Abg Cases

Inhaled Heroin-Induced Status Asthmaticus* : Five Cases and a Review of the Literature
James Cygan, Matthew Trunsky and Thomas Corbridge Chest 2000;117;272-275 DOI 10.1378/chest.117.1.272 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/117/1/272.full.html
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selected reports
Inhaled Heroin-Induced Status Asthmaticus*
Five Cases and a Review of the Literature
James Cygan, MD; Matthew Trunsky, MD; and Thomas Corbridge, MD, FCCP hospital. She was agitated in the emergency department with the following vital signs: temperature, 36.5C; pulse, 130 beats/min; BP, 124/80 mm Hg; and respiratory rate, 29 breaths/min by AMBU-bag ventilation. There were diffuse inspiratory and expiratory wheezes, and the expiratory phase was prolonged. Cardiac examination was notable for tachycardia. The results of abdominal and extremity examinations were normal. The initial arterial blood gas (ABG) measurements were the following: pH, 6.83; Pco2, 93 mm Hg; and Po2, 249 mm Hg. The patient was sedated, paralyzed, and placed on the following ventilator settings: synchronized intermittent mandatory ventilation rate, 12 breaths/ min; tidal volume (Vt), 750 mL; inspiratory flow rate, 80 L/min with a square waveform; fraction of inspired oxygen (Fio2), 1.0; and positive end-expiratory pressure (PEEP), 0 cm H2O (resulting in: peak airway pressure, 48 cm H2O; plateau pressure, 21 cm H2O; and auto-PEEP, 14 cm H2O). WBC count was 16,800/ L with 6% eosinophils. Urine toxicology was positive for opiates prior to in-hospital sedation. The chest radiograph demonstrated lung hyperinflation. The patient received methylprednisolone sodium succinate, albuterol by continuous nebulization, and aminophylline and was mechanically ventilated with settings chosen to limit lung hyperinflation at the cost of hypercapnia. On hospital day 4, there was convincing improvement in airway resistance and lung hyperinflation, and the patient was extubated. She continued to improve and was discharged on hospital day 10. Case 2 A 36-year-old African-American woman with a history of asthma, cigarette smoking, and heroin abuse called 911 because of severe shortness of breath immediately after snorting heroin that was not relieved by frequent doses of inhaled albuterol. Five days earlier, the patient had similarly become breathless after snorting heroin, but she improved after inhaling albuterol and did not seek medical care. One year earlier, the patient had had a respiratory arrest from asthma; she was not screened for illicit drug use at that time. In the emergency department, the patient was agitated, diaphoretic, and in extreme respiratory distress. Vital signs were the following: pulse, 120 beats/min; respiratory rate, 24 breaths/min; BP, 130/90 mm Hg; and temperature, 34.2C orally. On examination, there were diffuse inspiratory and expiratory wheezes and tachycardia. The results of a urine toxicology screen were positive for opiates and cocaine. The WBC count 14,900/ L with 7% eosinophils. Chest radiograph was normal. The patient was intubated shortly after admission for impending respiratory arrest. During assisted ventilation, airway resistive pressures were high and lung hyperinflation was present, as determined by the measurement of plateau pressure and auto-PEEP. The patient was intubated for 8 days, in part due to concurrent aspiration pneumonia. She was discharged on the hospital day 14. Case 3 A 46-year-old white man with a history of asthma and abuse of tobacco, heroin, and cocaine was brought to the emergency department by ambulance because of breathlessness that was unresponsive to -agonist therapy and that had begun shortly
Selected Reports
We report five cases of status asthmaticus (four requiring mechanical ventilation) that were triggered by inhaled heroin and review the pertinent literature. These cases share common features of sudden and severe asthma exacerbations temporally related to heroin use, stress the importance of considering illicit drug use in like cases, and call attention to a public health issue. (CHEST 2000; 117:272275)
Key words: asthma; diacetylmorphine; heroin; status asthmaticus Abbreviations: ABG arterial blood gas; Fio2 fraction of inspired oxygen; PEEP positive end-expiratory pressure; Vt tidal volume
e present below five cases of status asthmaticus in Chicago triggered by snorting or smoking heroin, and we review the pertinent literature. These cases share common features of sudden and severe asthma exacerbation with acute respiratory failure and a protracted clinical course: four of the five patients were intubated (and the fifth was nearly intubated) for an average of 5 days. These patients illustrate the importance of considering illicit drug use in like cases and draw attention to an important public health problem.
Case Reports
Case 1 A 30-year-old, nonsmoking, African-American woman with a history of asthma and heroin abuse was well until a few hours prior to admission when she became acutely breathless after snorting heroin. Despite the use of an inhaled -agonist, she was intubated in the field for respiratory arrest and brought to *From the Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL. Manuscript received March 24, 1999; revision accepted July 23, 1999. Correspondence to: Thomas Corbridge, MD, FCCP, 300 East Superior, Tarry 14-707, Chicago, IL 60611; e-mail: tcc734@ nwu.edu
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after snorting an unintentionally large dose of heroin. In the emergency department, the patient was severely dyspneic and monosyllabic. Initial vital signs were the following: temperature, 37.0C; BP, 134/73 mm Hg; pulse, 127 beats/min; and respiratory rate, 34 breaths/min. There was minimal air entry and diffuse wheezing, and the expiratory phase was prolonged. The results of cardiac examination were normal except for tachycardia. The patient was intubated shortly thereafter with the following periintubation blood gas measurements: pH, 6.94; Pco2, 106 mm Hg; and Po2, 355 mm Hg. He was placed on assist control at the following levels: rate, 12 breaths/min; Vt, 600 mL; PEEP, 0 cm H2O; Fio2, 1.0; and an inspiratory flow rate, 60 L/min. Airway resistive pressures were high, and lung hyperinflation was present. The WBC count was 5,800/ L with 7% eosinophils. The results of a urine toxicology screen prior to in-hospital sedation were positive for opiates. The patient improved over the next 24 h and was extubated on the second hospital day. He was discharged from the hospital on the fifth day. Case 4 A 26-year-old white man with a history of asthma and alcohol, tobacco, and heroin abuse developed refractory shortness of breath and a nonproductive cough after smoking heroin. He called 911 and was brought immediately to the emergency department in severe respiratory distress. On examination, he was anxious, diaphoretic, and monosyllabic. Vital signs were the following: temperature, 96.4C; pulse, 123 beats/min; BP, 125/78 mm Hg; and respiratory rate, 48 breaths/min. Lung auscultation revealed poor air movement, diffuse expiratory wheezes, and prolongation of expiration. The cardiac examination was notable only for tachycardia. The patient received continuous inhaled bronchodilators and subcutaneous epinephrine to no avail, and he was intubated in the emergency department. A chest radiograph demonstrated lung hyperinflation and no infiltrates. WBC count was 10,700/ L with 11% eosinophils. The results of a urine toxicology screen were positive for opiates. ABG analysis after sedation and paralysis on assist control (rate, 10 breaths/min; Vt, 500 mL; Fio2, 1.0; and PEEP, 5 cm H2O) yielded the following: pH, 7.19; Pco2, 61 mm Hg; and Po2, 511 mm Hg. Airway resistive pressures were high. Despite the development of ventilator-associated pneumonia, the patient was successfully extubated on hospital day 7. He left the hospital against medical advice on day 9. Case 5 A 39-year-old African-American man with a history of asthma, cigarette smoking, and heroin abuse was admitted for shortness of breath that had begun minutes after smoking heroin. The patient was brought to the emergency department after 20 consecutive puffs of albuterol by metered-dose inhaler failed to
relieve symptoms. The patient had been hospitalized previously for asthma on a number of occasions, but he had never been intubated. Outpatient therapy included prednisone, 10 mg daily, and albuterol by metered-dose inhaler. In the emergency department, vital signs were the following: temperature, 99F; pulse, 120 beats/min; respiratory rate, 30 breaths/min; and BP, 122/90 mm Hg. The peak expiratory flow rate was 190 L/min (30% of predicted). There were diffuse expiratory wheezes. The cardiac examination was notable only for tachycardia. WBC count was 10,700/ L with 10% eosinophils. Electrolytes were normal except for a potassium level of 3.4 mEq/L. ABG analysis on room air yielded the following: pH, 7.41; Pco2, 42 mm Hg; and Po2, 61 mm Hg. A chest radiograph was normal. The patient was admitted to the medical ICU where he received continuous albuterol by nebulization, heliox by tight-fitting face mask, intermittent subcutaneous epinephrine, and IV methylprednisolone sodium succinate. He did not require intubation and was discharged on the second hospital day.
Discussion
The five cases reported above are examples of status asthmaticus triggered by inhalation of heroin. Common features of these cases include a history of asthma, the sudden and severe nature of the exacerbations, the general lack of responsiveness -agonists, and peripheral blood eosinophilia (range, 6 to 11% of the total WBC count). Four of five patients were intubated (and the fifth nearly was intubated) for an average of 5 days (range, 2 to 8 days). This protracted course distinguishes these exacerbations from usual cases of sudden asphyxic asthma where rapid recovery is expected.1 There are eight other reported cases reported in the literature that demonstrate a temporal relationship between inhalation of heroin and acute asthma (Table 1).25 These cases include one death among three intubated patients3 and another death involving a prisoner found dead in his prison cell,4 supporting the view that inhaled heroin can induce severe and even fatal asthma. Also included in Table 1 is a report by Brander and Tukianinen6 of a patient who presented with asthma and eosinophilic pneumonia after repeated heroin inhalation, and a case reported by Ulinski and colleagues7 of occupational rhinitis and asthma related to powdered morphine sulfate. Additional data, not included in Table 1, support a temporal link between IV heroin use and acute asthma, including 31 cases reported by Ghodse and Myles8 in their retrospective study of 2,276 narcotic addicts.
Table 1Reported Cases of Asthma Exacerbation Associated With Inhaled Opiates*

Study Oliver Hughes and Calverley3 Merigian and Blaho4 Shaikh5 Brander and Tukianinen6 Ulinski et al7
2
No. of History of Patients Asthma 3 3 1 1 1 1 Y, N, N Y, Y, Y Y N N N
Type of Abuse Inhalation Inhalation Inhalation Inhalation Inhalation Powdered morphine exposure
Comments on Patients 1 admitted, 2 treated as outpatient Intubated/expired; intubated for 5 days; intubated for 2 days Died in prison Treated as outpatient Admitted for 7 d with an associated eosinophilic pneumonia Treated as outpatient
*Yes
yes; N
no.
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It is unclear whether asthma is a prerequisite for heroin-induced airflow obstruction. All patients reported in this paper had asthma, but other patients have been reported without a history of asthma (Table 1). Similarly, it is unclear whether the prevalence of asthma in the heroin-abusing population is different from that of the general population. In the study by Ghodse and Myles,8 the prevalence of asthma among addicts in England between the mid-1960s and the mid-1980s was 5%. Similarly, Sapira9 reported a prevalence of asthma among narcotic addicts in Lexington, KY, of between 5% and 8.8% between 1961 and 1966. These data compare to a prevalence of 5.4% in Americans in 1994, which represents a 75% increase since 1980.10 In Chicago, recent data suggest that 16% of seventh and eighth grade students have asthma, as assessed by a self-administered survey, with the highest prevalence rates seen in minority and low-income populations.11 The prevalence of asthma in the heroin-abusing population in Chicago is not known. According to the National Institute on Drug Abuse, approximately 2.4 million Americans had used heroin at some time in their lives by 1995.12 Also that year, approximately 500,000 people used heroin at least once, and there were 141,000 new heroin users, including a fourfold increase in first-time heroin use in youths age 12 to 17. Heroin use is on the rise, with many young abusers using relatively inexpensive, high-purity heroin that can be snorted or smoked instead of injected. In fact, in Chicago more drugs are administered by inhalation than by injection. Heroin use also has been reported to be increasing in affluent communities.12 From 1992 to 1995, the annual rate of emergency department visits for asthma increased 24%. Furthermore, the annual death rate from asthma increased 56% from 1980 to 1995.10 The reasons for these disturbing trends have been debated at length, but relatively little attention has been given to the connection between substance abuse and asthma, particularly in urban populations. Levenson and colleagues13 reported an association between substance abuse and asthma death in Chicago. By reviewing the information on asthma deaths reported by the Cook County Office of the Medical Examiner, these investigators showed that 32% of asthma deaths were confounded by substance abuse (mainly cocaine, heroin, and alcohol), and they concluded that this abuse has been partially responsible for the rise in asthma mortality. In a similar study, Weitzman and colleagues14 examined medical examiner asthma death autopsy records for the state of Maryland. Eight of 62 cases available for analysis showed positive results of screenings for substances of abuse: 3 with morphine, 1 with morphine and cocaine, 1 with cocaine, 1 with marijuana, and 2 with alcohol. Just how substances of abuse and asthma are linked is not entirely clear. Illicit drugs and alcohol may impair judgment during an acute asthma attack, leading to inadequate pharmacotherapy and late arrival at the hospital for care. It is also likely that specific drug effects (or drug contaminant effects) trigger asthma. For instance, in the paper by Levenson and colleagues,13 the authors concluded that asthmatics may be hypersensitive to -adrenergic agonists and that the use of cocaine may induce lethal arrhythmias. With regard to opioids, experiments
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dating back to 1903 have demonstrated that morphine (a heroin metabolite) is a bronchoconstrictor.15 Subsequent studies have demonstrated that opioid-induced bronchoconstriction is mediated by histamine release, and that heroin itself can degranulate mast cells and release preformed mediators of inflammation.16 Talc, a mineral used to cut heroin, also has been reported to cause bronchospasm in patients injecting heroin, although most of these patients had pulmonary edema, 1719 which may cause wheeze. We are unaware of an association between inhaled talc and asthma. Analysis of the contaminants/ composition of heroin sold in Chicago for inhalation is not yet available. The sudden yet protracted course in four of the five patients described in this paper, combined with the general lack of responsiveness to -agonists, suggests that these patients had a significant component of airway wall inflammation and/or airway wall architectural distortion. This contrasts with the usual patient with sudden asphyxic asthma who presents with a more pure form of bronchospasm, less airway wall inflammation, and the potential for a speedy recovery.1 Additional studies should help elucidate the mechanism(s) involved in heroininduced airflow obstruction. In summary, these cases demonstrate that sudden and severe asthma can be triggered by the inhalation of heroin. Clinicians should maintain a high index of suspicion for this association, because concurrent substance abuse identifies patients at risk for a more protracted course and the need for drug abuse counseling. These cases shed light on an important public health problem, particularly in highrisk communities, that may worsen if current trends in asthma and heroin prevalence continue. Additional research will help to establish the scope of this problem and to further our understanding of the relationship between substance abuse and asthma.
References
1 Corbridge T, Hall J. State of the art: the assessment and management of adults with status asthmaticus. Am J Respir Crit Care Med 1995; 151:1296 1316 2 Oliver RM. Bronchospasm and heroin inhalation [letter]. Lancet 1986; 1:915 3 Hughes S, Calverley PMA. Heroin inhalation, and asthma. BMJ 1988; 297:15111512 4 Merigian K, Blaho K. The role of pharmacology and forensics in the death of an asthmatic. J Anal Toxicol 1995; 19:522527 5 Shaikh WA. Allergy to heroin. Allergy 1990; 45:555556 6 Brander PE, Tukianinen P. Acute eosinophilia pneumonia in a heroin smoker. Eur Respir J 1993; 6:750 752 7 Ulinski S, Palczynski C, Gorski P. Occupational rhinitis and bronchial asthma due to morphine: evidence for inhalational and nasal challenges. Allergy 1990; 51:914 918 8 Ghodse AH, Myles JS. Asthma in opiate addicts. J Psychosom Res 1987; 31:41 44 9 Sapira JD. The narcotic addict as medical patient. Am J Med 1968; 45:564 566 10 U.S. Department of Health and Human Services. Surveillance for asthma-United States 1960 1995. MMWR Morb Mortal Wkly Rep April 24,1998; 47:SS-1 11 Persky VW, Slezak J, Contreras A, et al. Relationships of race and socioeconomic status with prevalence, severity, and
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12
13
14
15
16
17
18 19
symptoms of asthma in Chicago school children. Ann Allergy Asthma Immunol 1998; 81:266 271 National Institute on Drug Abuse. Research report: heroin abuse and addiction. Bethesda, MD: National Institutes of Health, 1997; Publication No. 97 4165 Levenson T, Greenberger PA, Donoghue ER, et al. Asthma deaths confounded by substance abuse: an assessment of fatal asthma. Chest 1996; 110:604 610 Weitzman JB, Kanarek NF, Smialek JE. Medical examiner asthma death autopsies: a distinct subgroup of asthma deaths with implications for public health strategies. Arch Pathol Lab Med 1998; 122:691 699 Dixon WE, Brodie TB. Contributions to the physiology of the lungs: Part 1. The bronchial muscles, their innervation, and the action of the drugs upon them. J Physiol 1903; 29:171 Withington DE, Patrick JA, Reynolds F. Histamine release by morphine and diamorphine in man. Anaesthesia 1993; 48: 26 29 Siegal H. Human pulmonary pathology associated with narcotic and other addictive drugs. Hum Pathol 1977; 3:5556 Napoli LD, Cigtay OS, Twigg H, et al. The lungs and drug abuse. Am Fam Physician 1974; 9:90 98 Davis LL. Pulmonary mainline granulamatosis: talcosis secondary to intravenous heroin abuse with characteristic x-ray findings of asbestosis. J Natl Med Assoc 1983; 75:1225 1230
is common approxiS yncope 5%a of hospitalsymptom representing Syncope mately admitting diagnoses. may be caused by a wide diversity of disorders accounting for the variable prognosis, ranging from a benign episode to sudden cardiac death. Cocaine use, although prevalent in inner cities, is not routinely considered as a cause. Adverse events have been reported in nearly every organ system with cocaine use. Cardiovascular complications include endocarditis, hemorrhagic and ischemic stroke, aortic dissection, accelerated coronary artery disease, myocardial infarction, and sudden cardiac death.1 Syncope may be the presenting symptom in these conditions. However cocaine-induced bradyarrhythmias have been scarcely mentioned.
Case Presentation
A 36-year-old black woman with apparently no significant medical history was brought by ambulance after a syncopal episode. The patient denied chest pain, palpitations, dyspnea, previous syncope, medication, or drug use. On physical examination, the patient was afebrile, with vital signs as follows: BP, 110/70 mm Hg; heart rate, 46 beats/min; and respiratory rate, 12 breaths/min. There was no jugular venous distention nor were any carotid bruits heard. The chest was clear, and heart sounds were normal without rubs, gallops, or murmurs. A neurologic examination revealed no focal deficits. The initial rhythm strip and ECG showed sinus arrest with junctional escape rhythm at 43 beats/min (Fig 1). Ancillary data including CBC count, serum chemistries, cardiac enzymes, chest radiograph, and head CT scan were normal. The results of toxicology were positive for cocaine. The patient admitted to cocaine use 1 h prior to admission. Telemetry and repeat ECG revealed a return to sinus rhythm 8 h later (Fig 2).
Cocaine-Induced Bradyarrhythmia*
An Unsuspected Cause of Syncope
Victor J. Castro, MD; and Robert Nacht, MD
Discussion
Cocaine use is associated with adverse events in nearly every organ system. Cardiovascular complications include hemorrhagic and ischemic stroke, aortic dissection, cardiomyopathy, accelerated coronary artery disease, myocardial infarction, and sudden cardiac death. Syncope may be the presenting symptom in these conditions. However, cocaine-induced bradyarrhythmias have been scarcely mentioned. As this case exemplifies, clinicians should be aware of this association when they evaluate syncope, especially in young patients. (CHEST 2000; 117:275277)
Key words: bradyarrhythmia; cocaine; syncope
*From the State University of New York Health Science Center at Brooklyn, Brooklyn, NY. Presented in part as an abstract at the Annual Scientific Meeting of the ACP-ASIM, May 15, 1999. Manuscript received May 4, 1999; revision accepted August 9, 1999. Correspondence to: Victor J. Castro, 130 Retreat Ave #C3, Hartford, CT 01606
Syncope is a sudden temporary loss of consciousness and postural tone with a spontaneous recovery not requiring electrical or chemical cardioversion. Syncope is not uncommon in healthy young adults. Its incidence increases with age and is associated with a high recurrence rate. Etiology can be classified into five major categories: neurologic, metabolic, psychiatric, cardiac mechanical disease, and cardiac arrhythmia. Cardiovascular disorders are the most frequent and important etiologic category, associated with the highest 1-year mortality rate.2 4 Cocaine use has been associated with multiple cardiac alterations. Autopsy findings include accelerated coronary artery disease, myocardial infarction, myocardial band necrosis, myocarditis, and dilated cardiomyopathy. Coronary spasm, transient hypercoagulability and increased myocardial oxygen demand can cause myocardial infarction even in the absence of significant coronary artery disease. Tachyarrhythmias and sudden cardiac death may occur secondary to ischemia, myocarditis, concomitant drug use, neurohormonal activation, and transient electrophysiologic abnormalities. Prolongation of PR, QRS, and QT intervals, ventricular effective refractory period, as well as class 1
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Figure 1.
antiarrhythmic type effects have been noted.57 At the cellular level, cocaine may cause early afterdepolarizations.8 Arrhythmias are a common cause of syncope. Either extreme of ventricular rate bradycardia or tachycardia can depress cardiac output to the point of critical hypotension with cerebral hypoperfusion and syncope.
Also, a neurocardiogenic reaction may be precipitated by the arrhythmia. Marked sinus bradycardia, sinoatrial exit block or sinus pause, high-grade AV block, supraventricular tachycardia, and ventricular tachycardia/ ventricular fibrillation are common syncope-producing arrhythmias. Cocaine use as the etiology for bradyarrhythmias has been barely mentioned or considered
Figure 2.
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Selected Reports
in the differential diagnosis.9,10 The mechanism remains unclear. In older noncocaine-user patients, primary degenerative disease of the sinus node and the conduction system is the most common cause of sinoatrial disease and high-grade AV block. This is unlikely to be present in young cocaine users. Experimental studies have shown cocaine to depress sinus node automaticity and block conduction at the AV node,11 prolonging AH and HV intervals.12 Localized spasm involving the sinoatrial artery, inferior myocardial infarction, vagal stimulation during nasal inhalation, overdrive suppression after supraventricular tachycardia, and a direct toxic effect may all contribute. With increasing cocaine use and more potent crack cocaine, physicians will be more frequently encountering cocaine-induced complications. Patients may present even with delayed toxicity, due to an active metabolite with long half-life.13 As this case exemplifies, clinicians should be aware of this association when they evaluate syncope, especially in young patients. If not correctly diagnosed, unrecognized and/or recurrent use may lead to life-threatening complications.
A Case of Cigarette SmokingInduced Acute Eosinophilic Pneumonia Showing Tolerance*

Hiromoto Shintani, MD; Masaki Fujimura, MD, FCCP; Yoshihisa Ishiura, MD; and Minoru Noto, MD
References
1 Mouhaffel AH, Madu EC, Satmary WA, et al. Cardiovascular complications of cocaine. Chest 1995; 107:1426 1434 2 Kapoor W, Karpf M, Wiend S, et al. A prospective evaluation and follow-up of patients with syncope. N Engl J Med 1983; 309:197204 3 Kapoor W. Evaluation and outcome of patients with syncope. Medicine 1990; 69:160 175 4 Silverstein MD, Singer DE, Mulley A, et al. Patients with syncope admitted to medical intensive care units. JAMA 1982; 248:11851189 5 Hale SL, Lehmann MH, Kloner RA. Electrical abnormalities after acute administration of cocaine in the rat. Am J Cardiol 1989; 63:1529 1530 6 Kloner RA, Hale S, Alker K, et al. The effects of acute and chronic cocaine use on the heart. Circulation 1992; 85:407 419 7 Clarkson CW, Chang C, Stolfi A, et al. Electrophysiological effects of high cocaine concentrations on intact canine heart: evidence for modulation by both heart rate and autonomic nervous system. Circulation 1993; 87:950 962 8 Kimura S, Basset AL, Xi H, et al. Early afterdepolarizations and triggered activity induced by cocaine: a possible mechanism of cocaine arrhythmogenesis. Circulation 1992; 85: 22272235 9 Om A, Ellenbogen K, Vetrovec G. Cocaine-induced bradyarrhythmias. Am Heart J 1992; 124:232234 10 Castro V. Cocaine-induced bradyarrhythmia: an unsuspected cause of syncope. Abstract presented at: Scientific Meeting of ACP-ASIM; May 15, 1999; NY 11 Przywara DA, Dambach GE. Direct actions of cocaine on cardiac cellular electrical activity. Circ Res 1989; 65:185 192 12 Tracy C, Bachenheimer L, Solomon A, et al. Evidence that cocaine slows cardiac conduction by an action on both AV node and His-Purkinje tissue in the dog [abstract]. J Am Coll Cardiol 1989; 13:79A 13 Chokshi SK, Gal D, Isner JM. Vasospasm caused by cocaine metabolite: a possible explanation for delayed onset of cocaine-related cardiovascular toxicity [abstract]. Circulation 1989; 80(II):351
It has been proposed that acute eosinophilic pneumonia (AEP), which is characterized by the absence of recurrence, is associated with cigarette smoking (CS), because Japanese patients with AEP are young and have a high incidence of short-term smoking history. However, there has been no direct evidence that CS causes AEP. We hypothesized that tolerance might develop against repeated resumption of smoking cigarettes in CS-induced AEP cases. In this connection, we challenged a patient with CS-induced AEP with repeated resumption of CS, and it was demonstrated that CS induced AEP in conjunction with tolerance to repeated resumption of smoking. (CHEST 2000; 117:277279)
Key words: acute eosinophilic pneumonia; challenge test, tolerance; cigarette smoking Abbreviations: AEP acute eosinophilic pneumonia; BALF BAL fluid; CRP C-reactive protein; CS cigarette smoking; ECP eosinophil cationic protein; IL-5 interleukin5; P(A-a)O2 alveolar-arterial oxygen pressure difference
Case Report
previously healthy 19-year-old started A smoking several cigarettes per Japanese manprior to day 3 weeks
admission. He developed a productive cough, dyspnea, and fever (38.5C) 2 days before admission. He was taken by ambulance to a nearby hospital with acute respiratory distress. On admission, he was pale, cyanotic, and febrile (38C). Auscultation revealed bilateral crackles in the late inspiratory phase. The results of the rest of the physical examination were normal. Arterial blood gas determination on room air revealed a pH of 7.43, Pao2 of 43.0 mm Hg, and Paco2 of 40.9 mm Hg. The patients peripheral WBC count was 15,000 cells/ L, with 75% neutrophils and 4% eosinophils. A chest radiograph revealed diffuse bilateral pulmonary infiltrates and pleural effusions. In the BAL fluid (BALF), marked neutrophilia (86%) and eosinophilia (14%) were observed. Cultures of BALF and stool for common bacteria, fungi, and parasite proved negative. On day 6, the shadows on the chest radiograph had improved remarkably without the aid of corticosteroids.
*From the Department of Internal Medicine (Drs. Shintani and Noto), Komatsu Municipal Hospital, Komatsu; and the Third Department of Internal Medicine (Drs. Fujimura and Ishiura), Kanazawa University School of Medicine, Kanazawa, Japan. Manuscript received April 15, 1999; revision accepted August 20, 1999. Correspondence to: Hiromoto Shintani, MD, the Department of Internal Medicine, Komatsu Municipal Hospital, Ho 60 Mukaimotoori-machi, Komatsu 923-8560, Japan
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Figure 1. The time axis of P(A-a)O2 in mm Hg (AaDO2; closed circles), degrees of body temperature in Celsius (C; open circles), schematic representation of chest radiograph findings, eosinophils, ECP, and IL-5 in peripheral blood, and percent eosinophils in BALF. The daily number of cigarettes smoked is shown at the top. Three episodes of fever, increase in P(A-a)O2, chest radiographic findings, and pulmonary symptoms correlated with cigarette smoking are marked on the date axis.
After a 2-week hospitalization, he was referred to our hospital, at which time his chest radiograph was normal. The peripheral blood examination showed that the results of sera Trichosporon mucoides and Trichosporon asahii tests, viral antibody tests, and bacterial examination were all negative. All of the precipitin tests were carried out thoroughly and extensively to rule out sensitivity to fungi such as Aspergillus fumigatus,1 and all of the results were negative. Total serum IgE was 62 IU/mL, and vital capacity was 4,530 mL (105.8% of the predicted value). Pao2 was 90.8 mm Hg, and Paco2 was 43.7 mm Hg. The patient was then challenged with smoking 10 cigarettes every day under informed consent. He developed a productive cough and dyspnea 13 h after he started smoking. Twenty-four hours later, his body temperature had risen from 36.5 to 37.5C, and Pao2 had decreased to 62.4 mm Hg and vital capacity to 3,520 mL. The C-reactive protein (CRP), WBC count, and alveolar-arterial oxygen pressure 0.25 difference (P[A-a]O2) before the challenge were mg/dL, 6,200 cells/ L, and 8.6 mm Hg, respectively, and rose to 0.8 mg/dL, 11,300 cells/ L, and 38.9 mm Hg after the challenge, respectively. The chest radiograph showed mild reticulonodular shadows. Bronchoscopy revealed that 78% of leukocytes in the BALF consisted of eosinophils, and transbronchial lung biopsy specimens demonstrated eosinophilic pneumonia. After cigarette smoking was discontinued, the symptoms subsided and laboratory findings returned to normal. Repeated BAL 24 days after the challenge showed a 1% differential in eosinophils. Eosinophil cationic protein (ECP) in BALF during and after the
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challenge was 130 g/L and 2.0 g/L, respectively. After a 6-week cessation of cigarette smoking, the patient resumed smoking 10 cigarettes per day but he did not experience any symptoms except a low-grade fever. The chest radiograph showed no infiltrates, and the low-grade fever subsided without the use of any specific therapy. We continued checking the patients condition very carefully for about 1 year. One year later, results of pulmonary function tests (spirometry, arterial blood gases, measurement of diffusing capacity) and chest radiograph were normal, although he had continued smoking 10 cigarettes per day. Skin testing by scratching techniques revealed a strongly positive immediate reaction to soluble tobacco smoke antigen (Torii Pharmaceutical; Tokyo, Japan) containing 100 g/mL of protein nitrogen. ECP in peripheral blood before, during the first challenge, and 1 year after the resumption of smoking was 19.2, 150, and 15.9 g/L, respectively. Interleukin-5 (IL-5) in peripheral blood before, during the first challenge, and 1 year after the resumption of smoking was 5.0, 59.1, and 5.5 pg/mL, respectively. Antigen-specific IgE antibody against tobacco leaf (Pharmacia & Upjohn; Tokyo, Japan) in peripheral blood before, during the first challenge, and 1 year after the resumption of smoking were all 0.34 UA/mL.
Discussion
Acute eosinophilic pneumonia (AEP), which is characterized by the absence of recurrence, was first described in
Selected Reports
1989.2,3 It has been proposed that AEP is associated with cigarette smoking (CS),4,5 because Japanese patients with AEP are young and have a high incidence of short-term smoking history. However, there has been no direct evidence that CS causes AEP. Sasaki et al5 reported that an 18-year-old man with AEP who was challenged with CS presented respiratory distress, but not fever, significant chest radiographic findings, or abnormal inflammatory data such as CRP and WBC count. We have experienced several cases of AEP in which CS was suspected to be causative, but no recurrence was recognized in spite of the resumption of smoking cigarettes. We therefore hypothesized that tolerance might develop against repeated resumption of smoking cigarettes in CS-induced AEP. We therefore challenged the case reported here with repeated resumption of smoking cigarettes under informed consent. The results indicate that the first challenge with CS induced symptoms including fever, abnormal laboratory findings such as an increase in CRP and WBC count, significantly symptomatic chest radiographic findings, and eosinophilic pneumonia documented by BAL and lung biopsy. Elevation of ECP concentration in BALF during the first challenge suggests that CS induced activation of eosinophils in the lungs. Furthermore, the present case demonstrated that the initial smoking episode was more significant and stronger as a cause of AEP than the first resumption of smoking, and that tolerance against repeated resumptions of smoking developed (Fig 1). Although the second episode of AEP observed on July 29, 1998, was less severe than the first episode observed on July 1, 1998, both the peripheral blood eosinophil count and the percentage of eosinophils in the BALF of the second episode were higher than those of the first episode. Iwami et al6 reported that at the onset of AEP, almost none of the cases showed an increase in eosinophils in the peripheral blood, but then an increase in eosinophils was observed a few days after the onset and in association with eosinophil dynamics. They also reported that in the early phase of AEP, eosinophils were detected in the transbronchial lung biopsy specimens, but not in the BALF, probably due to a hypersensitivity-like pulmonary reaction occurring originally in the lung. We therefore suspect that bronchoscopic and blood examinations of the first episode were done in the early phase of the disease. Questions remain as to why an increase in the number of eosinophils was associated with a less-severe episode and how this might or might not relate to immunologic tolerance. On the other hand, results of skin tests and blood studies concerning the specific IgE antibodies against components of cigarette smoke suggest that the mechanism of CS-induced AEP may be associated with an immediate allergic reaction to tobacco smoke, but probably not to tobacco leaf. Reduction of ECP and IL-5 concentration in peripheral blood 1 year after the resumption of smoking compared with during the first challenge suggests that tolerance to repeated resumption of CS in CS-induced AEP might be associated with suppression of CS-induced activation of eosinophils in the patient. Several Japanese patients with AEP with reportedly
unknown etiology were young and had a high incidence of short-term smoking history. However, there has been no direct evidence that cigarette smoking causes AEP. This is probably due to the development of tolerance to repeated resumption of smoking cigarettes in CS-induced AEP. This is the first report showing direct evidence that in CS-induced AEP cases tolerance develops to repeated resumption of smoking cigarettes. We should therefore pay attention to any history of CS in patients with AEP, especially in young patients
References
1 Ricker DH, Taylor SR, Gartner Jr JC, et al. Fatal pulmonary aspergillosis presenting as acute eosinophilic pneumonia in a previously healthy child. Chest 1991; 100:875 877 2 Allen JN, Pacht ER, Gadek JE, et al. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. N Engl J Med 1989; 321:569 574 3 Badesch DB, King TE, Schwarz MI. Acute eosinophilic pneumonia: a hypersensitivity phenomenon? Am Rev Respir Dis 1989; 145:716 718 4 Nakamura H, Kashiwabara K, Yagyu K, et al. Clinical evaluation of three cases of acute eosinophilic pneumonia. Jpn J Soc Bronchol 1995; 17:432 437 (English abstract) 5 Sasaki T, Nakajima M, Kawabata S, et al. Acute eosinophilic pneumonia induced by cigarette smoke. J Thorac Dis 1997; 35:89 94 (English abstract) 6 Iwami T, Umemoto S, Ikeda K, et al. A case of acute eosinophilic pneumonia: evidence for hypersensitivity-like pulmonary reaction Chest 1996; 110:1618 1621
The Role of BAL in the Diagnosis of Pulmonary Mucormycosis*

Mendel Glazer, MD; Samir Nusair, MD; Raphael Breuer, MD; Joel Lafair, MD; Yoav Sherman, MD; and Neville Berkman, MBBCh
Five patients with pulmonary mucormycosis diagnosed during life are described. All had underlying predisposing conditions: either posttransplant or hematologic malignancies. In all cases, the diagnosis was made using fiberoptic bronchoscopy. In three patients, BAL was diagnostic. In two of these patients, the diagnosis was made by identifying the typical hyphae of mucormycosis in the BAL fluid alone. Transbronchial biopsy was diagnostic in three patients. Treatment was based on IV antifungal che*From the Institute of Pulmonology (Drs. Glazer, Nusair, Breuer, Lafair, and Berkman) and the Department of Pathology (Dr. Sherman), Hadassah University Hospital, Jerusalem, Israel. Manuscript received April 15, 1999; revision accepted July 23, 1999. Correspondence to: Neville Berkman, MBBCh, Institute of Pulmonology, Hadassah University Hospital, PO Box 12000, Jerusalem, Israel, 91120.
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motherapy together with surgical removal of involved lung tissue whenever feasible. The clinical outcome of these patients was dismal and was determined primarily by the underlying condition. (CHEST 2000; 117:279 282)
Key words: BAL; immunocompromised; mucormycosis; neutropenia Abbreviations: AMB amphotericin B; BMT bone marrow transplantation; CSE corticosteroid; DM diabetes mellitis; renal-Tx renal transplantation; RLL right lower lobe; TBB transbronchial biopsy
M ucor, a fungus from the class of Zygomycetes, is a ubiquitous saprophyte that resides in soil and decay-
clinical and radiologic presentation, methods of diagnosis, treatment, and clinical outcome were documented in each case. The definitive diagnosis was made in all patients by fiberoptic bronchoscopy. BAL was performed in all patients, and TBB was performed whenever there was no coagulopathy and the thrombocyte count was 50,000 cells/ L. Material from TBB is embedded in paraffin blocks, and sections of 5 m are stained with hematoxylin-eosin. BAL fluid is routinely cytocentrifuged and stained with Papanicolaou stain, Gomori methenamine silver stain. BAL fluid is also sent for bacterial, fungal, viral, and mycobacterial cultures. A diagnosis of pulmonary mucormycosis was considered definite in the presence of histologic evidence of invasive fungal infection. For BAL, the finding of typical morphologic features of Mucor on direct staining or culture in the presence of compatible clinical presentation as well as favorable response to antifungal therapy was also considered diagnostic.
ing organic matter. Humans may be infected with Mucor after inhalation of airborne fungal spores. However, normal macrophage and neutrophil function provides immune protection against Mucor. Therefore, patients with neutrophil dysfunction, such as occurs in diabetes, renal failure, or prolonged steroid therapy, are particularly vulnerable to infections with Mucor. Additionally, neutropenic patients may also develop invasive mucormycosis. The most frequently observed manifestation of mucormycosis is the characteristic rhinocerebral infection, which may initially mimic bacterial sinusitis, and later extend to involve and destroy the hard palate and the orbit, and further invade the carotid artery. The GI tract and the brain may be involved in disseminated mucormycosis. The lung is more rarely involved by infection with this fungus. Such pulmonary involvement may progress and include invasion of blood vessels. In reported series of invasive pulmonary mucormycosis, the diagnosis is often made at postmortem or premortem examination by using transbronchial biopsy (TBB) or open lung biopsy. However, many patients at risk for this infection are thrombocytopenic, which precludes the performance of invasive diagnostic procedures. BAL has not been evaluated for the diagnosis of this infection. We present five patients with pulmonary mucormycosis that was diagnosed during life in our institution; three of the five patients had a diagnostic BAL.
Results Clinical Findings

The clinical details of the patients are summarized in Table 1. All patients were males, with a mean SD age at diagnosis of 40 8.3 years. Four patients had an underlying hematopoietic malignancy; two of the four patients had undergone bone marrow transplantation (BMT). The fifth patient was a kidney transplant patient. Diabetes mellitus (DM) secondary to corticosteroid (CSE) therapy, a well-known risk factor for rhinocerebral mucormycosis, was present in two cases. Four patients were receiving CSEs, and one patient (patient 1) was receiving cyclosporine A at the time of infection. Patient 5 had undergone autologous BMT, followed by administration of allogeneic stem cell transfusion. Two patients were neutropenic during the onset of infection with mucormycosis. The radiologic and bronchoscopic findings in our patients are outlined in Table 2. Four of the patients had unilateral lung involvement, and only one patient had bilateral lung disease. Three patients had cavitary lesions on chest plain radiography and CT. Other radiographic findings included a single mass in the right upper lobe and an additional nodule in the left lower lobe in one patient, and a right lower lobe (RLL) infiltrate in another patient. In our five patients with pulmonary mucormycosis, TBB was performed in three patients and was diagnostic in all. Of the five patients in whom BAL was performed, three patients had positive findings on direct microscopy. Only one of five patients had a positive finding on BAL culture (Table 2). In two cases, TBB findings were positive while
Materials and Methods

We searched the medical records of patients hospitalized in our institution between the years 1992 and 1997 and identified five patients in whom the diagnosis of pulmonary mucormycosis was made during life. Details regarding the underlying condition,
Table 1Demographic Data of the Patients*

Patient 1 2 3 4 5 Age, yr/Sex 46/M 53/M 37/M 30/M 34/M Basic Disease ALL, DM, BMT Renal-Tx, DM AML CML NHL, BMT Immunosuppression CSE, CSA CSE CTX, CSE CTX CSE, TCD-BM Blood Neutrophil Count 6,600 9250 0 77 3,540 Treatment AMB, pneumonectomy AMB, pneumonectomy AMB AMB AMB Survival 2 mo 1 mo 1 mo 2 wk 2 wk
*M male; F female; ALL acute lymphoblastic leukemia; AML acute myeloblastic leukemia; CML chronic myeloid leukemia; CSA cyclosporine A; CTX cytotoxic therapy; NHL non-Hodgkins lymphoma; TCD-BM T-cell depleted bone marrow. 280
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Table 2Diagnostic Modalities*

Patient 1 2 3 4 5 *LUL Chest Imaging RLL cavity RLL cavity LUL cavity RUL mass, LLL nodule RLL infiltrate left upper lobe; RUL right upper lobe; LLL BAL Negative Positive Positive Positive Negative left lower lobe; NA not available. TBB Positive NA NA Positive Mucormycosis BAL Culture Negative Negative Negative Positive Negative
BAL findings were negative for mucormycosis. In the two patients in whom TBB was not performed, BAL alone was diagnostic. Thus overall, BAL was diagnostic in three of the five patients (60%; Fig 1). Culture yielded mucormycosis in only one of five cases, and this patient had positive findings on both BAL and TBB. In one patient only (patient 1), an initial transthoracic needle aspiration of a lung cavity was performed, but was not diagnostic.
Outcome
The mean survival was 3.6 weeks. None of our patients survived beyond 3 months; however, the two patients who underwent lung resection did not have evidence of recurrence of mucormycosis up until their death. Patient 2 died of ventilator-associated pneumonia in the remaining lung, and patient 1 died 2 months after surgery because of progressive hepatic failure secondary to severe chronic graft-vs-host disease. Patient 3 survived at least 1 month past surgery but later died due to acute myeloblastic leukemia relapse in his home country.
Treatment
All patients were treated with high-dose amphotericin B (AMB); total dose was 1.5 g. In two patients, surgical resection of the involved lung was also performed.
Discussion
Mucor belongs to a unique group of fungi within the class Zygomycetes and is generally a noninvasive saprophyte in the normal host. Mucor infection invariably occurs in the presence of underlying disease, most commonly seen as an infectious complication of DM, and typically manifests as a rhinocerebral infection. In contrast, pulmonary mucormycosis is seen infrequently in diabetic patients.1 Besides DM, other well-recognized risk factors for invasive mucormycosis include neutropenia,2 hematopoietic malignancies, and CSE therapy.3 Among solid-organ transplants, patients undergoing renal transplantation (renal-Tx) for end-stage diabetic nephropathy, who are more likely to develop metabolic acidosis, may be more susceptible to mucormycosis.4 Two of our patients had CSEinduced DM, of which one had undergone renal-Tx. Neither patient had metabolic acidosis as a primary event during presentation with pulmonary mucormycosis. The most common radiographic manifestation in our patients was the presence of cavitary lesions. In a recent review of imaging findings in 32 cases of mucormycosis, two thirds of the patients had consolidation as a main finding.5 Forty-one percent of the patients had cavitation within pulmonary consolidation or masses. Other radiographic manifestations include multifocal consolidation, on air crescent sign whenever a pulmonary infarct results from vascular invasion, and rarely pleural effusion.6 The antemortem diagnosis of pulmonary mucormycosis is often missed because the diagnosis is not suspected or pursued thoroughly enough. Because postmortem examinations are rarely performed in our country, this series includes only diseases diagnosed antemortem. It is thus possible that the number of cases of pulmonary mucormycosis in our institution is much higher than that reported here. According to published studies, the diagnosis of pulmoCHEST / 117 / 1 / JANUARY, 2000
Figure 1. Mucormycosis in BAL. Top, a: Characteristic, right angle branching (long arrows), ribbon-like hyphal fragments without obvious septa. Bottom, b: Note the typical cellular bronchial background of columnar ciliated cells (arrowheads) and macrophages (short arrows; Papanicolaou stain, original magnification 400).
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nary mucormycosis requires the demonstration of the typical nonseptated right angle branching-shaped hyphae within the lung tissue.3 A positive finding from BAL culture is suggestive but not considered definitive.6 However, since hematologic patients are frequently thrombocytopenic, obtaining TBB is frequently not feasible. In such cases, BAL may be the only diagnostic modality available. Of our five cases, the BAL finding was positive in three (60%). Of these, two patients were unable to undergo TBB; in these cases, the diagnosis was made by BAL alone. In all three cases with a positive finding on BAL, mucormycosis proved to indeed be a true pathogen and not merely a coincidental finding; in one case, this was confirmed by surgery (thoracotomy), and in the second by a positive finding on TBB. In the third patient, the clinical response after the initiation of antifungal therapy, together with failure to respond to broad-spectrum antibacterial therapy or to identify another pathogen despite extensive evaluation, led us to believe that mucormycosis was a true pathogen in this patient (patient 3). There is little available literature that describes the diagnosis of mucormycosis by using BAL.7,8 A recent report described a diabetic patient in whom a diagnosis of pulmonary mucormycosis was made by BAL.9 Conventional recommendations in the literature require demonstration of Mucor hyphae within the pulmonary parenchyma in order to make the diagnosis of pulmonary mucormycosis.6 Our findings suggest otherwise. We believe that whenever mucormycosis is found in BAL cultures from a neutropenic or immunocompromised patient, the diagnosis of invasive mucormycosis is extremely likely and should be assumed until proven otherwise. The diagnostic yield of fungal culture was poor (20%; one of five cases). The culture finding was negative even in cases in which findings from direct microscopy of BAL or lung tissue were positive. Similar results of culture have been reported by others.5 This yield may be dependent on the specific laboratory performing these cultures, but in our hands, culture adds little to the histopathologic tests. Our data suggest that BAL could be a useful diagnostic procedure for pulmonary mucormycosis, with an acceptable risk for thrombocytopenic and critically ill patients in whom TBB is contraindicated. From our data, it is not possible to comment on the negative predictive value of BAL for excluding the diagnosis of pulmonary mucormycosis. Conclusions regarding this issue would require the performance of open lung biopsy or postmortem examination in all patients in whom BAL is analyzed. The recommended treatment for pulmonary mucormycosis includes treatment of the underlying condition, surgical removal of the devitalized tissue, and IV administration of AMB. According to recent reports, early surgical treatment may substantially reduce mortality (45% with surgery vs 70 to 80% with medical management only).5,7 Although surgical resection of pulmonary parenchyma involved with mucormycosis seems to have eradicated mucormycosis in our patients, the underlying con282
dition was the main factor that determined their outcome and survival. Consequently, overall survival in our group was dismal regardless of surgical intervention. In conclusion, pulmonary mucormycosis should be suspected in patients with a high risk for invasive fungal pulmonary infections, particularly when they present with single or multifocal pulmonary infiltrates with cavitation. The diagnosis of fungal pneumonia requires the demonstration of fungi within the pulmonary parenchyma on lung biopsy; however, BAL, a relatively safe diagnostic tool, may allow the diagnosis of mucormycosis in cases where lung biopsy is contraindicated. Our findings strongly imply that the presence of mucormycosis within the BAL fluid is diagnostic of pulmonary mucormycosis in patients who are prone to such an infection. Although surgical resection of pulmonary parenchyma involved with mucormycosis may have eradicated the infection, the underlying condition was the main factor that determined outcome and mortality.
References
1 Hansen LA, Prakash UBS, Colby TV. Pulmonary complications in diabetes mellitus. Mayo Clin Proc 1989; 64:791799 2 Baker RD. Leukopenia and therapy in leukemia as factors predisposing to fatal mycosis. Am J Clin Pathol 1962; 37:358 373 3 Lehrer RI, Howard DH, Sypherd PS, et al. Mucormycosis. Ann Intern Med 1980; 93:93108 4 Latif S, Saffarian N, Bellovich K, et al. Pulmonary mucormycosis in diabetic renal allograft recipients. Am J Kidney Dis 1997; 29:461 464 5 McAdams HP, de Christenson MR, Strollo DC, et al. Pulmonary mucormycosis: radiologic findings in 32 cases. AJR Am J Roentgenol 1997; 168:15411548 6 Murphy RA, Miller WT Jr. Pulmonary mucormycosis. Semin Roentgenol 1996; 31:83 87 7 Tedder M, Spratt JA, Anstadt MP, et al. Pulmonary mucormycosis: results of medical and surgical therapy. Ann Thorac Surg 1994; 57:1044 1050 8 Williams D, Yungbluth M, Adams G, et al. The role of fiberoptic bronchoscopy in the evaluation of immunocompromised hosts with diffuse pulmonary infiltrates. Am Rev Respir Dis 1985; 131:880 885 9 Al-Abbadi MA, Russo K, Wilkinson EJ. Pulmonary mucormycosis diagnosed by bronchoalveolar lavage: a case report and review of the literature. Pediatr Pulmonol 1997; 23:222225
Respiratory Bronchiolitis Associated With Severe Dyspnea, Exertional Hypoxemia, and Clubbing*
Ruxana T. Sadikot, MD; Joyce Johnson, MD; James E. Loyd, MD, FCCP; and John W. Christman, MD, FCCP
Respiratory bronchiolitis-associated interstitial lung disease (RBILD) is a distinct clinicopathologic disease described almost exclusively in cigarette smokSelected Reports
ers.1,2 The disease usually presents with mild symptoms and is associated with a good prognosis.2 Severe lung dysfunction has not been reported with RBILD, which is often confused clinically and radiographically with desquamative interstitial lung disease or idiopathic pulmonary fibrosis (IPF). Two patients with RBILD who developed severe dyspnea, hypoxemia, and clubbing are described. Initially, IPF was diagnosed in both patients. The severity of symptoms was such that the first patients room air saturation was 85% and the second patient had severe impairment of lung function, with FEV1 of 39% and FVC of 40%. Advanced lung disease required supplemental home oxygen therapy in the first patient and referral for lung transplant evaluation in the second patient. After a detailed review of histology revealed a diagnosis of RBILD, both patients were encouraged to stop smoking; smoking cessation led to considerable improvement in symptoms and lung function tests. We conclude that advanced lung dysfunction occurs in some patients with RBILD and should not dissuade that diagnosis. (CHEST 2000; 117:282285)
Key words: bronchiolitis; clubbing; dyspnea; smoking Abbreviations: DIP desquamative interstitial pneumonitis; Dlco diffusing capacity of the lung for carbon monoxide; HRCT high-resolution CT; IPF idiopathic pulmonary fibrosis; PFT pulmonary function test; RBILD respiratory bronchiolitis-associated interstitial lung disease; TLC total lung capacity
espiratory bronchiolitis is a well-recognized pathologic entity that occurs almost exclusively in smokers,3 but is usually mild and of little clinical significance. It is commonly referred to as smokers bronchiolitis. Far less commonly, a similar condition extends to the peribronchiolar interstitium; it is then referred to as respiratory bronchiolitis-associated interstitial lung disease (RBILD). RBILD has recently been proposed as a form of desquamative interstitial pneumonitis (DIP).4 Histologically, it is distinguished from classic DIP on the basis of bronchiolocentricity of macrophage aggregates, making RBILD a patchy rather than a diffuse inflammatory process.1 Clinically, the signs and symptoms of RBILD are very similar to those of idiopathic pulmonary fibrosis (IPF), although they are usually mild. Clubbing has not been previously reported with RBILD.2,5
*From the Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine (Drs. Sadikot, Loyd, and Christman), and the Department of Pathology (Dr. Johnson), Vanderbilt University School of Medicine and the Department of Veterans Affairs, Nashville, TN. This work was supported by The US Department of Veterans Affairs; and Grant No. HL 48164 and HL 07123, National Heart, Lung, and Blood Institute, National Institutes of Health. Manuscript received December 15, 1998; revision accepted August 13, 1999. Correspondence to: John W. Christman, MD, FCCP, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, T-1217 MCN, Center for Lung Research, Nashville, TN 37232-2650; e-mail: john.christman@ mcmail.vanderbilt.edu
Figure 1. Chest radiograph of case 1 showing reticular shadowing in both lung bases and prominent peripheral subpleural blebs.
Here we report two patients with symptomatic RBILD who presented with severe dyspnea, hypoxemia, and clubbing. Salient features of the conditions are highlighted.
Case 1
A 47-year-old previously well white man with a 25-year history of smoking had been treated at a local hospital for COPD and
Figure 2. HRCT of case 1 showing diffuse ground glass opacities predominantly involving the lung bases and peripheral subpleural blebs. P posterior; R right side.
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Figure 3. Histology of case 1 showing typical features of RBILD.
IPF for 4 years. The diagnosis of IPF was based on a chest radiograph, which showed reticular shadowing in both lung bases. He failed to improve with an empiric trial of steroids and continued to deteriorate to the point where he was unable to carry out his daily activities. Home oxygen therapy was necessary, and he was referred for further evaluation. Medications included albuterol and ipratropium inhalers. He worked as a clerk and smoked one pack of cigarettes per day until his most recent presentation. There was no history of exposure to dust, animals, or birds, and other history was noncontributory. On examination, he had normal vital signs. He had a thin body habitus and appeared comfortable at rest. Extremities showed clubbing of fingers and toes. Additional history indicated that he had noted changes in his nails over a long period of time. Chest examination revealed fine late inspiratory crackles with otherwise normal breath sounds. Laboratory testing revealed a hemoglobin of 16.2 g/dL; hematocrit, 47.2%; WBC count, 10.2 103/ L; and a platelet count, 299 103/ L. Electrolytes were normal. Rheumatoid factor, antinuclear antibodies, and anticytoplasmic antibodies were all negative, and an 1-antitrypsin level was within the normal range. Chest radiograph showed reticular shadowing in both lung bases and prominent subpleural blebs (Fig 1), and high-resolution CT (HRCT) showed diffuse ground glass opacities predominantly involving the lung bases and confirmed the subpleural blebs (Fig 2). A room air arterial blood gas analysis showed a pH of 7.4; Paco2, 32 mm Hg; Pao2, 58 mm Hg; and HCO3, 26 mEq/L, with a resting alveolar-arterial oxygen tension gradient of 54. Pulmonary function tests (PFTs) showed the following: FEV1 of 1.99 L (52%); FVC, 3.2 L (70%); FEV1/FVC, 62%; forced expiratory flow after 25 to 75% of vital capacity has been expelled, 28% of predicted; diffusing capacity of the lung for carbon monoxide (Dlco), 5.6 mL/mm Hg/min (18%); residual volume, 133%; and total lung capacity (TLC), 90% of predicted. An echocardiogram was normal.
Figure 4. Chest radiograph of case 2 showing reticular shadowing in both lung bases.
Open lung biopsy showed abundant pigment-laden intraalveolar macrophages in patchy aggregates, predominantly within the lumen of the respiratory bronchioles but extending into the alveolar spaces at multiple foci (Fig 3), and followed a peribronchial distribution. There was thickening of the bronchiolar walls by smooth muscle hypertrophy and mild edema, but no evidence of alveolar interstitial fibrosis. These histologic findings are characteristic of RBILD. The patient was entered into a smoking cessation program. After 3 months of not smoking, his symptoms improved and he was able to weaned from oxygen both at rest and during exercise when oximetry remained 90%. He is now able to perform his daily activities, and repeated PFTs showed improvement (Table 1).
Case 2
A 43-year-old white man with a diagnosis of COPD and 100 pack-year history of tobacco use presented with increasing dyspnea
Table 1PFT Results

Case 1 Variables FEV1, L (%) FVC, L (%) TLC, L (%) Dlco, mL/mm Hg/min (%) At Diagnosis 1.99 (52) 3.2 (70) 5.7 (90) 5.6 (18) 6 mo 2.38 (61) 3.5 (76) 6.42 (101) 7.7 (25) At Diagnosis 1.58 (39) 1.96 (40) 3.5 (52) 19 (67) Case 2 6 mo 1.98 (50) 2.58 (52) 4.08 (61) 23 (80)
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of 2 years duration. He worked as a roofer until 2 years prior to presentation, when his symptoms worsened and he had to quit working. His medical history was significant only for an episode of hepatitis A. Medications included albuterol, ipratropium, and salmeterol inhalers. On examination, he had normal vital signs. Extremities revealed early clubbing of fingers. Laboratory tests, including CBC count, electrolytes, and liver function tests, were all within normal limits. A chest radiograph showed reticulonodular infiltrates in the lung bases (Fig 4). PFTs showed FEV1 of 1.58 L (39%); FVC, 1.96 L (40%), TLC, 3.5 L (52%), and Dlco, 19 mL/mm Hg/min (67%), consistent with severe restriction and a moderate diffusion abnormality. A thoracoscopic lung biopsy was initially thought to show DIP, and the patient was treated with prednisone, and later, azathioprine. Despite the treatment, he continued to deteriorate and was referred for a second opinion. Review of histology showed the typical feature of RBILD. The patient reported that he was not smoking, but urinary cotinines were persistently positive. Intensive discussion of the critical need for smoking cessation was again undertaken with the patient and his spouse. Over a period of 6 to 9 months, his respiratory status gradually improved. The PFTs are summarized in Table 1.
Discussion
Cigarette smoking is a well-recognized cause of a variety of lung diseases, including COPD/emphysema, lung cancer, and respiratory bronchiolitis. Although interstitial fibrosis is recognized as a part of the histologic response to inhalation of cigarette smoke in both animals and humans,6,7 the role of smoke inhalation as a cause of clinically significant interstitial lung disease is less well defined. Respiratory bronchiolitis was first described in the early 1970s and is considered an anatomic correlate of small airways disease in cigarette smokers.2 It occurs almost exclusively in smokers and is thought to be of limited clinical significance. On occasion, a similar but more extensive condition is associated with interstitial edema and intraalveolar macrophages, referred to as RBILD. This entity has been proposed as a variant of DIP. Histologically, RBILD is distinguished from DIP on the basis of the distribution of macrophage aggregates, which is patchy and bronchiolocentric, with filling of both respiratory bronchioles and alveolar spaces by pigmented macrophages. The macrophages in smokers are discolored by the presence of inclusion bodies composed of kaolinite, aluminum silicate.1 Because of the accumulation of pigmented macrophages, RBILD may occasionally be confused with pulmonary hemorrhage syndromes. A negative iron stain excludes the diagnosis of a pulmonary hemorrhage syndrome. The clinical presentation of RBILD is similar to that of other interstitial lung diseases. Patients are typically young (mean age, 36 years), with an average of 30 to 40 years of smoking history. Most patients with RBILD are either asymptomatic or describe only mild symptoms. When present, symptoms include minimally productive cough and dyspnea. Physical signs include late inspiratory crackles, as in other interstitial diseases. Clubbing has not been described with RBILD. Chest radiographs usually reveal reticular shadowing in lung bases, and HRCT findings consist of centrilobular opacities and patchy areas of ground glass attenuation, attributed to smokers alveolitis. The changes are predominantly seen in the lower lobes. PFTs commonly reveal a mixed obstructive-restrictive
pattern with a reduced Dlco. Occasionally, PFTs may be normal. Interestingly, lung volumes are usually increased, indicating air trapping beyond the obstructed bronchiole. These two cases are unusual because of the marked severity of symptoms and associated clubbing. The diagnosis in both cases was delayed, during which period the patients continued to smoke, probably leading to further deterioration of lung function and progression of the disease process, resulting in severe hypoxemia and clubbing. Smoking cessation in both patients, in combination with prednisone and azathioprine in one patient, led to improvement in symptoms and PFTs. These cases illustrate severe RBILD and are a reminder that RBILD should be included in the differential diagnosis of interstitial lung disease. It is important to establish this diagnosis because of its significantly better prognosis, and also to avoid unnecessary treatment with potentially toxic medications. Increasing awareness of this condition is required, as abstinence from smoking may lead to regression of symptoms and improvement in lung functions as in these two patients. Documentation of smoking cessation by laboratory testing may be of even greater value than usually is the case, because of the possible pathogenetic relationship to the disease process. Whether persistent continued smoking in patients with RBILD might lead to irreversible end-stage disease is unknown.
References
1 Myers JL, Veal CF, Shin MS, et al. Respiratory bronchiolitis causing interstitial lung disease: a clinico pathologic study of six cases. Am Rev Respir Dis 1987; 135:880 884 2 King TE. Respiratory bronchiolitis associated interstitial lung disease. Clin Chest Med 1993; 14:693 698 3 Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291:755758 4 Katzenstein AA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:13011315 5 Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989; 64:13731380 6 Weiss W. Cigarette smoking and diffuse pulmonary fibrosis. Am Rev Respir Dis 1969; 99:6772 7 Hammond EC, Auerbach O, Kirman D, et al. Effects of cigarette smoking on dogs: I. Design of experiment, mortality, and findings in lung parenchyma. Arch Environ Health 1970; 21:740 753
Esophageal Perforation After Sequential Double-Lung Transplantation*

Federico Venuta, MD; Erino A. Rendina, MD; Tiziano De Giacomo, MD; Anna Maria Ciccone, MD; Edoardo Mercadante, MD; and Giorgio Furio Coloni, MD
The authors report a case of esophageal perforation after sequential double-lung transplantation for
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bronchiectasis. This complication was probably related to the devascularization of the esophageal wall during pneumonectomy. (CHEST 2000; 117:285287)
Key words: complications; esophageal perforation; lung transplantation
necrotic esophageal wall still evident. A transhiatal esophagectomy was planned, but the general condition of the patient rapidly deteriorated. He died 2 weeks later with multiple organ failure. Autopsy confirmed the presence of an unhealed esophageal fistula surrounded by a necrotic esophageal wall; the fistula was located posteriorly at the level of the midesophagus.
Comment
Esophageal perforation after lung transplantation never has been reported. However, the occurrence of an early or late esophagopleural fistula following pulmonary resection has been described as an uncommon, but serious, complication.13 Before 1960, these types of fistulas usually were found following pneumonectomy for tuberculosis or other suppurative diseases of the lung; they were rarely reported after pulmonary resections for cancer. In this setting, the most common causes for the development of an esophagopleural fistula were direct injury to the esophagus, devascularization during dissection, and infection of the pleural space. Esophageal damage also has been described after bronchial artery embolization,4 probably due to the acute occlusion of esophageal arteries or dominant collateral arteries from the bronchial circulation. In patients with chronic septic lung disease, the bronchial arteries are usually enlarged and tortuous and may engulf the pulmonary hila. During lung transplantation, careful ligation and cauterization of these vessels is necessary to allow dissection of the pulmonary vessels and main bronchi and to prevent bleeding in the postoperative course. Anastomoses between the bronchial and esophageal circulation exist5 and may be the cause of this complication, together with the possible ligation of a separate esophageal artery along with the bronchial vascular supply. Overuse of diathermy during heart-lung and double-lung transplantation also may lead to vagus nerve damage, as reported by other authors.6 However, these complications were more frequent with heart-lung and en bloc double-lung transplantation since a more extensive dissection of the middle and posterior mediastinum was required. During sequential double-lung transplantation, the dissection is performed around the pulmonary hila, which helps to simplify the surgical technique and to reduce the incidence of postoperative complications. The treatment of esophagopleural fistulas is difficult; it is usually complicated by a prolonged recovery period and is associated with a dismal outcome. Conservative approaches as well as extensive esophageal reconstructions have been advocated, but the results are often unsatisfactory. The complex posttransplant status, immunosuppression, and failure of esophageal diversion probably contributed to the poor outcome in our case. In conclusion, our report may serve as a reminder to us and to others to be aware of this complication and to be more conservative while performing a pneumonectomy for lung transplantation.
ung transplantation is considered to be a valuable option for patients with end-stage lung disease. The increase in the number of transplants and the standardization of surgical technique and postoperative care have led to a clear improvement in survival rates. However, morbidity still exists and unusual complications may appear due to the complexity of the surgical procedure and the peculiarity of the postoperative course. We report a case of esophageal perforation after sequential doublelung transplantation for bronchiectasis; this complication was probably due to devascularization of the esophageal wall related to the ligation or cauterization of the bronchial and/or esophageal arteries during pneumonectomy.
Case Report
A 45-year-old man with respiratory failure due to bronchiectasis was referred to our department for lung transplantation; a sequential double-lung transplantation was performed 9 months later. At operation, before the pneumonectomy, a great number of tortuous and enlarged bronchial arteries engulfing both pulmonary hila were either ligated or cauterized during dissection. Both lungs were sequentially transplanted without extracorporeal support. The patient was extubated after 48 h and started an intensive rehabilitation program, discontinuing oxygen support 2 days later. Three weeks after the transplant, he presented sudden dyspnea with a remarkable level of oxygen desaturation (89%). A chest radiograph showed a complete collapse of the left lung due to a pneumothorax. A chest tube was immediately placed for drainage, which allowed reexpansion of the transplanted lung. Oxygen saturation improved, and a bronchoscopy was performed that showed satisfactory healing of both bronchial anastomoses. The cause of the pneumothorax was thought to be the rupture of a small bleb on the surface of the left lung. However, after a few hours the general condition of the patient further deteriorated with hemodynamic instability and fever. The patient started to eat again, and food appeared in the chest drainage system. An esophagoscopy showed the presence, at the level of the pulmonary hilum, of a fistula that was 3 cm in diameter and that was surrounded by a necrotic esophageal wall. Neither nausea nor vomiting were present before the onset of the pneumothorax. Esophageal diversion was performed with a lateral cervical esophagostomy. The cervical and abdominal esophagus were closed with reabsorbable staplers; a drainage gastrostomy and a feeding jejunostomy also were performed. A paraesophageal transdiaphragmatic drainage tube was placed. The patient recovered well with total parenteral nutrition, but after 3 weeks he became septic again. An esophagoscopy showed a partial disruption of both of the stapler lines, with the fistula still open and the *From the Department of Thoracic Surgery, University of Rome La Sapienza, Rome, Italy. Manuscript received December 29, 1998; revision accepted August 9, 1999. Correspondence to: Federico Venuta, MD, Department of Thoracic Surgery, University of Rome La Sapienza, Policlinico Umberto I, Via le del Policlinico, 00100 Rome, Italy; e-mail: Fevenuta@tin.it
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References
1 Shama DM, Odell JA. Esophageal fistula after pneumonectomy for inflammatory disease. J Thorac Cardiovasc Surg 1985; 89:77 81
Selected Reports
2 Evans JP. Post-pneumonectomy oesophageal fistula. Thorax 1972; 27:674 677 3 Sethi GK, Takaro T. Esophagopleural fistula following pulmonary resection. Ann Thorac Surg 1978; 25:74 81 4 Hsu H, Su J. Giant bronchoesophageal fistula: a rare complication of bronchial artery embolization. Ann Thorac Surg 1995; 60:17971798 5 Charan NB, Carvalho PG. Anatomy of the normal bronchial circulatory system in humans and animals. In: Butler J, ed. The bronchial circulation: lung biology in health and disease (vol 57). New York, NY: Marcel Dekker, 1995; 4577 6 Au J, Hawkins T, Venable C, et al. Upper gastrointestinal dysmotility in heart-lung transplant recipients. Ann Thorac Surg 1993; 55:94 97
wish to report the first case of transcoronary chemoembolization therapy for relief of RV outflow obstruction derived from HCC.
Case Report
A 67-year-old woman was transferred to the coronary care unit of Nippon Medical School Hospital on June 5, 1998, with a diagnosis of RV tumor. The patient had received a diagnosis of HCC 3 years previously, and had undergone partial hepatectomy. The patient had been well until 2 months before admission, when she began to experience shortness of breath on exertion. She was admitted to another hospital, where she continued to have shortness of breath and dyspnea. Because a transthoracic echocardiogram (TTE) showed a large tumor in the right ventricle, she was referred to our hospital for further management. Her BP was 118/74 mm Hg, and her pulse rate was 84 beats/min. There was a grade 2/6 holosystolic murmur at the left lateral sternal border. The liver was not enlarged. Leg edema was observed. Her arterial oxygen pressure was 61 mm Hg, with oxygen saturation of 92%. Liver function tests performed at admission disclosed a higher level of glutamic oxaloacetic transaminase than that of glutamic pyruvic transaminase, and low hepaplastin test (27%), and positive hepatitis type C virus. Her protein induced by vitamin K absence II was high at 1,200 AU/mL. ECG showed regular sinus rhythm and inverted T wave in V1-V3. Chest radiography and CT scan of the chest showed a nodular lesion in the left superior lobe (S3), which would be probable evidence of a metastatic lesion. A CT scan of the abdomen demonstrated two tumor masses in the liver: one at the anterior inferior segment and another at the posterior superior segment, which would be probable evidence of recurrence. TTE revealed a large tumor (43 37 mm) occupying the anterior portion of the RV outflow tract; however, there was no mass lesion within the right atrium. Also noted were severe tricuspid regurgitation and poor RV contractility. The pulmonary valve was intact, although the tumor protruded into it. Right atrioventriculography exhibited tumor in the RV outflow tract, creating
Effectiveness of Transcoronary Chemoembolization for Metastatic Right Ventricular Tumor Derived From Hepatocellular Carcinoma*
Eitaro Kotani, MD; Kaname Kiuchi, MD; Morimasa Takayama, MD; Teruo Takano, MD; Mimiko Tabata, MD; Takumi Aramaki, MD; and Hiroshi Kawamata, MD
A right ventricular outflow tract was partially obstructed by a metastatic tumor from a hepatocellular carcinoma. This tumor was treated via chemoembolization of the right coronary artery, which resulted in tumor regression and improvement of the patients symptoms. (CHEST 2000; 117:287289)
Key words: hepatocellular carcinoma; metastatic cardiac tumor; right ventricular outflow obstruction; transcoronary chemoembolization Abbreviations: HCC hepatocellular carcinoma; RV right ventricular; SMANCS anticancer agent copoly (styrenemaleic acid) conjugated to neocarzinostatin; TTE transthoracic echocardiogram
A lthough a metastatic cardiac tumor thrombus is a rare complication of hepatocellular carcinoma (HCC), tu-
mor thrombosis may produce sudden death. Culpepper and von Haam1 reported a case of carcinoma of the liver with sudden death shown to have cardiac chamber involvement. Transcoronary chemoembolizations have been performed successfully to treat right ventricular (RV) outflow obstruction. To the best of our knowledge, we
*From the Coronary and Intensive Care Unit (Drs. Kotani, Kiuchi, Takayama, and Takano), the First Department of Internal Medicine (Drs. Tabata and Aramaki), and the Department of Radiology (Dr. Kawamata), Nippon Medical School, Tokyo Japan. Manuscript received April 7, 1999; revision accepted August 16, 1999. Correspondence to: Kaname Kiuchi, MD, Coronary and Intensive Care Unit, Nippon Medical School, 11-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 Japan
Figure 1. Right atrioventriculography demonstrating tumor in the RV outflow tract, creating a severe stenosis.
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Figure 2. Selective right coronary angiogram demonstrating tumor stain and some feeding arteries from the first, second, and third RV branches.
a severe stenosis (Fig 1). Selective right coronary angiogram demonstrated tumor stain and some feeding arteries from the first, second, and third RV branches (Fig 2). Some specimens were obtained from the RV tumor using the techniques of endomyocardial biopsy, and the pathologic finding was compatible with cardiac metastasis of moderately differentiated HCC that included infiltration of atypical cells with an increase of nucleus-cytoplasm ratio. Dyspnea was aggravated after 2 weeks, and arterial oxygen pressure decreased to 56 mm Hg on 10 L/min oxygen inhalation. Estimated RV systolic
pressure by TTE increased to 100 mm Hg. Open heart surgery for tumor removal was not thought to be a viable option because of advanced liver cirrhosis with low hepatic reserve and recurrences in liver and lung metastasis. We decided to perform transcoronary chemoembolization therapy. Informed consent was obtained. The second RV branch was selected as a major feeding artery using a normal guiding catheter and wire of percutaneous transluminal coronary angioplasty, and the anticancer agent copoly (styrenemaleic acid) conjugated to neocarzinostatin (SMANCS), 4 mg, which was dissolved in an oil contrast medium (lipiodol, 4 mg), and sterilized gelatin sponge 1/5 sheet were injected into the branch through 3F-sized infusion catheters (Venture II; Boston Scientific; Natick, MA). After this treatment, she could be weaned from oxygen inhalation, and the RV pressure by catheter decreased from 67 to 40 mm Hg with no complications. All feeding arteries were embolized 1 week later. Transient ST-segment elevation in II, III, aVF, and V4R without chest pain, and elevation of serum creatine phosphokinase levels (582 IU/L) were observed immediately after embolization. However, there were no detrimental effects such as hypoxia, elevation of venous pressure, or poor RV contractility. Tumor stain diminished in the right coronary angiogram (Fig 3), and tumor size also diminished in right atrioventriculography. The RV dimension, which was measured in the parasternal long-axis view, decreased from 48.8 to 30.8 mm. Directly measured RV pressure and estimated RV systolic pressure value by TTE decreased to 38/6 mm Hg and 40 mm Hg, respectively; the RV-pulmonary arterial systolic pressure gradient also decreased from 51 to 18 mm Hg, and oxygen was no longer required. There was RV free-wall akinesis before the therapy, whereas there was a striking recovery of RV free-wall contraction after the therapy. The RV ejection fraction increased from 22 to 49%. RV tumor did not develop during the 3-month follow-up period since discharge.
Discussion
RV metastasis is extremely rare in cases of HCC. Steffens et al2 reported the first echocardiographic diagnosis of metastatic HCC to the right ventricle. The incidence of HCC in Japan is about 10 times as high as in Western countries, and such an extension is encountered more frequently. Nevertheless, RV metastasis of HCC was reported in only three cases from 1986 to 1997 in Japanese literature.3 This is the first report of transcoronary chemoembolization therapy for the relief of RV outflow obstruction derived from HCC. Presumably, HCC metastasized to the RV by coronary embolism via arterial systemic spread because there was no mass lesion within the right atrium. In this case, RV tumor associated with HCC is fed from tumor vessels derived from the RV branches. Therefore, transcoronary chemoembolization therapy is considered to be an effective treatment against metastatic RV tumor. We selected zinostatin, lipiodol, and sterilized gelatin sponge as agents of intracoronary injection, because the pathologic findings were those of HCC obtained from specimens of RV tumor. SMANCS, a chemical conjugate of copoly (styrenemaleic acid) with neocarzinostatin, would be the most effective form of the drug against HCC. The advantage of this polymeric drug (SMANCS) is the most effective tumor targeting with the least systemic side effects and very prolonged slow release.4
Selected Reports
Figure 3. Right coronary angiogram demonstrating no tumor stain 2 weeks after transcoronary chemoembolization.
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Immediately after transcoronary chemoembolization therapy, hemodynamic and clinical improvement were observed. The mechanism of the diminution of metastatic RV tumor is thought to be necrosis. Transient ST-segment elevation in II, III, aVF, and V4R without chest pain and elevation of serum creatine phosphokinase levels (582 IU/L) were observed immediately after embolization, indicating RV free-wall ischemia secondary to RV branch occlusion. Therefore, the mechanism of immediate gradient reduction could be explained by reduced mass size due to lack of feeding artery flow, as well as by dilatation of RV outflow. There were no detrimental effects such as hypoxia, elevation of venous pressure, or poor RV contractility for the present patient after chemoembolization. RV tumor did not develop during the 3-month follow-up period since discharge. We believe that transcoronary chemoembolization therapy allows palliation of otherwise intractable symptoms caused by RV obstruction with resultant extension of the patients life.
found in significant numbers in the pleural fluid. Clinicians should be aware that the altered immune responses that occur in HIV-infected patients may affect the cytologic profile of tuberculous pleural effusions, and they should be cautious not to exclude this diagnosis based solely on the presence of mesothelial cells in the fluid. (CHEST 2000; 117:289 291)
Key words: mesothelial cells; pleural effusions; tuberculosis Abbreviations: AFB acid-fast bacilli; IL interleukin; LDH lactate dehydrogenase; TB tuberculosis; Th Thelper
References
1 Culpepper AL, von Hamm E. Primary carcinoma of the liver with extensive metastasis to the right heart, and tumorthrombosis of the inferior vena cava. Am J Cancer 1934; 21:355362 2 Steffens TG, Mayer HS, Das SK. Echocardiographic diagnosis of a right ventricular metastatic tumor. Arch Intern Med 1980; 140:122123 3 Tabata Y, Nakato H, Nakamura Z, et al. Metastatic cancer to the heart: a clinicopathological analysis of 64 autopsy cases. Respir Circ 1983; 31:569 573 (in Japanese) 4 Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res 1986; 46:6387 6392
paucity of mesothelial cells. It has been postulated that the relative absence of mesothelial cells was secondary to extensive chronic inflammation that either destroyed the mesothelium or covered it with fibrin and inflammatory cells, preventing the exfoliation of mesothelial cells into the pleural cavity.1 In HIV-infected tuberculosis (TB) patients, the immunopathogenicity could alter the host response and the pathologic presentation may be different from that of immunocompetent hosts. We have experienced three cases of tuberculous pleural effusions with remarkable numbers of mesothelial cells present.
an T uberculous pleural effusion is usually characterized asand exudate, with features of lymphocyte predominance
Case 1
A 48-year-old black woman presented with a 2-month history of progressive shortness of breath associated with fever and weight loss. Four days prior to admission, she developed a cough productive of whitish sputum. Physical examination revealed dullness to percussion and decreased breath sounds at both bases. A chest radiograph revealed bilateral pleural effusions. Thoracentesis was performed, in which 1,000 mL of pleural fluid was withdrawn. Analysis of the pleural fluid revealed the following: glucose, 67 mg/dL; protein, 6.5 g/dL; lactate dehydrogenase (LDH), 1,162 IU/L; pH, 7.49; adenosine deaminase, 159.6 IU/L (by colorimetric testing; [normal, 40 IU/L]); WBC count, 133 cells/ L (differential of neutrophils 20%, lymphocytes 50%, basophils 1%, mesothelial cells 26%), and RBC count, 13,687 cells/ L. The results of microbiological studies including bacterial culture, fungal culture, and acid-fast bacilli (AFB) smear were all negative in the pleural fluid. The patient was admitted, and three induced sputum samples disclosed negative AFB smear. The patient was found to be HIV infected, with a CD4 count of 86 cells/ L. The patient underwent thoracoscopic pleural biopsy, which revealed caseating granulomas and positive staining for AFB. This biopsy specimen and one culture of sputum collections became positive for Mycobacterium tuberculosis later on.
Mesothelial Cells in Tuberculous Pleural Effusions of HIV-Infected Patients*

Denis Jones, MD; Thomas Lieb, MD; Masahiro Narita, MD; Elena S. Hollender, MD; Arthur E. Pitchenik, MD; and David Ashkin, MD
The scarcity of mesothelial cells is a well-known characteristic of tuberculous pleural effusions. We report three HIV-infected patients with tuberculous pleural effusions, in which mesothelial cells were
*From the Department of Medicine (Dr. Jones), Division of Pulmonary and Critical Care Medicine (Drs. Lieb and Pitchenik), University of Miami, Miami; and A. G. Holley State Hospital (Drs. Hollender, Narita, and Ashkin), Lantana, FL. Manuscript received March 1, 1999; revision accepted August 17, 1999. Correspondence to: David Ashkin MD, A. G. Holley State Hospital, 1199 W. Lantana Rd, Lantana, FL 33462
Case 2
A 39-year-old man known to be HIV infected was admitted with a persistent cough and progressive weight loss. Bilateral infiltrates were noted on chest radiograph. He was severely immunosuppressed, with a CD4 count of 19 cells/ L and a viral load of 160,000 copies/mL (HIV RNA by polymerase chain reaction). The sputum was positive for AFB, and the diagnosis of TB was confirmed by a nucleic acid amplification test and later culture. Treatment was started with the usual four-drug regimen
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(isoniazid, rifampin, pyrazinamide, and ethambutol), but he failed to improve clinically. He was subsequently found to have multidrug-resistant TB, and he was admitted to A. G. Holley State Hospital. On admission, a large pleural effusion was documented. Analysis of the pleural fluid revealed an exudate with total protein of 2.5 g/dL (serum, 4.8 gm/dL); LDH, 135 IU/L; and pH of 7.4. The cytology showed reactive mesothelial cells, and the differential cell count was as follows: 7% neutrophils, 22% lymphocytes, 60% macrophages, and 10% mesothelial cells. The culture of the pleural fluid grew M tuberculosis. The patient was treated with a combination of six anti-TB medications and was started on an antiretroviral regimen. His condition gradually improved over the course of several weeks of inpatient treatment.
tuberculosis, and the patient was started on anti-TB drugs. He responded well to treatment, and there was no recurrence of the pleural effusion.
Discussion
The paucity of mesothelial cells in tuberculous-related pleural effusions was described by Spriggs and Boddington in 1960.2 They examined 65 specimens of pleural fluid from 59 patients with tuberculous pleural effusions and found that in no instance did the number of mesothelial cells exceed 2.5 per 1,000 WBCs.2 These findings were later supported by Yam in 1967,1 who postulated that the relative absence of mesothelial cells was secondary to extensive chronic inflammation that either destroyed the mesothelium or covered it with fibrin and inflammatory cells, preventing the exfoliation of mesothelial cells into the pleural cavity. The use of mesothelial cell counts has subsequently become standard practice when considering TB in the differential diagnosis of a pleural effusion. On the other hand, there have been reports of numerous mesothelial cells in tuberculous pleural effusions in patients not known to be HIV infected.3,4 These observations were partly ascribed to an early developing phase of tuberculous effusion when the inflammatory process is acute and not extensive. However, there were some cases in which serial thoracentesis revealed persistently increased number of mesothelial cells, but their HIV status was unknown. Ellison et al5 found higher numbers of mesothelial cells in HIV-infected patients with TB-related pleural effusions. In our series, we report three patients with TB pleuritis who had high mesothelial cell counts in their pleural fluid. All the patients in this series were HIV infected with CD4 counts ranging from 19 to 86 cells/ L. The pathogenesis of numerous mesothelial cells in TB pleural effusion in HIV-infected patients has yet to be elucidated; however, this phenomenon may result from an alteration in the immune response in HIV-infected patients. The host response to M tuberculosis is known to be responsible for granuloma formation in immunocompetent subjects. This response is believed to be mediated by CD4 T-cell clones of the T-helper (Th) 1 type. Th1-type cells are important mediators of delayed-type hypersensitivity responses and are involved in activation of macrophages. The Th1-type pattern of cytokine secretion includes tumor necrosis factor- , interferon- , interleukin (IL)-2, and IL-12. However, with HIV infection and its progression, a shift from a Th1-type to a Th2-type pattern is believed to occur.6 9 Th2-type cells preferentially support IgE and IgG1 synthesis and are mediators of eosinophilia. One could postulate that the characteristic granulomatous inflammation and fibrosis of TB pleuritis may be reduced or may not occur with a shift from a Th1-type to a Th2-type pattern; this could then lead to the exfoliation of mesothelial cells into the pleural cavity. Further evidence of an altered immune response comes from a series published by Trejo et al,10 who found a significant decrease in the number of monocytes in TBSelected Reports
Case 3
A 57-year-old man with a history of being HIV infected presented to the hospital with weight loss, fevers, and cough. He was found to have a unilateral pleural effusion on admission chest radiograph, and a diagnostic pleural tap was performed. The fluid was an exudate with total protein of 5.8 g/dL; LDH, 901 IU/L; and pH of 7.48. Staining for AFB was negative. The cytology was evaluated using the cell block and smear techniques and showed prominent mesothelial cells including acute and chronic inflammatory cells (the precise differential was not done; Fig 1). His CD4 count was 73 cells/ L, and he was not taking any antiretroviral medication. The pleural fluid subsequently grew M
Figure 1. A cytology slide demonstrating numerous mesothelial cells in the pleural fluid of an HIV-infected patient with cultureproven tuberculous pleuritis (case 3; Papanicolaou stain, original 400).
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related pleural effusions of HIV-infected patients. Interferon- appears to enhance the production of chemokines such as macrophage inflammatory protein-1 and monocyte chemotactic factor-1 from pleural mesothelial cells, whereas IL-4 inhibits expression of chemokines11; therefore, a shift from a Th1-type to a Th2-type pattern could downregulate chemokine expression in pleural mesothelial cells and subsequent suppression of monocyte/macrophage recruitment. In summary, these cases serve to remind clinicians that TB remains a diagnostic possibility in HIV-infected patients even in the presence of significant numbers of mesothelial cells in the pleural fluid. Further studies are warranted to clarify the issue of mesothelial cells in tuberculous pleural effusions in HIV-infected patients
6 7
References
1 Yam LT. Diagnostic significance of lymphocytes in pleural effusions. Ann Intern Med 1967; 66:972982 2 Spriggs AI, Boddington MM. Absence of mesothelial cells from tuberculous pleural effusions. Thorax 1960; 15:169 171 3 Lau KY. Numerous mesothelial cells in tuberculous pleural effusions. Chest 1989; 96:438 439 4 Santos-Sastre S, Barrot-Cortes E, Barragan-Marquesz, FL. 10
11
Mesothelial cells and tuberculous pleuritis [letter]. Chest 1990; 98:518 Ellison E, Lapuerta P, Martin SE. Cytologic features of mycobacterial pleuritis: logistic regression and statistical analysis of a blinded, case controlled study. Diagn Cytopathol 1998; 19:173176 Shearer GM. HIV-induced immunopathogenesis. Immunity 1998; 9:587593 Carter LL, Dutton RW. Type 1 and type 2: a fundamental dichotomy for all cell subsets. Curr Opin Immunol 1996; 8:336342 Clerici M, Hakim FT, Venzon DJ, et al. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest 1993; 91:759 765 Shearer GM, Clerici M. Type 1 and type 2 responses in HIV infection and exposure. In: Gupta S, ed. Immunology of HIV infection. New York, NY: Plenum Press, 1996; 229 241 Trejo O, Giron JA, Perez-Guzman E, et al. Pleural effusion in patients infected with the human immunodeficiency virus. Eur J Clin Microbiol Infect Dis 1997; 16:807 815 Mohammed KA, Nasreen N, Ward MJ, et al. Helper T cell type 1 and 2 cytokines regulate C-C chemokine expression in mouse pleural mesothelial cells. Am J Respir Crit Care Med 1999; 159:16531659
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Inhaled Heroin-Induced Status Asthmaticus* : Five Cases and a Review of the Literature James Cygan, Matthew Trunsky and Thomas Corbridge Chest 2000;117; 272-275 DOI 10.1378/chest.117.1.272 This information is current as of October 14, 2011
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/117/1/272.full.html References This article cites 16 articles, 3 of which can be accessed free at: http://chestjournal.chestpubs.org/content/117/1/272.full.html#ref-list-1 Cited Bys This article has been cited by 1 HighWire-hosted articles: http://chestjournal.chestpubs.org/content/117/1/272.full.html#related-urls Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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Inhaled Heroin-Induced Status Asthmaticus* : Five Cases and a Review of the Literature

Table 1Reported Cases of Asthma Exacerbation Associated With Inhaled Opiates*

No. of History of Patients Asthma 3 3 1 1 1 1 Y, N, N Y, Y, Y Y N N N

A Case of Cigarette SmokingInduced Acute Eosinophilic Pneumonia Showing Tolerance*

The Role of BAL in the Diagnosis of Pulmonary Mucormycosis*

Results Clinical Findings

Materials and Methods

Table 1Demographic Data of the Patients*

Table 2Diagnostic Modalities*

Figure 3. Histology of case 1 showing typical features of RBILD.

Table 1PFT Results

Esophageal Perforation After Sequential Double-Lung Transplantation*

Mesothelial Cells in Tuberculous Pleural Effusions of HIV-Infected Patients*

CHEST / 117 / 1 / JANUARY, 2000

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