Agranulocytosis is characterized by a greatly decreased number of circulating neutrophils. Severe neutropenia is the term usually applied to patients with fewer than 500 neutrophils per microliter (μL) (including bands).
Agranulocytosis usually refers to patients with fewer than 100 neutrophils/μL.The reduced number of neutrophils makes patients extremely vulnerable to infection. Cardinal symptoms include fever, sepsis, and other manifestations of infection. Causes can include
drugs, chemicals, infective agents, ionizing radiation, immune mechanisms, and heritable genetic aberrations.
PATHOPHYSIOLOGYAgranulocytosis may be broadly divided into 2 groups: hereditary disease due to genetic mutations and acquired disease.
Hereditary disease due to genetic mutationsMany hereditary disorders are due to mutations in the gene encoding neutrophil elastase, or ELA2. Several alleles are involved. The most common mutations are intronic substitutions that inactivate a splice site in intron 4. Genes other than ELA2 are also involved.
A strong family history of recurrent infections, usually beginning in childhood, is strongly indicative of a genetic defect.
Acquired diseaseAcquired agranulocytic disease may be due to
drugs, chemicals, autoimmunity, infectious agents, or other causes.
Drugs or chemical is the most common cause of agranulocytosis. About one half of patients have a history of medication or chemical exposure. The patient's history must be carefully taken to elicit this information. (
read : list of drugs causing agranulosytosis)Bone marrow and peripheral blood are the organ systems affected. Agranulocytosis is characterized by inadequate production of neutrophils, excessive destruction of neutrophils, or both. The resulting infections tend to involve the oral cavity, mucous membranes, and skin. Systemic life-threatening sepsis may ensue. The most common infecting organisms are staphylococci, streptococci, gram-negative organisms, and anaerobes. Fungi are also commonly involved as secondary infective agents.
The occurrence of infection depends on the degree and duration of neutropenia. When the ANC (absolute neutrophil countis) persistently fewer than 100/µL for longer than 3-4 weeks, the incidence of infection approaches 100%.
EPIDEMIOLOGYFrequencyThe exact frequency of agranulocytosis is unknown. The estimated frequency of agranulocytosis is 1.0-3.4 cases per million population per year.
RaceAgranulocytosis has no racial predilection.
SexAgranulocytosis occurs slightly more frequently in women than in men, possibly because of their increased rate of medication usage. Whether this higher frequency is related to the increased incidence of autoimmune disease in women is unknown.
AgeAgranulocytosis occurs in all age groups.
The congenital forms are most common in childhood.
Acquired agranulocytosis is most common in the elderly population.
SIGN AND SYMPTOMSHistoryPatients with agranulocytosis usually present with the following:
- Sudden onset of malaise
- Sudden onset of fever, possibly with chills and prostration
- Stomatitis and periodontitis accompanied by pain
- Pharyngitis, with difficulty in swallowing
- If treatment is not promptly instituted, the infection progresses to generalized sepsis, which may become life threatening.
- Patients often report a history of a new drug being used or a recent change in medication.
- Occupational or accidental exposure to chemicals or physical agents (eg, ionizing radiation) may have occurred.
- The patient may have experienced a recent viral infection, although such infections are rarely associated with severe neutropenia. Certain bacterial infections may also precede agranulocytosis.
- A history of periodically recurring infections is suggestive of cyclic neutropenia.
- A history of autoimmune diseases may be associated with antineutrophil antibodies. Such antibodies may also be the only manifestation of autoimmune disease. A number of test methods are available, but none is widely used.
- A strong family history of recurrent infections, usually beginning in childhood, is strongly indicative of a genetic defect.
Physical- Fever may be present (temperature often 40 º C or higher).
- Rapid pulse and respiration may be evident.
- Hypotension and signs of septic shock if infection has been present
- Painful aphthous ulcers may be found in the oral cavity.
- Swollen and tender gums may be present.
- Usually, purulent discharge is not present, because not enough neutrophils exist to form pus.
- Skin infections are associated with painful swelling, but erythema and suppuration are usually absent.
DIFFERENTIAL DIAGNOSIS- Large granular lymphocyte leukemia
- Autoimmune diseases
- Chronic myelomonocytic leukemia
- Congenital neutropenia
- Cyclic neutropenia
- Drug-induced neutropenia
- Large granular lymphocytic leukemia
- Pseudoneutropenia
TREATMENTMedical care for patients with neutropenia is mostly supportive and based on the etiology, severity, and duration of the neutropenia. Fever and infections occurring as complications of neutropenia require specific treatment.
General Care:- Removal of any offending drugs or agents is the most important step in most cases involving drug exposure; if the identity of the causative agent is not known, stop administration of all drugs until the etiology is established
- Use careful oral hygiene to prevent infections of the mucosa and teeth; control oral and gingival lesion pain with saline and hydrogen peroxide rinses and local anesthetic gels and gargles
- Avoid rectal temperature measurements and rectal examinations
- Administer stool softeners for constipation
- Use good skin care for wounds and abrasions; skin infections should be managed by someone with experience in the treatment of infection in neutropenic patients
AntibioticsStart specific antibiotic therapy to combat infections. This often involves the use of third-generation cephalosporins or equivalents
Colony-Stimulating Factor TherapyMyeloid growth factors—specifically, granulocyte colony-stimulating factors (G-CSFs) and granulocyte-macrophage colony-stimulating factor (GM-CSFs)—may shorten the duration of neutropenia
Granulocyte TransfusionNeutrophil (granulocyte) transfusions have undergone a cycle of popularity followed by disfavor. These transfusions are accompanied by many complications, including severe febrile reactions. Their use is controversial.
PROGNOSISIf agranulocytosis is untreated, the risk of dying is high. Death results from uncontrolled sepsis.
If the condition can be reversed with treatment, the risk of dying is low. Antibiotic and antifungal medications can cure the infection if the ANC rises.
Morbidity is entirely due to infections that complicate agranulocytosis. The infections may be superficial, involving mainly the oral mucosa, gums, skin, and sinuses, or they may be systemic, with life-threatening septicemia.
Reference
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