med Sci 1999; 317:416-8.
- Pomerance HH, Rader RE. Crystal formation: a new complication of total parenteral nutrition. Pediatr 1973; 52:864-866.
- Knowles JB, Cussons G, Smith M, et al. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. J Parent Enteral Nutr 1989;13:209-213.
- Reid JD, Andersen MS. Calcium oxalate in sarcoid granulomas. Am J Clin Pathol 1988; 90:545-558.
- Fenton JJ, Johnson FB, Przygodzki RM, Kalasinsky VF, Al-Dayel F, Travis WD. Sodium polystyrene sulfonate (Kayexalate) aspiration. Histological appearance and infrared microspectrophotometric analysis of two cases. Arch Pathol Lab Med 1996; 120:967-9.
- Hammar S, Williams MG, Dodson RF. Pulmonary granulomatous vasculitis induced by insolule particulates: a case report. Ultrastructural Pathology 2003; 27:439-449.
- Abraham J, Tomashefski JF Jr, Andersen M. Diagnosis of Munchausen syndrome using microanalytical techniques. Lab Invest 1982; 46:082