Chlorambucil-Associated Pneumonitis

of elevation of total creatine kinase activity. 8 The source for these atheroemboli is unknown, but most probably is the atherosclerosis of the patient's native coronary arteries or aorta. The demonstration of coronary artery atheroemboli by endomyocardial biopsy in our case adds to the growing list of indications for endomyocardial biopsy. We suggest that similar future cases of worsening congestive heart failure in patients with severe coronary atherosclerosis and a history of past or present interventional procedures might benefit from right (or left) heart catheterization and endomyocardial biopsy to rule out such emboli. Sampling error could be reduced by ensuring that an adequate number ofbiopsy specimens are obtained, as has been shown for cardiac transplant rejection biopsies.9 General criteria for the pathologic diagnosis of arterial embolism have been formulated.10 Although atheromatous emboli have been shown to lyse rather quickly, 11 and would not be amenable to embolectomy, their recognition in biopsy specimens would nevertheless allow for more informed treatment of the patient, possibly by institution of anticoagulant therapy. for example, to treat any concomitant fibrin-platelet microemboli released from the same site as the atheromatous debris. Future studies using endomyocardial biopsy might, therefore, better delineate the role of atheromatous microemboli both in worsening of congestive heart failure in end-stage ischemic heart disease patients and in the generation of ventricular arrhythmias in patients with coronary artery atherosclerosis.5•11 REFERENCES 1 Virchow R. Ud:>o:r c:apillare ~rnboli~. VirchOWli Arch Pathol Anat

1856; 6:307 2 Prize! KR. Hutchins GM. Bulkley BH. Coronary artery embolism and myocardial infarction: a clinicopathologic study of 55 patients. Ann Intern Med 1978; 88:155-61 3 Hamman L. Coronary embolism. Am Heart J 1941; 21:401-22 4 Roberts WC. Coronary embolism: a review of causes, consequences, and diagnostic considerations. Cardiovasc Med 1978; 3:699-710 5 Atkinson JB, Fonnan MB. Vinnani R. Emboli and thrombi in coronary arteries. In: Virmani R. Forman MB, eds. Nonatherosclerotic ischemic heart disease. New York: Raven Press, 1989; 355-85 6 Yutani C, lmakita M, Ishibashi H, Katsuragi M. Fujita H. Coronary artery embolism with special reference to procedures as the source. Mod Patholl992; 5:244-49 7 Pifarre R. Grieco J, Sullivan HJ. Scanlon PJ, Johnson SA, Gunnar RM. Coronary embolism: surgical management. Ann Thorac Surg 1980; 30:564-68 8 Dillon MC, Calbreath OF, Dixon AM, et al. Diagnostic problem in acute myocardial infarction: CK-M B in the absence of abnonnally elevated total creatine kinase levels. Arch Intern Med 1982; 142:33-8 9 Zerbe TR, Arena V. Diagnostic reliability of endomyocardial biopsy for assessment of cardiac allograft rejection. Hum Pathol 1988; 19:1307-14 10 Oeser J. Zur Coronarembolie im Rechtsmedizinischen Sektionsgut. Z Rechtsmedizin 1977; 79:311-17 11 Stehbens WE. Relationship of coronary artery thrombosis to myocardial infarction. Lancet 1985; 2:639-42

834

Chlorambucil-Associated Pneumonitis* Brune Cll1-ftani, M.D.; Arnaud Jaccard, M.D.; Dominique Israel-Biet, M.D.; Loub-Jean Couderc, M.D. ; Jacques Frija, M.D. ;and Jean-Pierre Clauvel, M.D.

A patient developed an intentitial pneumonitis while receiving chlorambucil for a chronic lymphocytic leukemia (cumulative dose, 8,340 mg). Withdrawal of drug treatment was followed by rapid improvement in the clinical condJtion. Bronchoalveolar lavage showed a T-lymphocytic alveolitis, whereas blood lymphocytes were predominantly of the 8 phenotype. The Tlymphocytic alveolitis persisted 6 weeks after drug therapy cessation with a predominant CD8 +phenotype, as observed in some hypersensitivity pneumonitis induced by drugs. (Cheat; 105: 634-36)

I BAL =broocboalveolar lavage; CLB = chlorambucil I (CLB) is an alkylating agent widely used in C hlorambucil the treatment oflymphoproliferative diseases. Although the pulmonary toxicity of other alkylating agents such as busulfan and cyclophosphamide is not rare, only 13 cases of CLB-induced pulmonary disease have been reported in the literature.1·7 We report the first case, to our knowledge. of CLB pneumonitis with documented bronchoalveolar lavage (BAL) cell data. The results suggest a cell-mediated immunologic mechanism in the pathogenesis of this iatrogenic pneumonitis. CASE REPORT

A48-year-old male nonsmoker was admitted to the hospital because of a 2-week history of nonproductive cough and exertional dyspnea. He had been treated with CLB from 1985 to 1988 and again since July 1991 for 8 months for chronic lymphocytic leukemia. The cumulative dose of CLB ingested was 8,340 mg. He did not receive any other treatment. Anamnesis did not detect any exposition to inhaled antigens. At the time of hospital admission, the patient was in good general condition; his temperature was 38°C. Physical examination revealed bibasilar crackles. Achest radiograph, which was nonnal 3 years earlier, disclosed a diffuse reticulonodular pattern. High-resolution computed tomography of the chest disclosed an important profusion of micronodules diffusely and homogenously disseminated in both lungs (Fig 1). No mediastinal lymphadenopathy was found. Arterial blood gas analysis detected severe hypoxemia (50 mm Hg) with hypocapnia (30 mm Hg) while breathing room air. The blood white cell count was 17.4 x 10"/L with 12.2 X I()'IlL lymphocytes. Lactate dehydrogenase level was nonnal, and no other biologic abnonnality was present. Serologic testing for Mycoplasma, Chlamydia, Legionella, and HIV-1 was negative. Results of flberoptic endobronchical examination were normal. The BAL cell analysis disclosed a high cell count with marked lymphocytosis (1,000 X 103 cells per milliter with 68 percent lymphocytes). Speciflc stains and cultures for pathogens were negative. Hemosiderin-laden macrophage stains were negative. Diagnosis ofCLBassociated lung disease was suspected and the drug treatment was withdrawn. Within 24 h, apyrexia was observed and clinical condition rap"From the Immuno-Hematology Unit (Drs. Crestani, Jaccard, and Clauvel) and the Radiology Unit (Dr. Frija), HOpital Saint Louis, Paris, France; the Pulmonology Unit (Dr. lsnU!l-Biet), HOpital Laennec, Paris, France; and the Pulmonology Unit (Or. Couderc), HOpital Foch, Suresnes, France. Chlorambucli-asaociated Pneumonitis (CffiBtsnl et al)

larly in the treatment of chronic lymphocytic leukemia.'·' The clinical and radiographic features are nonspecific and usually include cough, dyspnea of subacute onset, fever, and anorexia. Bibasilar crackles are common. Chest radiographs reveal a diffuse bibasilar reticulonodular pattern. A restrictive ventilatory defect and a marked reduction in the Dco have been reported. 4 ~ In the previously reported cases, diagnosis was made on the basis of the pulmonary histopathologic results. Findings are similar to those associated with other alkylating agents, involving hyperplasia of alveolar lining cells with marked nuclear atypia along with a mononuclear cell interstitial infiltrate and focal interstitial fibrosis.•.s In a few cases, pulmonary disease developed while the patients rec:eived a combination of CLB and corticosteroids. 2·3·6·' There was no correlation between the cumulative oral dose of the medication and the development of lung toxicity since total doses ranged between 2,000 mg' and 7,500 m!f and treatment duration ranged from 6 months to 3.5 years.

FrcuRE l. High-resolution computed tomography of the right lung showing numerous micronodules homogeneously disseminated into the lung. idly improved without any treatment. Six days after withdrawal of the drug thempy. the blood gas values and the chest radiogr<~ph had returned to nonnal. The lung volumes, as measured by spirometry, were within the nonnal range, whereas the diffusing capa<.ity of carbon monoxide was slightly reduc:ed (68 percent of predic:ted value). Six weeks later, while the clinic-al c:ondition and the chest radiograph were nonnal, a second BAL was perfom1ed. The BAL cell results are shown in Table l. A marked alveolar T lymphocytosis, predominantly of the CDS + phenotype. WdS found. contr<~Sting with the peripheral blood B lymphocytosis. Resumption of drug therapy was not attempted because this proc-edure \V'dS judged to be potentially harmful. DISCUSSION

Pleuropulmonary damage associated with CLB has been reported in 13 cases since the original report of Rubio et aJI in 1972, despite its wide use as an antineoplastic agent, particuTable 1-Bronchoalveolar Lavage CeU Data• BAL Cell Population At Hospital Admission Total t.-ell number X 10'/ml Macrophages,% Lymphocytes, % Neutrophils, % Eosinophils, %

6wk After CLB Cessation

1.000 24 68 4 4

980 27 71

2 0

Lymphocyte Phenotyping (6 wk After CLB Cessation)

B lymphocytes, % T lymphocytes, % CD4+,% CDS+,% CD4+/CD8+ mtio

Blood

Bal

89 7

95

56 44 1.27

*CLB =chlorambucil; BAL = bronchoalveolar lavage.

0.2 32 62 0 .51

In our patient, CLB-induced interstitial pneumonitis seems likely. First, the rapidly favorable outcome without specific treatment and the BAL lymphocyte phenotyping ruled out pulmonary involvement by the chronic lymphocytic leukemia. Second, neither infectious cause nor any systemic disease c:ould be detected on the basis of clinical and biologic data. Finally, the patient received no other medication and there was no exposition to inhaled antigens. This pneumonitis had the clinical, radiologic, and functional features of hypersensitivity pneumonitis. Withdrawal of CLB therapy was immediately followed by relief of symptoms arid clearing of chest radiographs without the need for steroids. The BAL cell analysis gave results similar to those obtained in hypersensitivity pneumonitis due to inhalation of organic dusts"

or to treatment with other drugs,9•10 namely, lymphocytosis and a decrease in the helper/suppressor (CD4/CD8) T-cell ratio. Persistent BAL lymphocytosis 6 weeks after cessation of drug therapy is not surprising in this context.10 In our patient, 16 percent of CD8+ BAL lymphocytes were also HLA-DR-positive, suggesting that they were activated. A substantial proportion of alveolar T lymphocytes have been shown to be activated in organic antigen-induced hypersensitivity pneumonitis. 11 In summary, this patient presented with a CLB-associated interstitial pneumonitis with characteristics of an hypersensitivity pneumonitis. Bronchoalveolar lavage ruled out the pulmonary involvement of chronic lymphocytic leukemia and an infectious process, and suggested the diagnosis of drug-induced pneumonitis. Early diagnosis of CLB-associated interstitial pneumonitis is needed because drug treatment cessation provides resolution of symptoms and possibly inhibits development of irreversible pulmonary fibrosis . REFERENCES

1 Rubio FA. Possible pulmonary effects of alkylating agents. N Eng! J Med 1972; 287:1150-51 2 Rose MS. Busulfan toxicity syndrome eaused byehlor<~mbucil. BMJ 1975; 1:123 3 Refyem 0 . Fatal intrd-alveolar and interstitial lung fibrosis in chlorambucil-treated chronic lymphocytic leukemia. Mt Sinai J Med (NY) 1977; 44:847-51 4 Cole SR. Myers TJ, Klatsky AU . Pulmonary disease with chlommbucil ther<~py. Cancer 1978; 41:455-59 CHEST I 105 I 2 I FEBRUARY, 1994

635

chlonnnhncil. Chest 1979:76:471-73 6 Lane SD. Bes;l EC. Justh G, Joseph RR. Fatal interstitial lung dise:L~I' following high dose t•hloramhucil therupy. Proc Am Soc Clin Ont'OI1979: 20:313 7 Giles FC. Smith MP. Goldstone AH. Chlorambucil lung toxicity. Acta Hat·matol1990: 83:156-58 8 Hirata T. Nagai S. Ohshima S. Izumi T. Comparative study ofTt't'll subsets in BAL fluid patients with hypersensitivity pneumonitis and sart~lidosis. Chest 1982: 82:232 9 Israel-Bid D. Vcnet A. Caubarrere I, Bonan G. Dane! C. Chretien J. t-t al. Bnmchoalveolar lavage in amiodarone pneumonitis: cellular abnormalities and their relevant-e to pathogenesis. Chest 1987; 91:214-19 10 Akoun GM. Cadranel JL. Milleron BJ. D'Ortho MP. Mayaud CM. Bronchoalveolar lavage cell data in 19 patients with drug-associated pneumonitis. Chest 1991 ; 99:91!- 104 II S<' nWn7.ato G. Agll.~tini C. Zamhello R. Trentin L. Chilosi M. Pizzolo G. <'t al. Lung T t't'lls in hypersensitivity pneumonitis: phenotypic and functional analyses. J lmmunol1986: 137:1164-72

Platypnea Related to Constrictive Pericarditis* \Vnltc:r E. Maslwum. M.D.: mul Mnrk E. Si/r.;cmum , M.D.

Platypnea is the rare symptom of dyspnea in the upright positio n, which is r e lieved by assumption of the recumbent position. This symptom has been previously described in association with seve ral conditions, but never with constrictive pericarditis. The authors report the case of a patient with constrictive pericarditis and severe platypnea, which resolved afte r pericardiectomy. (Cheet 1994; 105: 636-31)

P

latypnea is the rare and poorly understood symptom of dyspnea in the upright position. which is relieved by recumben<:y. lt is the conve rse of orthopnea. Platypnea is often seen in conjunction with orthodeoxia, which is arterial desaturation in the upright position. This curious phenomenon was first descrilwd in 1949 by Burchell and a..~sociates. 1 In 1969, Altman and Robin! coined the term "platypnea," which can be t ranslated lit<"mlly to mean "flat breathing." They reported the ca..~e of a patie nt with seve re obstructive lung disease and platypnea who eventually died of respiratory compromise. Since these reports. others have provided examples of platypnea in association with several pathologic states (Table 1). We have studied a patie nt with platypnea and constrictive pericarditis whose platypnea resolved after an extensive pericardiectomy. The association of platypnea and constrictive pericarditis has not, to our knowledge. been previously reported. CASE R EPORT

A 49-yt•ar-old man w·as admitted \vith progressive and severe dyspnea

on ext>rtion and platypnea. Seven years previously. aspergillosis had been dia~nosed. ;md. after episodes of hemoptysis, the patient underwent an unt'Omplic-o~tt>d left upper lobectomy. He was otherwise in fairly ~nod hl·alth and did well postoperatively until6 years later. when he devt'loped rt'('urrent hemoptysis. which necessitated a complete •from the Division of Cardiology. Piedmont Hospital (Or. Silvennan); and Division of Cardiology. Emory University School of Medicine (Drs. Mashman and Silvem1an). Atlanta.

left pneumonectomy. At the time of surgery. pericarditis was discovered, and a 65 percent pericardiectomy was perfonned. In the months that followed, he developed progressive dyspnea on exertion, peripheral edema, and debilitating platypnea. The physical examination was noteworthy for a b ol od pressure of 90nO mm Hg. There was no orthostasis. The neck veins were fully distended at 90 degrees with prominent X and Ydescents. There was dullness to percussion over the left thorax, and the breath sounds were diminished on the left. The heart sounds were nonnal with no gallop. rub, or knock. There was marked hepatomegaly and 2+ pedal edema. The ECG showed a rightward axis of the QRS complex, an incomplete right bundle branch block, and a diffuse nonspecific repolarization abnonnality. Echocardiography revealed nonnallefi ventricular systolic function and mild tricuspid regurgitation. The right atrium and ventricle were mildly dilated, and there were no other valvular abnonnalities. Contrast echocardiography done in both the recumbent and upright positions did not demonstrate a shunt. Arterial blood gas analysis ofspecimens obtained while breathing room air and at an Flo1 of 1.00 showed no significant difference between recumbent and upright postures. Cardiac catheterization revealed elevated and equalized right ventricular, left ventricular, and right atrial end-diastolic pressures with a dip-and-plateau configuration to the ventricular pressure tracings consistent with constriction. There was no oximetric evidence of an intracardiac shunt. Magnetic resonance imaging of the thorax showed a slightly thickened pericardium. The patient underwent a pericardiectomy. At surgery. the heart was found to be encased in a thick fibrous mass of tissue. As much of the pericardium as possible was removed, predominantly over the right side of the heart. The pathologic evaluation revealed extensive fibrosis and small foci of inflammation. Thepatient made a brisk postoperative recovery with resolution of his platypnea and only mild dyspnea on exertion. DISCUSSION

Platypnea is apoorly understood phenomenon. Zone I pulmonary physiology occurs in areas of lung where the pulmonary alveolar pressure exceeds the pulmonary arteriolar pressure. These areas, therefore, are not perfused, which creates small amounts of pulmonary dead space in normal states. The underlying mechanism of platypnea is thought to be an increase in pulmonary dead space when the patient is. u{>right, which leads to an increased ventilation-perfusion (V!Q) mismatch, hyperventilation, increased work of breathing, and breathlessness. This positional change to zone I can be the result of a variety of pathologic states, as mentioned above. Many mechanisms have been proposed to explain the V/Q mismatch. With severe COPD, Altman and Robin2 suggested that there are large areas of the lung with markedly elevated alveolar pressures, which exceed pulmonary arteriolar pressures, such that these areas are not perfused. This effect is more pronounced in the upright position, where gravitational forces exert an influence to diminish pulmonary arteriolar pressure in the upper lung fields. Several authorsM believe that

Table 1- Pathologic Staus Associated With Pwtypnea COPOU Shunts lntracardiac'"' Peripheral'·1 Postpneumonectomy" "'" Interstitial lung disease" Autonomic dysfunction•• Recovery from adult respiratory distress syndrome" Platypnea

Related to Constrictive Pericarditis (Mashman, Silwlrmsn)