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Severe Neutropenia during Pentamidine Treatment of Pneumocystis carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome -- New York City

During November 1983, three patients at one New York City hospital who had the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia (PCP) developed severe neutropenia while being treated with pentamidine isethionate. Since August 1981, 23 other patients with AIDS and PCP had been treated with pentamidine at this institution. None developed neutropenia that could not be explained by the simultaneous administration of another drug.

Case 1: A 43-year-old male with recently diagnosed Kaposi's sarcoma (KS) was suspected of having PCP in late October 1983, based on symptoms of cough, dyspnea on exertion, a chest roentgenogram showing bilateral interstitial pulmonary infiltrates, and pulmonary-function tests showing a drop in arterial p0))2)) with exercise. He was begun on sulfamethoxazole/trimethoprim (SXT) (20 mg trimethoprim/kg/day orally) as an outpatient. Before treatment, his white blood cell count (WBC) was 5,700/mm((3)) (4,560 neutrophils/mm((3))). After 9 days of SXT, he developed a maculopapular rash, an elevated serum glutamic-oxaloacetic transaminase (SGOT), an elevated serum creatinine, and neutropenia (WBC = 1,700/mm((3)) with 816 neutrophils/mm((3))). SXT was discontinued. The patient was admitted to the hospital 4 days later. Toluidine-blue and Gram-Weigert stains of a bronchoalveolar lavage showed P. carinii cysts, and the patient was started on pentamidine isethionate 4 mg/kg/day intravenously.* Two days before pentamidine was started, his WBC was 2,700/mm((3)) (1,377 neutrophils/mm((3))) but rose to 4,000/mm((3)) at initiation of pentamidine. All other manifestations of SXT toxicity had resolved. The patient's WBC ranged between 3,200/mm((3)) and 5,600/mm((3)) during the first 5 days of treatment. He experienced transient flushing during the treatment infusion, which disappeared when the infusion time was increased from 45 to 90 minutes. On day 6 of pentamidine, he developed a fever but no thrombocytopenia or anemia. His WBC was 1,900/mm((3)) and dropped to 300/mm((3)) (36 neutrophils/mm((3))) on day 7. The drug was discontinued, and gentamicin plus moxalactam were begun. During the 10 days after discontinuation of pentamidine, his WBC rose gradually to 2,800/mm((3)) (868 neutrophils/mm((3))), and a bone-marrow aspirate showed an increased myeloid to erythroid stem-cell ratio. The patient received no further therapy for PCP, and a repeat bronchoalveolar lavage revealed no P. carinii. His respiratory symptoms improved markedly. However, Mycobacterium avium-intracellulare was found in a blood culture that had been taken in late October, and the patient was treated with ansamycin. During the first 4 days of ansamycin, his WBC ranged from 2,800/mm((3)) to 4,300/mm((3)) (neutrophils 868 mm((3)) to 1,785/mm((3))) but fell to 1,900/mm((3)) on day 5 when the drug was discontinued. The following day, his WBC was 1,500/mm((3)), with 405 neutrophils/mm((3)). Five days later, the patient was discharged with a WBC of 1,500/mm((3)). Thereafter, he remained well, and during the 25 days after discharge, his WBC rose gradually to 2,200 mm((3)).

Case 2: A 30-year-old male, referred for diarrhea and started on tetracycline as an outpatient, was admitted with fever, dyspnea, abnormal chest roentgenogram, and abnormal pulmonary-function tests. P. carinii cysts were seen on toluidine-blue and Gram-Weigert stains of a bronchoalveolar lavage, as well as on a methenamine-silver stain of a transbronchial biopsy and a Gram-Weigert stain of bronchial brushings. Vibrio parahemolyticus and Giardia lamblia were found in his stool. He was begun on SXT (20 mg trimethoprim/kg/day intravenously) and tetracycline. After 8 days of SXT, he developed a rash, and his WBC fell from a pretreatment level of 5,400/mm((3)) (3,888 neutrophils/mm((3))) to 1,900/mm((3)). SXT and tetracycline were discontinued. The following day, his WBC was 1,800/mm((3)), with 1,026 neutrophils/mm((3)). Over the next 4 days, the rash disappeared, and his WBC rose to 2,900/mm((3)) (2,175 neutrophils/mm((3))). The patient was then started on pentamidine isethionate 2 mg/kg/day intravenously, which was increased to 4 mg/kg/day after 2 days. During the first 6 days of pentamidine, his WBC rose to 4,300/mm((3)) but then gradually fell to 1,700/mm((3)) (980 neutrophils/mm((3))) by the 11th day of therapy. Pentamidine was discontinued, and his WBC fell to 1,600/mm((3)) 2 days later. He did not develop anemia or thrombocytopenia. However, his respiratory status had improved markedly, and he was discharged from the hospital. Quinacrine was begun for his Giardia infection as an outpatient. After 7 days, his WBC rose to 2,800/mm((3)). He remained clinically well 2 weeks after all therapy was discontinued.

Case 3: A 29-year-old male was admitted with a history of fever and dyspnea for 2 weeks. P. carinii cysts were seen on a Gram-Weigert stain of a bronchoalveolar lavage. Since the patient gave a history of a diffuse pruritic rash when treated with SXT in August 1983 for an upper respiratory infection, he was started on pentamidine isethionate 4 mg/kg/day intravenously at the outset. With each infusion of the drug, he developed hypotension, flushing, and chills, which were controlled by increasing the infusion time from 1 to 3 hours and by pretreatment with meperidine and diphenhydramine. His WBC before pentamidine administration was 1,300/mm((3)) with 910 neutrophils/mm((3)). His WBC initially was stable but fell from 1,400/mm((3)) on day 6 to 500/mm((3)) (55 neutrophils/mm((3))) on day 7. He developed a fever and was placed on gentamicin and ticarcillin. The following day, with a WBC of 400/mm((3)) (8 neutrophils/mm((3))), pentamidine was discontinued. Throughout this period, the patient did not develop anemia or thrombocytopenia. He was begun on SXT (15 mg trimethoprim/kg/day intravenously); the drug was continued for 11 days, during which his WBC rose to 1,700/mm((3)). SXT was well tolerated, except for mild pruritis and an erythematous rash that disappeared when the drug was stopped. His chest film and respiratory symptomatology had improved markedly. The patient was discharged 12 days later and remained well at a follow-up appointment 7 days thereafter. Reported by B Polsky, MD, J Dryjanski, MD, E Whimbey, MD, B Wong, MD, JWM Gold, MD, D Armstrong, MD, Infectious Disease Svc, Dept of Medicine, Memorial Sloan-Kettering Cancer Center, New York; Parasitic Diseases Drug Svc, Div of Parasitic Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: For each patient, this was the first admission for PCP, and each showed clinical recovery. In two, recovery occurred while on pentamidine therapy. Folinic acid, topical antifungal agents, benzodiazepines, and in one patient, meperidine and diphenhydramine, were administered during the period in which the pentamidine-associated neutropenia developed. Furthermore, despite intensive screening, only a few other infectious agents (G. lamblia, V. parahemolyticus, M. avium-intracellulare, and superficial Candida) complicated these cases. In two of these, neutropenia developed or worsened during the administration of other anti-infective drugs. Thus, despite the close temporal relationship between neutropenia and the administration of pentamidine and the gradual improvement of the neutropenia after withdrawal of the drug, it should not be presumed that these reactions were specifically related to pentamidine.

CDC's Parasitic Diseases Drug Service has received standard report forms for 179 patients with AIDS and PCP treated with pentamidine from January 1982 to September 1983. Of these, 26 (14.5%) developed leukopenia, with decreases in leukocyte counts from pre-therapy to mid- or post-therapy of 50% or more. In 12 instances, the physician discontinued pentamidine because of leukopenia, and in six of these 12, neutropenia or granuocytopenia was specifically mentioned as a complication. However, standard report forms ask only for WBC and are otherwise not sufficient to further characterize this phenomenon. CDC has sent a questionnaire to physicians for 114 randomly selected patients for whom pentamidine was released from October 1, to December 16, 1983, to obtain a more complete characterization and incidence estimate. In addition, physicians using pentamidine are encouraged to provide more detailed information on hematologic changes occurring during pentamidine treatment on the standard patient report form for pentamidine therapy. *Since intravenous administration of pentamidine can be hazardous, CDC recommends that it be given intramuscularly whenever possible.

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