Clinical Otolaryngology 1977, 2, 131-137
Pulmonary complications of methotrexate therapy J. J . MANNI AND P . VAN DEN BROEK Department of OtoRhinoLaryngology, University of Nimegen, Philips van Leydenlaan 15, Nqmegen. The Netherlands
'
Accepted for publication I November 1976
MANNIJ.J. & VANDEN BROEKP. (1977) Clinical Otolaryngology 2, 131-137 Pulmonary complications of methotrexate therapy Diffuse interstitial pulmonary infiltration was first reported in I 969, occurring during intermittent methotrexate therapy and it is suggested that it represents an adverse reaction to this drug. Despite the severity of the clinical and radiological changes, the disease is usually self-limiting. An additional case is presented and the previous 28 reported cases of this syndrome are summarized. Since intermittent methotrexate therapy is becoming more widely used, the importance of recognizing this respiratory illness as a possible complicating reaction to the drug is stressed. Keywords methotrexate interstitial pulmonary infiltration laryngeal carcinoma
Introduction
In 1969 Clarysse described a severe, but self-limiting respiratory disease in 7 patients receiving intermittent methotrexate as maintenance therapy for acute lymphoblastic leukaemia.' Since then several authors2-' have reported this acute pulmonary syndrome in patients with leukaemia receiving this therapy to maintain the haematological and clinical remission. More recently this complication has been described in other clinical conditions like psoriasis,' mycosis fungoides and pemphigus," carcinoma of the hypopharynx' ', carcinoma of the lung,' * scirrhous adenocarcinoma of the breast with diffuse bony metastases.' This paper reports a patient receiving intermittent methotrexate therapy, 2.5 mg orally on alternate days for a regional recurrence of a glottic and supraglottic squamous cell carcinoma (UICC stage T,NoMo)l who developed a severe pulmonary disease. Initially a diagnosis of lymphangitis carcinomatosa was made, but the picture cleared about two weeks after the methotrexate was discontinued.
Case report
A 45 year old man with a 3 month history of hoarseness, dysphagia and stridor was admitted on I April 1975 to the ENT Department of the University Hospital St Radboud, Nijmegen, 13'
132
J . J . MANNI AND P. VAN DEN B R O E K
The Netherlands. Indirect laryngoscopy revealed a large transglottic tumour of the right side of the larynx extending into both the glottic and supraglottic regions. The true vocal cord could not be seen on the right side; the left vocal cord was diffusely oedematous, but moved normally. The laryngeal lumen was grossly obstructed by tumour. No neck nodes were palpable. Tomography of the larynx confirmed the clinical extent of the tumour with growth into the right thyroid cartilage. A chest radiograph was normal. The tumour was staged as T,NoMo. The ESR was 36. The haemoglobin peripheral blood film examination as well as routine tests of liver and kidney function all showed normal values. Sputum cultures and skin test for tuberculosis as well as serological tests for syphilis were negative. Because of the serious respiratory distress, investigations like laryngography and direct laryngoscopy with biopsy, were abandoned. The same applied to preoperative cobalt radiation therapy, which is routinely given in our department for these extensive lesions. On 4 April 1975 a tracheotomy was performed under local anaesthesia. A frozen section of a biopsy of the vocal cord revealed a moderately differentiated squamous cell carcinoma. During the same session a total laryngectomy, hemi-thyroidectomy and neck dissection on the right side was performed. The postoperative course was uneventful and he was discharged 40 days later. During the second week of oesophageal speech training, the patient suddenly felt ill and reported chest pains. Chest radiographs revealed massive infiltration of the apicoposterior segment of the left upper pulmonary lobe. No malignant cells or acid fast bacilli could be demonstrated in the sputum. No pathogenic microorganism could be cultured. After tomography, bronchography and bronchoscopy with biopsy, unfortunately an anaplastic carcinoma of the left upper lobe bronchus with homolateral hilar enlargement was diagnosed. Telecoblat radiation therapy was started. The patient received 2500 rad in a 2 week course to the left upper lobe and mediastinum. On 5 August 1975 a left thoracotomy and palliative pneumectomy (metastatic growth in aortic lymph nodes) were performed. Discharge from the hospital followed on 19 August 1975. The chest radiograph revealed a hydrothorax on the left side, but no treatment was started. The patient attended for regular check-up. On 15 October 1975 a solid immobile mass (4-5 cm) was found in the left side of the neck behind the angle of the mandible, extending beneath the origin of the sternocleidomastoid muscle. Despite telecobalt radiation therapy, 5000 rad in 5 weeks, the mass remained fixed and only regressed by about 30%. Methotrexate therapy, 2.5 mg orally on alternate days, was started, on 17 December 1975, and changed to daily intake from 29 December 1975. He was readmitted on 21 February 1976, 66 days later, beginning the methotrexate with a history of dry cough and progressive shortness of breath associated with fever and general malaise. Physical examination at the time revealed a patient in respiratory distress with cyanosis, a temperature of 39.4"C and a pulse rate of 108/min. Coarse crepitations were heard over the right lung, especially the bases. The left thorax was dull on percussion and no breath sounds
Pulmonary complications of methotrexate therapy
‘33
could be heard. The previously mentioned subdigastric node measured 5-5 cm. On physical examination, no abnormalities were found, i.e. no signs of cardiac failure, other pathological lymph nodes, liver enlargement, exanthema, scratching effects or mucositis of the buccal cavity. The chest radiograph showed unilateral patchy, non-homogeneous opacities, most prominent in the lower field of the right lung, and the picture described by the radiologist was one of suspected lymphangitis carcinomatosa (Figure I ) . The left side of the chest radiograph showed no recent changes. The ESR was 125 mm, leucocytes 10.8 x 10’11, thrombocytes 220.0 x 109/l Hb 7.3 g/dl. Liver function tests: SGOT, SGPT slightly elevated. Sputum cultures revealed a normal flora. Because of this serious complication further therapy was abandoned except for pain medication. The methotrexate was stopped. Within three days the temperature fell to normal and a significant improvement in the general condition of the patient was noticed. A chest radiograph three weeks later showed a completely normal right lung (Figure 2).
Figure I Admission chest radiograph. Extensive infiltrates in the right lung. Hydrothorax on left side from previous pneumonectomy.
'34
J. J . M A N N I AND P. VAN DEN B R O E K
Figure 2 Chest radiograph taken three weeks after admission shows almost complete clearing.
Methotrexate therapy was not resumed. Gradually the general condition deteriorated and the patient died on 10 April 1976 due to cachexia. Shortly before, an empyema drained spontaneously. Autopsy revealed that death was due to tumour cachexia. Histologic examination of lung specimens of the upper lung fields showed slight to moderate fibrosis due to radiation of the mediastium. The basal fields were congested and oedematous with very slight fibrosis. Pneuinocystis cariniz was found consistent with a slight concomitant infection.
Discussion Methotrexate was the probable cause of the lung disease in this patient. The clinical findings are consistent with previous reports.' The respiratory syndrome is characterized by sudden onset, fever, a non-productive cough, dyspnoea and cyanosis, followed by spontaneous resolution in I 0-15 days. The chest radiograph reveals bilateral interstitial infiltrates, most prominent at the bases. p3
Pulmonary complications o f methotrexate therapy
I35
The eosinophilic leucocyte count of the peripheral blood film is increased in half the cases. Laboratory studies have been unrevealing in most cases. Sputum smears and cultures, blood cultures, skin tests for tuberculosis and fungi and iral studies, have been negative. No relation could be found between the institution of therapy and the onset of symptoms, which may appear as early as 10 days6 and as late as 196 days.3 In one patient symptoms appeared even as late as 5 years.' Also the total amount of methotrexate before the occurrence of the syndrome varies: 60 mg6 to 6500 mg.' The treatment was given i.m. once or twice weekly in most cases (no record in 4 publications). Intermittent oral medication was usually ~ s e d . ' , ~Daily , ~ , ~ treatment was only used o c ~ a s i o n a l l yas~ ~in~the second period of treatment of the patient presented in this paper. The use of steroids, with or without antibiotics to treat the pulmonary disease, reduced the duration of the symptoms to about 50% compared with patients treated only with antibiotics or not at all. The response to steroids and not to antibiotics is in keeping with the suggested aetiology of this syndrome. None of the patients died of the acute pulmonary disease and the radiographic changes resolved completely in all except 3 patient^."^'^ Early in the disease a predominantly interstitial infiltration appears, with fine reticular densities and small nodules (up to 2 mm), usually lasting 7-30 days. The infiltrates are diffuse and symmetrical. Pathologic changes of the lung tissue of patients with this acute pulmonary syndrome have been reported in 8 of the 28 cases. Lung tissue was obtained by open biop~y.',~-'' Histology shows a diffuse interstitial pneumonitis and granulomas containing multinucleated giant cells are often found. Sometimes clusters of lymphocytes and eosinophils were seen, but no typical picture could be described. The aetiology of this acute pulmonary syndrome is not known. Patients on immunosuppressive chemotherapy are prone to diffuse interstitial pulmonary diseases caused by various infectious agents ; the commonest being Pneumocystis carinii. ' 4 This infection usually causes a rapidly progressive diffuse interstitial pneumonia. Without treatment all patients died." In a study of 500 selected cases of the prevalence of pneumocystis in sputum or lung tissue (obtained by biopsy, brush or autopsy) 38 positive examinations were discovered. Nine of them were reported to be directly related to the cause of death, due to the number of cysts counted.16 More often a concomitant clinical latent infection was found. Autopsy of the patient reported in this paper 60 days after spontaneous resolution of the pulmonary disease, revealed only a few thick-walled cysts found on light microscopic examination of lung fractions, and the infection was classified as slight. These findings together with the clinical sequence make it unlikely that Pneumocystis carinii could account for the acute pulmonary syndrome in our patient. A direct toxic effect of methotrexate on lung tissue has been s ~ g g e s t e d Tracer .~ studies showed that lung and liver have a relatively high uptake of this drug compared with other organs. But the apparent lack of relationship between the onset of pulmonary symptoms and the duration and total dose of methotrexate does not support this. The pulmonary disease might be an adverse, hypersensitivity reaction to methotrexate.' The increased eosinophilic leucocytes count as well as the prompt reaction to steroid treatment are in keeping with this postulate.
136
J . J . M A N N I AND P . VAN D E N B R O E K
The mechanism of adverse drug reactions is not known, especially the reactions involving visceral organs such as the lung.'* The most common agents producing adverse pulmonary reactions are antibiotics, antihypertensive drugs and antimetabolites. The pulmonary pathology of adverse drug reactions are not all alike. Methotrexate causes an overall microscopic picture of allergic granulomatous pneumonia, whereas bleomycin causes intra-alveolar fibrosis. The radiographic pattern produced by adverse drug reactions are also not all alike: the most common is an acute diffuse alveolar abnormality, a pattern entirely typical of pulmonary oedema. Adverse pulmonary reactions to methotrexate cause both interstitial and alveolar abnormalities. In the presence of other symptoms of a generalized hypersensitivity reaction, the diagnosis is simple, but in their absence it may easily be overlooked that a patient on methotrexate, for a serious underlying disease, has a drug induced pulmonary syndrome. The recognition of this syndrome is important: any pulmonary symptoms demand a chest radiograph. A differential count and eosinophilic cell count is mandatory, as is routine estimation of thrombocytes and lymphocytes of the peripheral blood film, as soon as methotrexate therapy is instituted.
Acknowledgements The authors are grateful to Dr J. H. E. Th. Meuwissen (Parasitological Department) for advice and examination of lung specimens for Pneumocystis carinii; and to Miss T. M. Garretsen for preparing the manuscript.
References CLARYSSE A.M., CATHEY W.J., CARTWRIGHT G.E. & WINTROBE M.M. (1969)Pulmonary disease complicating intermittent therapy with methotrexate. Journal of the American Medical Association 209, 1861. 2 SCHWARTZ J. & KAJANI M.K. (1969)Methotrexate therapy and pulmonary disease.Journa1 of the American Medical Association 210, 1924. J.H. (1970)Pneumonia and methotrexate. British MedicalJournal ii, 156. 3 ROBERTSON 4 PASQUINUCCI G., FERRARA P. & CASTELLARI R. (1971)Daunorubicin treatment of methotrexate pneumonia. Journal of the American Medical Association 216, 2017. 5 EVERTS CH. S., WESTIOTT J.L. & BRAGGD.G. (1973) Methotrexate therapy and pulmonary disease. Diagnostic Radiology 107, 539. 6 BELLINIF. & MASERA G. (1973) Pulmonary disease complicating therapy with methotrexate. Annales de Radiologie 16, 267. 7 LISBONA A., SCHWARTZ J., LACHANCE CL., FRANK H. & PALAYEW M.J. (1973) Methotrexate induced pulmonary disease. Journal of the Canadian Association of Radiologists 24, 215. 8 BHATK.S.S., ANDERSON K. R. & STEWART R.D.H. (1974)AustralianandNew ZealandJournal of Medicine 4, 277. 9 FILIPD.J., LOGUEG.L., HARLE THS.,FARROR W.H. (1971)Pulmonary and hepatic complications of methotrexate therapy of psoriasis. Journal of the American Medical Association 216, 881. I
Pulmonary complications of methotrexate therapy
'37
GOLDMAN G.C. & MOSCHELLA S.J. (1971) Severe pneumonitis occurring during methotrexate therapy. Archives of Dermatology 103, 194. I I MEINESZD. & SELDENRATH J.J. (1972) Longcomplicaties bij het gebruik van cytostatica. Nederlands Tijdschrift voor Geneeskunde 116, 292. 12 WHITCOMB M.E., SCHWARZ M.J. & TORMEY D.C. (1972)Methotrexate pneumonitis. Thorax 27,636. 13 T N M C ~ a s s ~ c a t i ofnMalignant Tumors (1974) Union Internationale contre le cancer, Geneva. 14 GOODELL B., JACOBS J.B. & POWELL R.D. (1970) Pneumocystis Carinii, the spectrum of diffuse interstitial pneumonia in patients with neoplastic diseases. Annals of Internal Medicine 72, 337. 15 SIZOO W., WOLVIUS G.G. (1976) Pneumocystis pneumonia complicating cytostatic therapy. Nederlands Tijdschrzji voor Geneeskunde 120, 418. 16 MEUWISSEN J.H.E. TH.,TAUBER J., LEEUWENBERG A.D.E.M., BECKERS P.J.A. & SIEBEN M. (1977) Parasitological and serological observations on pneumocystis infections in man. 3jurnal of Infectious Diseases. In press. 17 ANDERSON L.A., COLLINS G.T., OJIMAY. (1970) A study of the distribution of methotrexate in human tissues and tumors. Cancer Research 30, 1344. 18 BRETTNER A., HEITZMAN E.R. & WOODIN W.G. (1970) Pulmonary complicationsof drug therapy. Radiology 96, 31. 10
Pulmonary complications of methotrexate therapy J. J . MANNI AND P . VAN DEN BROEK Department of OtoRhinoLaryngology, University of Nimegen, Philips van Leydenlaan 15, Nqmegen. The Netherlands
'
Accepted for publication I November 1976
MANNIJ.J. & VANDEN BROEKP. (1977) Clinical Otolaryngology 2, 131-137 Pulmonary complications of methotrexate therapy Diffuse interstitial pulmonary infiltration was first reported in I 969, occurring during intermittent methotrexate therapy and it is suggested that it represents an adverse reaction to this drug. Despite the severity of the clinical and radiological changes, the disease is usually self-limiting. An additional case is presented and the previous 28 reported cases of this syndrome are summarized. Since intermittent methotrexate therapy is becoming more widely used, the importance of recognizing this respiratory illness as a possible complicating reaction to the drug is stressed. Keywords methotrexate interstitial pulmonary infiltration laryngeal carcinoma
Introduction
In 1969 Clarysse described a severe, but self-limiting respiratory disease in 7 patients receiving intermittent methotrexate as maintenance therapy for acute lymphoblastic leukaemia.' Since then several authors2-' have reported this acute pulmonary syndrome in patients with leukaemia receiving this therapy to maintain the haematological and clinical remission. More recently this complication has been described in other clinical conditions like psoriasis,' mycosis fungoides and pemphigus," carcinoma of the hypopharynx' ', carcinoma of the lung,' * scirrhous adenocarcinoma of the breast with diffuse bony metastases.' This paper reports a patient receiving intermittent methotrexate therapy, 2.5 mg orally on alternate days for a regional recurrence of a glottic and supraglottic squamous cell carcinoma (UICC stage T,NoMo)l who developed a severe pulmonary disease. Initially a diagnosis of lymphangitis carcinomatosa was made, but the picture cleared about two weeks after the methotrexate was discontinued.
Case report
A 45 year old man with a 3 month history of hoarseness, dysphagia and stridor was admitted on I April 1975 to the ENT Department of the University Hospital St Radboud, Nijmegen, 13'
132
J . J . MANNI AND P. VAN DEN B R O E K
The Netherlands. Indirect laryngoscopy revealed a large transglottic tumour of the right side of the larynx extending into both the glottic and supraglottic regions. The true vocal cord could not be seen on the right side; the left vocal cord was diffusely oedematous, but moved normally. The laryngeal lumen was grossly obstructed by tumour. No neck nodes were palpable. Tomography of the larynx confirmed the clinical extent of the tumour with growth into the right thyroid cartilage. A chest radiograph was normal. The tumour was staged as T,NoMo. The ESR was 36. The haemoglobin peripheral blood film examination as well as routine tests of liver and kidney function all showed normal values. Sputum cultures and skin test for tuberculosis as well as serological tests for syphilis were negative. Because of the serious respiratory distress, investigations like laryngography and direct laryngoscopy with biopsy, were abandoned. The same applied to preoperative cobalt radiation therapy, which is routinely given in our department for these extensive lesions. On 4 April 1975 a tracheotomy was performed under local anaesthesia. A frozen section of a biopsy of the vocal cord revealed a moderately differentiated squamous cell carcinoma. During the same session a total laryngectomy, hemi-thyroidectomy and neck dissection on the right side was performed. The postoperative course was uneventful and he was discharged 40 days later. During the second week of oesophageal speech training, the patient suddenly felt ill and reported chest pains. Chest radiographs revealed massive infiltration of the apicoposterior segment of the left upper pulmonary lobe. No malignant cells or acid fast bacilli could be demonstrated in the sputum. No pathogenic microorganism could be cultured. After tomography, bronchography and bronchoscopy with biopsy, unfortunately an anaplastic carcinoma of the left upper lobe bronchus with homolateral hilar enlargement was diagnosed. Telecoblat radiation therapy was started. The patient received 2500 rad in a 2 week course to the left upper lobe and mediastinum. On 5 August 1975 a left thoracotomy and palliative pneumectomy (metastatic growth in aortic lymph nodes) were performed. Discharge from the hospital followed on 19 August 1975. The chest radiograph revealed a hydrothorax on the left side, but no treatment was started. The patient attended for regular check-up. On 15 October 1975 a solid immobile mass (4-5 cm) was found in the left side of the neck behind the angle of the mandible, extending beneath the origin of the sternocleidomastoid muscle. Despite telecobalt radiation therapy, 5000 rad in 5 weeks, the mass remained fixed and only regressed by about 30%. Methotrexate therapy, 2.5 mg orally on alternate days, was started, on 17 December 1975, and changed to daily intake from 29 December 1975. He was readmitted on 21 February 1976, 66 days later, beginning the methotrexate with a history of dry cough and progressive shortness of breath associated with fever and general malaise. Physical examination at the time revealed a patient in respiratory distress with cyanosis, a temperature of 39.4"C and a pulse rate of 108/min. Coarse crepitations were heard over the right lung, especially the bases. The left thorax was dull on percussion and no breath sounds
Pulmonary complications of methotrexate therapy
‘33
could be heard. The previously mentioned subdigastric node measured 5-5 cm. On physical examination, no abnormalities were found, i.e. no signs of cardiac failure, other pathological lymph nodes, liver enlargement, exanthema, scratching effects or mucositis of the buccal cavity. The chest radiograph showed unilateral patchy, non-homogeneous opacities, most prominent in the lower field of the right lung, and the picture described by the radiologist was one of suspected lymphangitis carcinomatosa (Figure I ) . The left side of the chest radiograph showed no recent changes. The ESR was 125 mm, leucocytes 10.8 x 10’11, thrombocytes 220.0 x 109/l Hb 7.3 g/dl. Liver function tests: SGOT, SGPT slightly elevated. Sputum cultures revealed a normal flora. Because of this serious complication further therapy was abandoned except for pain medication. The methotrexate was stopped. Within three days the temperature fell to normal and a significant improvement in the general condition of the patient was noticed. A chest radiograph three weeks later showed a completely normal right lung (Figure 2).
Figure I Admission chest radiograph. Extensive infiltrates in the right lung. Hydrothorax on left side from previous pneumonectomy.
'34
J. J . M A N N I AND P. VAN DEN B R O E K
Figure 2 Chest radiograph taken three weeks after admission shows almost complete clearing.
Methotrexate therapy was not resumed. Gradually the general condition deteriorated and the patient died on 10 April 1976 due to cachexia. Shortly before, an empyema drained spontaneously. Autopsy revealed that death was due to tumour cachexia. Histologic examination of lung specimens of the upper lung fields showed slight to moderate fibrosis due to radiation of the mediastium. The basal fields were congested and oedematous with very slight fibrosis. Pneuinocystis cariniz was found consistent with a slight concomitant infection.
Discussion Methotrexate was the probable cause of the lung disease in this patient. The clinical findings are consistent with previous reports.' The respiratory syndrome is characterized by sudden onset, fever, a non-productive cough, dyspnoea and cyanosis, followed by spontaneous resolution in I 0-15 days. The chest radiograph reveals bilateral interstitial infiltrates, most prominent at the bases. p3
Pulmonary complications o f methotrexate therapy
I35
The eosinophilic leucocyte count of the peripheral blood film is increased in half the cases. Laboratory studies have been unrevealing in most cases. Sputum smears and cultures, blood cultures, skin tests for tuberculosis and fungi and iral studies, have been negative. No relation could be found between the institution of therapy and the onset of symptoms, which may appear as early as 10 days6 and as late as 196 days.3 In one patient symptoms appeared even as late as 5 years.' Also the total amount of methotrexate before the occurrence of the syndrome varies: 60 mg6 to 6500 mg.' The treatment was given i.m. once or twice weekly in most cases (no record in 4 publications). Intermittent oral medication was usually ~ s e d . ' , ~Daily , ~ , ~ treatment was only used o c ~ a s i o n a l l yas~ ~in~the second period of treatment of the patient presented in this paper. The use of steroids, with or without antibiotics to treat the pulmonary disease, reduced the duration of the symptoms to about 50% compared with patients treated only with antibiotics or not at all. The response to steroids and not to antibiotics is in keeping with the suggested aetiology of this syndrome. None of the patients died of the acute pulmonary disease and the radiographic changes resolved completely in all except 3 patient^."^'^ Early in the disease a predominantly interstitial infiltration appears, with fine reticular densities and small nodules (up to 2 mm), usually lasting 7-30 days. The infiltrates are diffuse and symmetrical. Pathologic changes of the lung tissue of patients with this acute pulmonary syndrome have been reported in 8 of the 28 cases. Lung tissue was obtained by open biop~y.',~-'' Histology shows a diffuse interstitial pneumonitis and granulomas containing multinucleated giant cells are often found. Sometimes clusters of lymphocytes and eosinophils were seen, but no typical picture could be described. The aetiology of this acute pulmonary syndrome is not known. Patients on immunosuppressive chemotherapy are prone to diffuse interstitial pulmonary diseases caused by various infectious agents ; the commonest being Pneumocystis carinii. ' 4 This infection usually causes a rapidly progressive diffuse interstitial pneumonia. Without treatment all patients died." In a study of 500 selected cases of the prevalence of pneumocystis in sputum or lung tissue (obtained by biopsy, brush or autopsy) 38 positive examinations were discovered. Nine of them were reported to be directly related to the cause of death, due to the number of cysts counted.16 More often a concomitant clinical latent infection was found. Autopsy of the patient reported in this paper 60 days after spontaneous resolution of the pulmonary disease, revealed only a few thick-walled cysts found on light microscopic examination of lung fractions, and the infection was classified as slight. These findings together with the clinical sequence make it unlikely that Pneumocystis carinii could account for the acute pulmonary syndrome in our patient. A direct toxic effect of methotrexate on lung tissue has been s ~ g g e s t e d Tracer .~ studies showed that lung and liver have a relatively high uptake of this drug compared with other organs. But the apparent lack of relationship between the onset of pulmonary symptoms and the duration and total dose of methotrexate does not support this. The pulmonary disease might be an adverse, hypersensitivity reaction to methotrexate.' The increased eosinophilic leucocytes count as well as the prompt reaction to steroid treatment are in keeping with this postulate.
136
J . J . M A N N I AND P . VAN D E N B R O E K
The mechanism of adverse drug reactions is not known, especially the reactions involving visceral organs such as the lung.'* The most common agents producing adverse pulmonary reactions are antibiotics, antihypertensive drugs and antimetabolites. The pulmonary pathology of adverse drug reactions are not all alike. Methotrexate causes an overall microscopic picture of allergic granulomatous pneumonia, whereas bleomycin causes intra-alveolar fibrosis. The radiographic pattern produced by adverse drug reactions are also not all alike: the most common is an acute diffuse alveolar abnormality, a pattern entirely typical of pulmonary oedema. Adverse pulmonary reactions to methotrexate cause both interstitial and alveolar abnormalities. In the presence of other symptoms of a generalized hypersensitivity reaction, the diagnosis is simple, but in their absence it may easily be overlooked that a patient on methotrexate, for a serious underlying disease, has a drug induced pulmonary syndrome. The recognition of this syndrome is important: any pulmonary symptoms demand a chest radiograph. A differential count and eosinophilic cell count is mandatory, as is routine estimation of thrombocytes and lymphocytes of the peripheral blood film, as soon as methotrexate therapy is instituted.
Acknowledgements The authors are grateful to Dr J. H. E. Th. Meuwissen (Parasitological Department) for advice and examination of lung specimens for Pneumocystis carinii; and to Miss T. M. Garretsen for preparing the manuscript.
References CLARYSSE A.M., CATHEY W.J., CARTWRIGHT G.E. & WINTROBE M.M. (1969)Pulmonary disease complicating intermittent therapy with methotrexate. Journal of the American Medical Association 209, 1861. 2 SCHWARTZ J. & KAJANI M.K. (1969)Methotrexate therapy and pulmonary disease.Journa1 of the American Medical Association 210, 1924. J.H. (1970)Pneumonia and methotrexate. British MedicalJournal ii, 156. 3 ROBERTSON 4 PASQUINUCCI G., FERRARA P. & CASTELLARI R. (1971)Daunorubicin treatment of methotrexate pneumonia. Journal of the American Medical Association 216, 2017. 5 EVERTS CH. S., WESTIOTT J.L. & BRAGGD.G. (1973) Methotrexate therapy and pulmonary disease. Diagnostic Radiology 107, 539. 6 BELLINIF. & MASERA G. (1973) Pulmonary disease complicating therapy with methotrexate. Annales de Radiologie 16, 267. 7 LISBONA A., SCHWARTZ J., LACHANCE CL., FRANK H. & PALAYEW M.J. (1973) Methotrexate induced pulmonary disease. Journal of the Canadian Association of Radiologists 24, 215. 8 BHATK.S.S., ANDERSON K. R. & STEWART R.D.H. (1974)AustralianandNew ZealandJournal of Medicine 4, 277. 9 FILIPD.J., LOGUEG.L., HARLE THS.,FARROR W.H. (1971)Pulmonary and hepatic complications of methotrexate therapy of psoriasis. Journal of the American Medical Association 216, 881. I
Pulmonary complications of methotrexate therapy
'37
GOLDMAN G.C. & MOSCHELLA S.J. (1971) Severe pneumonitis occurring during methotrexate therapy. Archives of Dermatology 103, 194. I I MEINESZD. & SELDENRATH J.J. (1972) Longcomplicaties bij het gebruik van cytostatica. Nederlands Tijdschrift voor Geneeskunde 116, 292. 12 WHITCOMB M.E., SCHWARZ M.J. & TORMEY D.C. (1972)Methotrexate pneumonitis. Thorax 27,636. 13 T N M C ~ a s s ~ c a t i ofnMalignant Tumors (1974) Union Internationale contre le cancer, Geneva. 14 GOODELL B., JACOBS J.B. & POWELL R.D. (1970) Pneumocystis Carinii, the spectrum of diffuse interstitial pneumonia in patients with neoplastic diseases. Annals of Internal Medicine 72, 337. 15 SIZOO W., WOLVIUS G.G. (1976) Pneumocystis pneumonia complicating cytostatic therapy. Nederlands Tijdschrzji voor Geneeskunde 120, 418. 16 MEUWISSEN J.H.E. TH.,TAUBER J., LEEUWENBERG A.D.E.M., BECKERS P.J.A. & SIEBEN M. (1977) Parasitological and serological observations on pneumocystis infections in man. 3jurnal of Infectious Diseases. In press. 17 ANDERSON L.A., COLLINS G.T., OJIMAY. (1970) A study of the distribution of methotrexate in human tissues and tumors. Cancer Research 30, 1344. 18 BRETTNER A., HEITZMAN E.R. & WOODIN W.G. (1970) Pulmonary complicationsof drug therapy. Radiology 96, 31. 10
