Respiratory failure due to Pneumocystis carinii following methotrexate therapy for gestational trophoblastic disease
Article first published online: 22 OCT 2004
BJOG: An International Journal of Obstetrics & Gynaecology
Volume 112, Issue 3, pages 382–383, March 2005
How to Cite
Barbier, C., Arnaout, L., Schmit, C., Aucouturier, J.-S., Ricome, J.-L. and Loubières, Y. (2005), Respiratory failure due to Pneumocystis carinii following methotrexate therapy for gestational trophoblastic disease. BJOG: An International Journal of Obstetrics & Gynaecology, 112: 382–383. doi: 10.1111/j.1471-0528.2004.00399.x
- Issue published online: 12 JAN 2005
- Article first published online: 22 OCT 2004
A 33 year old woman presented with nausea, pelvic pain, bleeding and elevated β-hCG level at 190,000 UI/L at seven weeks of gestation. The diagnosis of molar pregnancy was made by ultrasound and she underwent suction evacuation of the uterus. Despite this, there was a persistently raised hCG level of 110,000 UI/L and a 3 cm uterine lesion was identified on repeat ultrasonography. Hepatic ultrasonography and chest X-ray were normal. The diagnosis of invasive mole was confirmed by pathological examination of the uterine lesion after repeat evacuation. The patient was then staged in the low risk FIGO stage I:5 group and a single regimen therapy of methotrexate (35 mg/m2 weekly) was initiated six weeks after termination of pregnancy to be continued for up to six weeks after normalisation of hCG level. The treatment was well tolerated and the patient's β-hCG level returned to a normal range within 16 weeks. On the last (21st) week of methotrexate therapy (cumulative dose = 1260 mg), she presented with dry cough, fever (38.5°C) and shortness of breath. The general practitioner had prescribed azithromycin (500 mg day one then 250 mg/day) eight days earlier for a suspected atypical pneumonia. Her symptoms had not responded and she was admitted to intensive care with a diagnosis of respiratory failure. Clinical examination revealed cyanosis, a blood pressure of 90/50 mmHg, heart rate at 145 beats per minute, respiratory rate at 40/minute and temperature of 42°C. Crackles were present at the lung bases. Arterial blood gases analysis under 15 L/minute of oxygen therapy gave the following results: pH 7.4, Pao2 56 mmHg (normal value: 78 to 90), Paco2 39 mmHg (normal value: 37 to 43). White blood cell count was 10 × 109/L and C-reactive protein 80 mg/L. Chest radiography revealed diffuse mixed interstitial and alveolar infiltrates predominately in the lower lung fields. Urine and blood cultures, serology for atypical pneumonia microbial agents (Mycoplasma pneumoniae, Chlamydia, Legionella) and urinary antigen detection of Legionnella pneumophila were negative. Peripheral blood T4 lymphocyte count was normal and the human immunodeficiency virus test was negative. hCG level was also negative and an echocardiogram was normal. In view of the negative investigations, the patient underwent bronchoscopy and bronchoalveolar lavage. Absolute cell numbers in the bronchoalveolar fluid (116,000/mL) were not increased but the ratio of lymphocytes (59%, 68,000/mL) and neutrophils (27%, 31,300/mL) were increased. Direct examination of lavage fluid after Grocott silver staining revealed the presence of low numbers of Pneuomcystis carinii cysts. Culture for other organism was negative. A combination of trimethoprim 960 mg/day and sulfamethoxazole 4800 mg/day for three weeks and corticosteroids (methylprednisolone 240 mg/day gradually decreased over nine days) was initiated and the patient's pulmonary function improved dramatically over a few days. She was discharged 12 days after admission.
The presence of P. carinii cysts by direct examination of sputum or bronchoalveolar fluid samples is diagnostic of P. carinii pneumonia. P. carinii pneumonia should always be considered in HIV-negative patients treated by methotrexate despite normal T4 lymphocytes count. P. carinii pneumonia following methotrexate therapy in the management of rheumatic disease has been reported,1 but to our knowledge, P. carinii pneumonia after methotrexate therapy for trophoblastic disease has not been reported before. In AIDS patients, symptoms of P. carinii pneumonia may be present for weeks or months before diagnosis, whereas in HIV-negative immunocompromised patients, the clinical presentation is usually more explosive.2
On cytologic examination of bronchoalveolar lavage samples, P. carinii pneumonia is characterised by a neutrophil alveolitis especially in HIV-negative patients.3 In a series of 56 cases of P. carinii pneumonia in HIV-negative patients, an increased ratio of neutrophils in the bronchoalveolar lavage and a higher parasite count were significantly correlated with lower arterial oxygen tension and poorer survival.3 The authors reported macrophage and neutrophil ratio of 52.5% and 18.5%, respectively. Interestingly, bronchoalveolar lavage fluid from our patient was characterised by the presence of a large number of lymphocytes (59%). We had previously considered the diagnosis of methotrexate-induced pneumonitis as another possible cause of respiratory failure in this patient. The severe lymphocytic alveolitis was consistent with this hypothesis but drug-induced lung injury remained a diagnosis of exclusion.
The presentation of P. carinii pneumonia despite a normal T4 lymphocyte count raises the issue of P. carinii pneumonia prophylaxis. Currently, the place of P. carinii pneumonia prophylaxis in HIV-negative immunocompromised patients is not clearly defined and further investigations are needed to assess which patients may benefit from P. carinii pneumonia prophylaxis. Because the trimethoprim/sulfamethoxazole combination therapy inhibits folate metabolism, its concomitant use with methotrexate may lead to enhanced haematologic toxicity, and may require a protocol including folinic acid rescue.
In summary, it is important to consider the possibility of opportunistic infection (particularly P. carinii pneumonia) in patients who develop pulmonary symptoms with fever while receiving methotrexate. Bronchoalveolar lavage examination is helpful to identify infective agents or to identify a typical cytological picture of methotrexate-induced pneumonitis. Patients receiving methotrexate should be informed of these possible complications and instructed to consult their physicians if pulmonary symptoms occur.
Accepted 9 June 2004