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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