cyclophosphamide pneumonitis - thorax

Thorax, 1978, 33, 89-93

Cyclophosphamide pneumonitisGENE J. MARK, A. LEHIMGAR-ZADEH, AND BRUCE D. RAGSDALE

From the Department of Pathology, Massachusetts General Hospital, Boston, Mass, and theRenal and Pathology Services, US Public Health Service Hospital, Staten Island, NY, USA

Mark, G. J., Lehimgar-Zadeh, A., and Ragsdale, B. D. (1978). Thorax, 33, 89-93.Cyclophosphamide pneumonitis. Cyclophosphamide can rarely cause interstitial pneumonitisand fibrosis. Although it has been reported previously in patients being treated for lymphoma,it occurred in this case in a man under treatment for glomerulonephritis. The temporal sequenceof the respiratory insufficiency and the histopathology, when compared to the previous examplesin the literature, suggest that cyclophosphamide was aetiologically responsible for the lungdisease. There may be an interval of one or more months after discontinuation ofcyclophosphamide therapy before clinical or radiological improvement occurs.

Cyclophosphamide is an alkylating agent which isutilised for its anti-neoplastic and anti-inflam-matory properties. Inflammation or fibrosisinduced by cyclophosphamide seems paradoxical.Nevertheless, a few reports indicate that cyclo-phosphamide may induce interstitial pulmonaryinflammation and fibrosis. We report a patient inwhom interstitial pneumonitis occurred duringadministration of cyclophosphamide and whosesymptoms and radiographs improved when thedrug was stopped.

Case report

A 25-year-old white man, who had previously beenhealthy, was admitted to hospital in March 1975because of nephrotic syndrome. Renal biopsyshowed membranoproliferative glomerulonephritis(dense deposit variety) with crescent formationand necrosis. Systemic blood pressure and renalfunction were normal and he was discharged onno treatment. During outpatient follow-up pro-gressive systemic hypertension required treatmentfirst with hydrochlorthiazide and later withmethyldopa and hydralazine. The nephrotic syn-drome persisted, and renal function, as measuredby endogenous creatinine clearance, deterioratedfrom 125 ml/min in March to 20 ml/min inOctober, when he was readmitted to hospital. Thepatient was started on a combination of cyclo-phosphamide, 2-5 mg/kg/day, prednisone, 40 mg/day, dipyridamole, heparin, and frusemide.He was readmitted on 17 December, 1975 be-

cause of the sudden onset of dry cough, dyspnoea,

fever, and chills. Physical findings were limitedto a temperature of 1020F, tachypnoea, andcrackles over the left posterior chest. A chestradiograph on admission showed patchy reticulardensities in the left lower zone. The white cellcount was 4 5X 109 per 1 with a normal dif-ferential. Arterial blood gases on room air werepH 7-38, Po2 37 mmHg, and Pco2 24 mmHg.Repeated cultures of sputum and blood werenegative. Cyclophosphamide and dipyridamolewere discontinued on admission and prednisonewas gradually reduced over one month. Fever per-sisted despite the administration of cephalothinand gentamicin for one week. Febrile agglutininswere negative. Acute and convalescent sera forviral and fungal antibody titres were not diag-nostic. Antinuclear factor, cold haemagglutinins,and Coombs's test were negative. Serial chestradiographs showed an increasingly prominentreticular pattern, which gradually spread to in-volve all zones (Fig. 1). On 14 January, 1976,with the patient still febrile, dyspnoeic, and hy-poxaemic, methyldopa and hydralazine werediscontinued. Frusemide was now the only medica-tion being given. Pulmonary function tests showedsevere restriction and reduction in transfer factor.Oxygen was not administered. An open lungbiopsy was performed on 23 January, 1976. With-out any treatment the temperature graduallydecreased and became normal on 9 February,1976. Renal function deteriorated further andhaemodialysis was begun.During the year following lung biopsy the

patient did well on haemodialysis and had no89

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Gene J. Mark, A. Lehimgar-Zadeh, and Bruce D. Ragsdale

Fig. 1 Chest radiograph fourdays before lung biopsy. Reticularinfiltrates are most prominent atthe hila and extend to all lungfields.

Fig. 2 Low magnification of lung biopsy. The architecture is obscured by anextensive intra-alveolar histiocytic infiltrate. Interalveolar septa are uniformlythickened (Haematoxylin and eosin X 125).

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Cyclophosphamide pneumonitis

respiratory symptoms. Chest radiographs showedgradual clearing. Repeat pulmonary functionstudies showed a marked improvement in therestrictive disease and a slight increase in transferfactor.

HISTOLOGICAL FINDINGSThe lung biopsy disclosed that approximately50% of the alveoli and alveolar ducts were filledwith desquamated granular pneumocytes andhistiocytes (Fig. 2). These histiocytes hadabundant vacuolated cytoplasm and contained agranular brown dust pigment that stainednegatively by the periodic acid-Schiff reaction forglycoprotein and the Prussian blue reaction foriron. Among the intra-alveolar histiocytes weresome polymorphonuclear leucocytes and red bloodcells and a small amount of fibrin. Bronchiolarlumens, containing only a few cells, appearedprominent against the background of obscuredalveoli (Fig. 3). The interalveolar septa were allthickened to 20-60 microns, due in part to aninfiltrate of lymphocytes and plasma cells and inpart to collagen, as demonstrated by the vanGieson connective tissue stain. Collagen was not

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increased in the interlobular septa or aroundvessels. Granular pneumocytes were uniformlyhyperplastic. They had enlarged, angular, hyper-chromatic nuclei with moderate pleomorphismand an occasional prominent nucleolus. Cytoplasmwas abundant and eosinophilic, giving these typeII pneumocytes a cuboidal appearance (Fig. 4).The pulmonary vessels, major bronchi, and

pleura were normal.Electron microscopy confirmed the hyperplasia

of the type IL pneumocytes, the interstitial inflam-mation, and the production of new interstitialcollagen. Within the interstitium were occasionalmacrophages, which contained within their cyto-plasm scroll-like inclusions, composed of parallelor convoluted tubular structures, which werebounded by a multilayered outer membrane.Cross sections of the tubular structures weresimilar to cross sections of cilia, but other defini-tive characteristics of cilia could not be identified.Endothelial cells were swollen. No viral inclusionwas present.The biopsy specimen of lung was cultured in

various microbiological media. No aerobic oranaerobic bacteria, mycobacteria, fungi, orviruses could be isolated from it.

4~~~~~~~~

Fig. 3 Respiratory bronchiole with intact ciliated columnar epithelium (right).Lymphocytes aggregate adjacent to the smooth muscle of the bronchiole anddiffusely infiltrate the interalveolar septa (H and E X480).



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Fig. 4 High magnification of interalveolar septa. Alveolar lining cells have angularhyperchromatic nuclei and densely staining cytoplasm (H and E X480).

Discussion

Many drugs can elicit undesired pulmonary re-actions (Rosenow, 1972). In some instances thesereactions may be on the basis of hypersensitivity.In other instances, as with some antineoplasticagents, the drugs may exert part of their effectmore directly by interfering with the metabolicfunction of normal cells. Cyclophosphamide canproduce several well-known adverse effects, in-cluding suppression of bone marrow, mucosalulceration with stomatitis and colitis, haemor-rhagic cystitis with bladder fibrosis, and gonadalsuppression. Pneumonitis attributable to cyclo-phosphamide therapy is much less common.The five best documented records of pulmonary

interstitial inflammation and fibrosis attributableto cyclophosphamide were in patients being treatedfor lymphoma. Andre et al. (1967), Dohner et al.(1972), Topilow et al. (1973), and Patel et al. (1976)all reported adults who developed pulmonarysymptoms and interstitial infiltrates. Two of thepatients died of respiratory insufficiency, and theother two patients recovered with disappearanceof the infiltrates after discontinuation of cyclo-phosphamide. Rodin et al. (1970) reported a 3-

year-old child who developed lung infiltrates anddied in respiratory distress. Duration of therapywith cyclophosphamide in these five patients wasfor a period between one and 36 months. Thiscompares with two months of therapy in the pres-ent case. In these five earlier cases there was aninterval of between one and seven months fromcessation of therapy to the onset of sufficientrespiratory distress either to prompt open lungbiopsy or to cause death. This interval suggeststhat the inflammatory stimulus provided by cyclo-phosphamide continues for one or more monthsafter the drug has been withdrawn. In the threepatients who died in respiratory failure, thisstimulus continued between three and sevenmonths. In the other two patients and in thecurrent report, the stimulus ceased and thepatients recovered.Other authors have mentioned an association of

histologically proven interstitial pneumonitis withcyclophosphamide therapy but associated withPneumocystis carinii infection, with therapy byadditional chemotherapeutic agents known toproduce pneumonitis, or with oxygen therapy(Karnofsky, 1967; Meschan et al., 1969; Sohier andNash, 1972; Stutz et al., 1973). Retrospective inter-

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pretation of the significance of the role of cyclo-phosphamide in these cases is difficult. Threeexamples of the association are alluded to in areview article but are not further described(Rosenow, 1972). Pulmonary oedema after intra-venous administration of cyclophosphamide wasalso reported (Maxwell, 1974).The histopathology of the cases previously re-

ported is remarkably consistent. It includesmoderate degrees of interstitial and subpleurallymphoid aggregates with only small numbers ofneutrophils or eosinophils, hyperchromatic andpleomorphic granular pneumocytes, and fibro-blastic proliferation, resulting in both septalwidening and intra-alveolar fibrosis with segmen-tal obliteration of pulmonary architecture. Thehistopathology described and depicted in thesecases, including the abnormal nuclei of thegranular pneumocytes, is seen again in the presentcase.

Because of the large number of known or sus-pected causes of interstitial pneumonitis, the link-ing of drug to pneumonitis in a causal relationshipmust be made with care. The histopathology ischaracteristic but not specific, and proof of therelationship must include the circumstantialevidence of drug therapy followed by pneumonitisand cessation of drug therapy followed by dis-appearance of pneumonitis, after other knowncauses of pneumonitis have been excluded. Thepresent case fulfils this criterion in linkingcyclophosphamide to interstitial pneumonitis andfibrosis.

Dohner, V. A., Ward, H. P., and Standord, R. E.(1972). Alveolitis during procarbazine, vincristiiieand cyclophosphamide therapy. Chest, 62, 636-639.

Karnofsky, D. A. (1967). Late effects of immuno-suppressive anticancer drugs. Federation Proceed-ings, 26, 925-932.

Maxwell, I. (1974). Reversible pulmonary edemafollowing cyclophosphamide treatment. Journal ofAmerican Medical Association, 229, 137-138.

Meschan, I., DeArmas, C. R., and Scharyj, M. (1969).Adult bronchopulmonary dysplasia-the similarityin roentgen and histopathologic appearance be-tween some cases of oxygen toxicity, radiationpneumonitis, and post-cytotoxic nonspecificbronchopneumonia. Radiology, 92, 612-615.

Patel, A. R., Shah, P. C., Rhee, H. L., Sassoon, H.,and Rao, K. P. (1976). Cyclophosphamide therapyand interstitial pulmonary fibrosis. Cancer, 38,1542-1549.

Rodin, A. E., Haggard, M. E., and Travis, L. B.(1970). Lung changes and chemotherapeutic agentsin childhood. A merican Journal of Diseases ofChildren, 120, 337-340.

Rosenow. E. C. III (1972). The spectrum of drug-induced pulmonary disease. A nnals of InternalMedicine, 77, 977-991.

Sohier, W. D., and Nash, G. (1972). Case records ofthe Massachusetts General Hospital. New EnglandJournal of Medicine, 286, 1405-1411.

Stutz, F. H., Tormey, D. G., and Blom. J. (1973).Non-bacterial pneumonitis with multidrug anti-neoplastic therapy in breast carcinoma. CanadianMedical Association Journal, 108, 710-714.

Topilow, A. A., Rothenberg, S. P., and Cottrell, T. S.(1973). Interstitial pneumonia after prolonged treat-ment with cyclophosphamide. American Review ofRespiratory Disease, 108, 114-117.

References

Andre, R.. Rochant, H., Dreyfus, B., Duhamel, G.,and Pechere, J. C. (1967). Fibrose interstitiellediffuse du poumon au cours d'une maladie deHodgkin traitee par des doses elevees d'endoxan.Bulletin et Memoires de la Societe Medicale desH6pitaux de Paris, 118, 1133-1141.

Requests for reprints to: Dr. G. J. Mark, JamesHomer Wright Pathology Laboratory, MassachusettsGeneral Hospital, Boston, Massachusetts 02114, USA.

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