CD-ROM Today 1996 January/CD-ROM Today 1996 January.iso/dp/0343/03433.txt

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$Unique_ID{BRK03433}
$Pretitle{}
$Title{Agranulocytosis, Acquired}
$Subject{Agranulocytosis, Acquired Malignant Neutropenia Primary
Granulocytopenia Agranulocytic Angina}
$Volume{}
$Log{}

Copyright (C) 1986, 1989 National Organization for Rare Disorders, Inc.

209:
Agranulocytosis, Acquired

** IMPORTANT **
It is possible the main title of the article (Acquired Agranulocytosis)
is not the name you expected.  Please check the SYNONYMS listing to find the
alternate names and disorder subdivisions covered by this article.

Synonyms

     Malignant Neutropenia
     Primary Granulocytopenia
     Agranulocytic Angina

General Discussion

** REMINDER **
The information contained in the Rare Disease Database is provided for
educational purposes only.  It should not be used for diagnostic or treatment
purposes.  If you wish to obtain more information about this disorder, please
contact your personal physician and/or the agencies listed in the "Resources"
section of this report.


Acquired Agranulocytosis is a disorder characterized by an impairment in
the formation of granulocytes (white blood cells containing granules) in the
bone marrow which is caused by chemical or pathogenic agents.  The resulting
lack of granulocytes results in an increased susceptibility to bacterial
infections.

Symptoms

The symptoms of Acquired Agranulocytosis depend upon the type, severity and
duration of the bacterial infection.  Painful mucous membrane ulcers in the
lining of the cheeks and throat associated with difficulty in swallowing may
herald the onset of acute granulocytopenia.  The initial symptoms of Acquired
Agranulocytosis may be fever, chills, and weakness or extreme exhaustion due
to the presence of bacteria in the tissues of the body.  Untreated, the
disease can progress rapidly to bacterial shock.  Chronic granulocytopenia
may have a similar acute onset, but frequently the disease progresses more
slowly with a series of multiple focal infections that commonly involve the
skin, perirectal (around the rectum) region, and bronchopulmonary system
involving the lungs and their air passages.  Some patients with the disorder
may develop either recurrent canker sores in the mouth or other infections
that occur in a cyclic pattern.

Causes

Acquired Agranulocytosis is caused by impaired granulocyte (white blood cells
containing granules) production, accelerated destruction or utilization of
these cells, or a combination of these.  The resulting granulocytopenia (lack
of granulocytes) is accompanied by a reduction in the large reserve pool of
another kind of white blood cell, called bone marrow neutrophil.

The most common cause of Acute Agranulocytosis is drug-induced dose-related
impairment of granulocyte production.  Cancer chemotherapy drugs are the most
frequently involved agents.  Less commonly involved are many of the alkylating
agents which substitute an alkyl group for an active hydrogen atom in an
organic compound, chemotherapeutic antimetabolites (substances structurally
resembling other substances and interfering with their utilization in their
metabolism), phenothiazine derivatives, dibenzazepine compounds, antithyroid
drugs, sulfonamides, antihistamines and anticonvulsants.  Synthetic
penicillins, chloramphenicol (an antibiotic), benzene, nitrous oxide, and
arsenic have also been known to cause agranulocytosis.

Idiosyncratic (non-dose-related) forms of drug-induced depression of
granulocyte production can also occur.  These may be either acute (e.g.,
cinchona alkaloids, indomethacin, procainamide, phenylbutazone,
nitrofurantoin, sulfonamides, antithyroid compounds, and thiazides), or
chronic (e.g., benzene, chloramphenicol, gold salts, and phenylbutazone).

Some drugs (e.g., cytarabine, phenytoin, methotrexate, and pyrimethamine) may
produce granulocytopenia as a consequence of excessive destruction of
granulocyte precursors within the bone marrow.  Rarely, Acute Agranulocytosis
due to excessive granulocyte destruction is caused by the presence of a
drug-induced leukocyte antibody (e.g., aminopyrine, dipyrone, phenylbutazone,
meralluride, sulfapyridine, and gold salts).

Most disease-associated granulocytopenia is due to accelerated neutrophil
destruction through a variety of mechanisms.  This may occur in association
with excessive leukophagocytosis; i.e., the destruction of leukocytes by
histiocytes such as lymphoma (malignancy of the lymph tissue).  It may occur
in association with infections affecting the whole body (e.g., viral,
protozoal, severe bacterial infection), various forms of hypersplenism
(exaggeration of the functions of the spleen) such as Felty's Syndrome,
congestive splenomegaly (enlarged spleen) in association with collagen
(connective tissue) disease, intrinsic granulocyte defects such as Chediak-
Higashi Syndrome, and, rarely, leukocyte isoantibody (an antibody produced by
one individual that reacts with antigens - isoantigens - of another
individual of the same species) such as neonatal immunization neutropenia
(lack of neutrophil cells).  Complement-mediated acute reversible neutropenia
sometimes occurs during hemodialysis (removal of certain elements of the
blood by kidney dialysis).

The drugs in the United States with the highest risk of inducing
granulocytopenia (excluding the cancer chemotherapy drugs) are the
phenothiazines, antithyroid compounds, sulfonamides, and phenylbutazone.  The
greatest relative risk, however, is from phenylbutazone.

Therapies:  Standard

Treatment of Acquired Agranulocytosis consists of identifying and eliminating
any possible offending agents (drugs, occupational exposure, etc.).  If there
is a significant fever spike of over 38.3 C (101 F), shock, a significant
focus of local infection, or a positive blood culture, antimicrobial therapy
is administered.  This therapy must be designed to cover a wide range of
bacteria.  Combination antimicrobial therapy with an aminoglycoside such as
gentamycin or tobramycin plus a penicillinase-resistant penicillin such as
cephalothin, oxacillin or carbenicillin is recommended as the initial therapy
for adults.  Appropriate antibiotics for the types of identified infections
should be continued from 7 to days following abatement of fever.

Extended antibiotic treatment may predispose a patient to the development
of renal (kidney) complications and superinfection ( a new infection
complicating the course of antimicrobial therapy with resistant bacteria and
fungi).  Infection and fever usually ebb with the return of 1000 to 1500
granulocytes/cu mm in the peripheral blood.

There is no certain method to stimulate bone marrow myeloid recovery.
Corticosteroids may be used in the management of bacterial shock, but are not
recommended to treat Acute Agranulocytopenia since they may mask bacterial
infections and can impede the migration of granulocytes into tissues.
Androgenic steroid therapy for treatment of the disorder has been
disappointing.

Human gamma-globulin should be given to patients with low levels of gamma
globulin in their blood (hypogammaglobulinemia).

Severely neutropenic patients with antibiotic-resistant sepsis (presence
of pathogenic microorganisms or their toxins) may benefit from repeated
infusions of massive numbers of leukocytes from compatible normal donors, but
this procedure is costly and not without risk.  It is therefore not
recommended for routine use.  The value of antimicrobial drug sterilization
of the gastrointestinal tract and the maintenance of agranulocytic patients
in sterile environments during cancer chemotherapy remains uncertain.

Saline or hydrogen peroxide gargles or anesthetic lozenges may relieve
the discomfort associated with mouth and throat ulcerations.  Oral thrush is
treated with myastatin mouth washes.  A semi-solid or liquid diet may be
necessary during acute inflammation of the mucous membranes.

Chronic granulocytopenic patients are hospitalized during acute episodes
of infection; therapy is similar to that for patients with acute
granulocytopenia.  Patients should be taught to recognize the early symptoms
and signs of acute infection and to seek immediate medical attention.  Those
patients who take low-dose oral antibiotics on a rotating basis must be
monitored for the emergence of resistant bacterial strains and infections
with opportunistic organisms such as fungi, pneumocystis, cytomegalovirus,
etc.  Therapy directed at improving the number of neutrophils depends on the
type of granulocytopenia.  Patients with decreased granulopoiesis (formation
of granulocytes) may be tried on a course of lithium carbonate.  If this form
of therapy is unsuccessful, adult patients may be give oxymetholone combined
with a small dose of prednisone.  Patients with primary and secondary
hypersplenic (having exaggerated functions of the spleen) forms of
granulocytopenia who have had repeated infections usually will respond well
to splenectomy (excision or extirpation of the spleen).  Improvement with
splenectomy also usually occurs in some patients with systemic lupus
erythematosus, cyclic neutropenia, and certain forms of marrow dysplasia
either with or without splenomegaly (enlarged spleen).

Therapies:  Investigational

This disease entry is based upon medical information available through May
1990.  Since NORD's resources are limited, it is not possible to keep every
entry in the Rare Disease Database completely current and accurate.  Please
check with the agencies listed in the Resources section for the most current
information about this disorder.

Resources

For more information on Acquired Agranulocytosis, please contact:

     National Organization for Rare Disorders (NORD)
     P.O. Box 8923
     New Fairfield, CT  06812-1783
     [phone]

     NIH/National Heart, Lung, and Blood Institute
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]

References

THE MERCK MANUAL 15th ed:  R. Berkow, et al:  eds; Merck, Sharp & Dohme
Research Laboratories, 1987.  P. 1173.

CECIL TEXTBOOK OF MEDICINE, 18th ed.:  James B. Wyngaarden, and Lloyd H.
Smith, Jr., Eds.:  W. B. Saunders Co., 1988.  Pp. 1325, 1699.