Joseph F. Tomashefski

The pulmonary vascular lesions of intravenous drug abuse

Abstract We examined microscopic sections of lungs from 70 autopsies on persons who abused drugs by intravenous injection in order to evaluate systematically the spectrum of pulmonary vascular lesions resulting from this practice. Angiothrombosis, the most frequent pulmonary vascular lesion, occurred in 13 instances. Morphologic subgroups of this category include weblike and eccentric intimai fibrous lesions, “plexiform-like” lesions, and aneurysmally dilated, tortuous small vessels. Thrombotic changes typically are induced by intravenous injections of solutions derived from tablets or capsules that ethically are intended for oral consumption, because oral pharmaceutical preparations usually contain insoluble microcry-stals such as talc, starch, or cellulose. Ordinary illicit heroin does not contain enough insoluble crystalline debris to induce extensive pulmonary angiothrombosis. We found only two specimens with vascular changes indicative of nonthrombotic pulmonary hypertension; one of these persons had concomitant cirrhosis of the liver, and the other had aortic and mitral valvular bacterial endocarditis. Morphometric studies of the muscular arteries in all other lung samples containing scant embolic foreign material did not show a significant difference between drug abusers and normal control subjects, a finding that fails to support the hypothesis that vasoconstriction or other nonthrombotic reactions to intravenous drug abuse cause pulmonary hypertension and cor pulmonale.

Granulomatous disease associated with pulmonary deposition of titanium.

A patient presented with granulomatous lung disease associated with the pulmonary deposition of various metallic particles. To evaluate the relation between the metallic dust and the granulomatous process, lymphocyte transformation tests to aluminium sulphate, titanium chloride, beryllium sulphate, and nickel sulphate were performed. A lymphocyte proliferative response to titanium chloride was observed on two separate occasions; no responses to the other metals were shown. These results are consistent with hypersensitivity to titanium, and suggest, in this individual, a possible aetiological role between the inhalation of titanium and a granulomatous disease process.

Longterm histopathologic follow-up of bronchial arteries after therapeutic embolization with polyvinyl alcohol (Ivalon) in patients with cystic fibrosis.

We used light microscopy to examine, at autopsy, bronchial arteries in three patients with cystic fibrosis who died, respectively, 10, 16, and 28 months after bronchial artery embolization with barium sulfate-impregnated polyvinyl alcohol (PVA) to control hemoptysis. PVA was not identified beyond the midsegmental bronchus in any patient. Persistent focal fibrovascular occlusion was noted in two patients, and recanalized and/or partially obstructed vessels were associated with PVA in all. The histologic reaction to PVA included fibrosis, mild chronic inflammation, localized foreign body reaction, and, in two patients, focal calcification of PVA spicules. Within the inflammatory milieu were numerous macrophages containing BaSO4. Extensive vascular mural destruction and fibrosis associated with PVA were also observed. Both PVA and BaSO4 were also frequently present in the perivascular connective tissue. These findings indicate that, although longterm occlusion persists after therapeutic arterial embolization with PVA, focal recanalization also occurs. The extent of vascular mural injury following PVA embolization in humans has been previously underestimated by animal experiments. Finally, perivascular deposition of PVA represents a common reaction to diverse foreign body emboli in both systemic and pulmonary arteries.

Cardiopulmonary pathology in patients with sleep apnea/obesity hypoventilation syndrome

We reviewed clinical data, autopsy reports, and microscopic slides on 10 patients with sleep apnea/obesity hypoventilation syndrome (SA/OHS) to define the cardiopulmonary pathological features and establish clinicopathologic correlations. Ten obese (>136 kg) patients without SA/OHS were studied as controls. Patients with SA/OHS exhibited biventricular cardiac failure and pulmonary hypertension with a higher prevalence of moderate/severe pulmonary hemosiderosis (8 v 0 patients), alveolar hemorrhage (7 v 4 patients), capillary proliferation (4 v 0 patients), iron encrustation of elastica (1 v 0 patients) and medial hypertrophy of muscular pulmonary arteries (11.9 +/- 2.4 v 9.7 +/- 1.6%) (P < .05). In two patients capillary proliferation resembled capillary hemangiomatosis. Mean right ventricular thickness was higher in the SA/OHS group (0.71 +/- 0.17 v 0.42 +/- 0.1 cm) (P < .01). Four patients with SA/OHS and three controls had moderate/severe myocardial fibrosis. Biventricular cardiac failure caused death in seven patients with SA/OHS. Hypoxia is probably the most important cause of pulmonary hypertension, arterial muscularization, and right ventricular hypertrophy in SA/ OHS. Left ventricular failure in some SA/OHS patients may be the result of hypertensive cardiac disease. In others, the etiology of left ventricular failure was not determined morphologically, suggesting functional abnormalities related to obesity and/or apneic episodes.

Embolized Crospovidone (poly[ N -vinyl-2-pyrrolidone]) in the Lungs of Intravenous Drug Users

Crospovidone is an insoluble polymer of N-vinyl-2-pyrrolidone that is used as a disintegrant in pharmaceutical tablets. It can potentially embolize to the lung when aqueous tablet suspensions are injected intravenously. In this report, we identified embolized crospovidone in autopsy-derived lung tissue from three adult IV drug users, 1 man and 2 women, whose ages respectively were 27, 38, and 40 years. Suspected crospovidone was compared with pharmaceutical-grade crospovidone by means of histochemical stains, transmission electron microscopy, and infrared spectroscopy. Similar particles were also observed by light microscopy in a 4-mg tablet of hydromorphone, a preparation prescribed to two of the patients. Two patients had sickle cell disease and were taking methadone and/or hydromorphone for pain management; the third was receiving parenteral hyperalimentation after small bowel resection. Crospovidone appeared as deeply basophilic, coral-like particles within pulmonary arteries and in extravascular foreign-body granulomas. Intrapulmonary crospovidone stained similarly to the pure substance, including intense staining with mucicarmine, Congo red, and Masson trichrome. With Movat pentachrome stain, both intravascular and purified crospovidone appeared orange-yellow, whereas most interstitial particles associated with giant cells stained blue-green. Alcian blue failed to stain intravascular or purified crospovidone but strongly decorated some phagocytized particles. Ultrastructurally, both purified powder and tissue deposits of crospovidone appeared as irregular, electron dense, laminated, and finely granular material. Intrapulmonary crospovidone was associated with inflammatory cells and exhibited degenerative changes. By infrared spectroscopy, crospovidone in tissue had the same spectral characteristics as pharmaceutical grade crospovidone and the library reference, polyvinylpyrrolidone (PVP). We conclude that crospovidone contributes to pulmonary vascular injury in some persons who illicitly inject pharmaceutical tablets. It is readily identifiable histologically and distinguishable from other tablet constituents, such as cornstarch, talc, and microcrystalline cellulose. The variable staining with Alcian blue and Movat suggests that crospovidone is altered in vivo by the inflammatory response.

Severe Intrahepatic Cholestasis Caused by Amiodarone Toxicity After Withdrawal of the Drug A Case Report and Review of the Literature

Cholestasis has been reported as a rare presentation among patients with severe liver injury secondary to amiodarone hepatic toxicity. We report an unusual case of amiodarone-induced cholestatic hepatotoxicity occurring after amiodarone had been discontinued and the initial abnormal liver function findings had improved. The patient, without jaundice at the initial presentation, developed severe jaundice about 4 months after withdrawal of amiodarone. Light and transmission electron microscopic examination of a specimen secured by computed tomographically guided liver biopsy was consistent with amiodarone hepatic toxicity as the cause of intrahepatic cholestasis. An abdominal ultrasound, endoscopic retrograde cholangiography, and dimethyl iminodiacetic acid and computed tomographic scans of the abdomen all failed to demonstrate any other causes for jaundice other than amiodarone toxicity. Thus, amiodarone hepatic toxicity may occur after drug withdrawal even if results of liver function tests improve. Histopathologic examination of a liver biopsy specimen is of value for diagnosis and prognosis. The liver biopsy findings, clinical course, and liver function test results are discussed, and the English-language literature on amiodarone cholestatic hepatotoxicity is reviewed.

Pulmonary air cysts in cystic fibrosis: Relation of pathologic features to radiologic findings and history of pneumothorax**

One lung obtained from each of 21 consecutive autopsies in adolescents and young adults with cystic fibrosis was studied prospectively by macroscopic morphometry and light microscopy to determine the prevalence, morphology, and radiographic appearance of subpleural air cysts, which potentially contribute to spontaneous pneumothorax. In 15 lungs, 41 cysts of three anatomic types were identified: bronchiectatic cysts (23), interstitial cysts (13), and emphysematous bullae (5). All cysts were significantly more numerous in the upper lobe. Bronchiectatic cysts had the largest mean diameter, occupied from less than 1 per cent to 47.7 per cent of upper lobe volume in nine patients, and produced large multiloculated hyperlucencies on chest radiographs in five cases. All six lungs with prior pneumothorax contained at least one cyst, but no significant difference was found in the type or proportion of lung volume occupied by cysts between lungs with and without pneumothorax. Patients with large cysts had significantly lower chest radiograph scores, but there was no correlation between the proportion of lung volume occupied by cysts and patient age or duration of either symptomatic lung disease or colonization by bacteria. On chest radiographs only bronchiectatic cysts with conglomerate diameters of greater than 3 cm were visible. Smaller lesions could not be separated from ring shadows produced by bronchiectasis.

Destruction and loss of bronchial cartilage in cystic fibrosis

We studied by means of serial sections of intact isolated bronchi, the distribution and morphology of bronchial cartilage in lobar and segmental airways of 6 patients with cystic fibrosis (CF). Findings were compared to those of 4 young adults without CF who served as controls. Compared to the controls, cartilage in CF airways extended for a shorter absolute distance along the bronchial tree and disappeared at a more proximal branching level. Loss of cartilage appeared to correlate with the severity of bronchiectasis. In proximal airways chronic inflammation, destruction and fibrous replacement of cartilage preceded its disappearance. Immunohistochemical staining indicated that cells of monocyte/macrophage lineage (CD68, MAC387 positive) were most closely associated with chondrolysis. Dystrophic calcification and ossification were more commonly seen in CF bronchi and dystrophic calcification was present even in the lobar branches. Destruction of bronchial cartilage is the result of sustained bronchial infection and chronic inflammation and is an additional contributory factor to bronchiectasis and airway instability in patients with CF.

The pathology of fungal infection and colonization in patients with cystic fibrosis

We used methenamine silver stains to retrospectively evaluate the prevalence of fungi and their associated inflammatory reactions in 63 patients with cystic fibrosis (CF) autopsied between 1982 and 1987. Fungi were detected in 13 patients (21%) who fell into three groups: respiratory tract colonization (five patients); localized infection (five patients); and disseminated infection (three patients). Hyphae consistent with Aspergillus sp were present in five patients; yeast-like cells and/or pseudohyphae consistent with Candida sp occurred in eight patients; and Histoplasma capsulatum produced fibrocaseous lymph node and splenic granulomas in one patient. Acute inflammation typified most fungal lesions, while bronchocentric granulomatosis affected one patient. Compared with patients with no fungi, those with fungi were more frequently treated with indwelling central venous catheters (P less than .05). Autopsy reports on 156 CF patients from 1964 to 1982 disclosed only one with disseminated mycosis (P less than .05). We conclude that stainable fungi can be found in CF patients at autopsy more frequently than previously realized. Fungi usually represent respiratory tract colonization or minimal localized infection, but the prevalence of fatal disseminated infection (4.8%) has also increased. Fungal infection in CF appears to be most closely associated with aggressive therapeutic intervention.

Infant animal model of pulmonary mycotoxicosis induced by Stachybotrys chartarum

In recent years cases of often fatal pulmonary hemorrhage in infants have been associated with water damaged homes and the toxigenic fungusStachybotrys chartarum. The fungal spores contain mycotoxins which could be injurious to the rapidly developing lung. In order to understand the developmental pathophysiology of this disease we developed an infant rat model of stachybotrytoxicosis describing the effects of fungal spores on survival, growth, histopathology of the lung and respiration. Conidia ofS. chartarum were instilled intratracheally (1.0–8.0 × 105/gm wt.) in 4-dold Sprague-Dawley rat pups. Two control groups received either sterile PBS or a suspension of spores extensively extracted with ethanol to remove toxins. Lethal dose response was determined (LD50 = 2.7 × 105 spores/gm wt.). All dead pups had extensively hemorrhagic lungs. Growth of surviving animals was impaired in a dose-dependent manner. Changes of pulmonary function parameters in rats treated with 1.1 × 105 spores/g were consistent with an increased respiratory resistance. Histology of lungs revealed fresh hemorrhage, sparse hemosiderin-laden macrophages, and evidence of inflammation including thickened alveolar septa infiltrated by lymphocytes and mononuclear cells and intra-alveolar macrophages. Significant increases (p = 0.001) in numbers of macrophages (2-fold), lymphocytes (5-fold) and neutrophils (7-fold) were found in BAL fluid. Hemoglobin was elevated 2-fold (p = 0.004). Proinflammatory mediator IL-1β increased more than 6-fold and TNF-α30-fold (p = 0.001). Extracted spores had a minimal effect on all examined parameters in BAL fluid indicating that mycotoxins are primarily responsible for the hemorrhagic and inflammatory response.