1551

Actuarial risk of inhibitor development in patients with or

moderate

severe

haemophilia A.

formation took place before age 5, the actuarial incidence being 20% by this age (figure). No patient with mild haemophilia (FVIIIC > 0-05 IU/ml) developed persistent inhibitors. The number of cases with inhibitor per 1000 patient-years and the cumulative age-dependent risk were both lower than those in Ehrenforth’s study, although higher than those reported by others.l,2 The oldest patient in whom we discovered an inhibitor was the same age as in Ehrenforth’s study, suggesting that our follow-up allowed early detection. We believe that frequency of testing could affect incidence estimates by detecting transitory or recently arisen antibodies, but persistent or clinically important inhibitors would also be discovered with less frequent testing. Thus, the estimates based on our study could be close to the true incidence of important inhibitors in hemophilia A. On the assumption of similar factor VIII usage in our patients and those of Ehrenforth et al, and allowing for statistical error (see SEM in figure), differences between the studies could be attributable to the criteria used for sporadic and transitory inhibitors. We would not have classified Ehrenforth’s patients 3 and 6 as having inhibitors; if these 2 cases were excluded the incidence would drop and results of the two studies would be closer. We suggest that testing on an annual basis would be adequate to assess the development of important inhibitors. Unit of

Congenital Coagulation Disorders, Hospital La Fe, 46009 Valencia, Spain

JOSÉ IGNACIO LORENZO RAIMUNDO GARCIA RAFAEL MOLINA

1. McMillan CW, Shapiro SS, Whitehurst D, et al. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study II: observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71: 344-48. 2. Rasi V, Ikkala E. Haemophiliacs with factor VIII inhibitors in Finland: incidence and outcome. Br J Haematol 1990; 79: 369-71.

Fatal

pneumocystis pneumonia in asthmatic patient treated with methotrexate

SIR,-Low-dose methotrexate has been used successfully in the arthritis, and polymyositis, and

treatment of psoriasis, rheumatoid

has been proposed for inflammatory bowel diseases and

corticosteroid-dependent asthma,l where it would have a steroidsparing effect. However, digestive, hepatic, haematological, and respiratory side-effects have been related to this drug. Opportunistic infections were very common with low-dose methotrexate; a case of pneumocystosis (1983), cryptococcosis (1984), and nocardiosis have now been reported (1988). For the past 2 years, the prevalence of Pneumocystis carinii pneumonia (PCP) during low-dose methotrexate therapy has increased in a subset of immunocompetent patients.2 We report a new case of PCP with fatal outcome in an asthmatic patient treated with methotrexate. A 61-year-old man with aspirin-induced asthma needed a minimum average dose of 15 mg per day prednisolone for 20 years. Corticosteroid-induced osteoporosis complications led to the use of

low-dose intramuscular methotrexate in August, 1991, at a weekly dose of 15 mg. Asthma improved and corticosteroid dosage could be progressively tapered to 9 mg per day at the end of February, 1992. 8 days after the last injection of methotrexate (total dose 90 mg), the patient was admitted for multilobar pneumonia and was initially treated with intravenous co-amoxyclav. On the third day, a temperature of395°C persisted, chest radiograph showed diffuse bilateral interstitial infiltrates, and arterial oxygen pressure decreased (7 kPa). The total white cell count was 6-6 x 109/1 (10% lymphocytes), renal function was normal, and antibody to HIV-1/2 was negative (ELISA). Bronchoalveolar lavage fluid contained P carinii cysts. Co-trimoxazole (1280/6400 mg per day) was administered intravenously and ventilatory support started by mask. On the 15th day, co-trimoxazole was discontinued because of severe pancytopenia (platelets 8 x 109/1, neutrophils 0-8 x 109/1, lymphocytes 0.3 x 109/1), and aerosolised pentamidine 300 mg daily was started. 4 days later, a temperature of 39-2° reappeared, while radiological changes and hypoxaemia worsened. Despite intravenous pentamidine, imipenem, and ofloxacin and intubation for mechanical ventilation, the patient died 72 h later because of

hypoxia. The efficacy of methotrexate in asthma remains controversial,33 though its anti-inflammatory activity has been recognised, particularly its ability to inhibit polymorphonuclear leucocyte chemotaxis. The asthma did improve in our patient. What about systematic primary prophylaxis for PCP during treatment with low-dose methotrexate, as used in patients affected by HIV or after organ transplantation? The frequency of this opportunistic infection is increasing. 9 cases have been reported over 2 years, including our observation: 6 in rheumatoid and psoriatic arthritis4 and 3 in asthma.s We note lack of predictive factors for PCP in these cases, and their particular severity, partly due to diagnostic difficulties. The efficacy, tolerance, and cost of this prophylaxis have to be considered, as in AIDS. However, co-trimoxazole, the main oral prophylactic drug for PCP, could increase the side-effects of methotrexate by interfering with its metabolism. The risk of PCP in patients treated with low-dose methotrexate, whose use is widening, has to be defined in prospective studies. The number of such cases, although increasing, is still too low to warrant systematic primary prophylaxis. Furthermore, this "new" sideeffect of low-dose methotrexate provides a caution against its indication in severe asthma, pending confirmation of efficacy.

Departments of Respiratory Disease and Medicine, CHRU de Reims, 51092 Reims, France

H. VALLERAND C. COSSART D. MILOSEVIC F. LAVAUD J. LEONE

1.

Mullarkey MF, Lammert JK, Blumenstein BA. Long-term methotrexate treatment in corticosteroid-dependent asthma. Ann Intern Med 1990; 112: 577-81. 2. Jacobs JL, Libby DM, Winters RA, et al. A cluster of Pneumocystis carinii pneumonia m adults without predisposing illnesses. N Engl J Med 1991; 324: 246-50. 3. Erzurum SC, Leff JA, Cochran JE, et al. Lack of benefit of methotrexate m severe, steroid-dependent asthma. Ann Intern Med 1991; 114: 353-60. 4. Wollner A, Mohle-Boetani J, Lambert RE, Perruquet JL, Raffin TA, Mc Guire JL. Pneumocystis carinii pneumonia complicating low-dose methotrexate treatment for rheumatoid arthritis. Thorax 1991; 46: 205-07. 5. Kuitert LM, Harrison AC. Pneumocystis carinii pneumonia as methotrexate treatment of asthma. Thorax 1991; 46: 936-37.

a

complication of

Oesophageal candidosis in patients on high-dose inhaled steroids SIR,-With increasing use of high-dose inhaled steroids for asthma, we report three patients who developed oesophageal candidosis. Case 1

(M/56, non-insulin-dependent diabetic with longstanding asthma, four week history ofretrostemal burning pain and occasional odynophagia unresponsive to antacid therapy).-Six weeks previously he had been prescribed a budesonide inhaler (Pulrnicort Turbuhaler) 400 g twice daily without mouth rinsing for exacerbation of asthma. He had been treated with prednisolone 5 mg daily intermittently but was not on oral corticosteroids at presentation. Examination, including the oropharynx, was normal apart from a hyperinflated chest without wheeze. Oesophagoscopy

Fatal pneumocystis pneumonia in asthmatic patient treated with methotrexate.

1551 Actuarial risk of inhibitor development in patients with or moderate severe haemophilia A. formation took place before age 5, the actuarial...
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