Inherited agranulocytosis:Hereditary disease is due to genetic mutations in the gene coding for neutrophils elastase or ELA2.
- Intronic substitutions that inactivate a splice site in intron 4 (M/C seen mutations)
Acquired agranulocytosis:Acquired diseases may be due to various medications, chemicals, autoimmune conditions, and infections.
Idiosyncratic drug-induced agranulocytosis (IDIA)Increasing age and female sex have been considered as risk factors for the development of this condition.
- Cancer chemotherapies
- Analgesic and anti-inflammatory (gold, naproxen, and penicillamine)
- Anti-thyroid (carbimazole, propylthiouracil)
- Anti-arrhythmics (quinidine, procainamide)
- Anti-hypertensives (captopril, enalapril, nifedipine)
- Anti-depressants/psychotropics (clozapine, amitriptyline, dosulepin, mianserin)
- Anti-malarials (pyrimethamine, dapsone, sulfadoxine, chloroquine)
- Anticonvulsants (phenytoin, sodium valproate, carbamazepine)
- Antibiotics (sulphonamides, penicillin, cephalosporins)
- Miscellaneous (cimetidine, ranitidine, chloropropamide, zidovudine)
- Bacterial (typhoid fever, shigella enteritis, brucellosis, tularemia, tuberculosis)
- Rickettsial (rickettsialpox, human granulocytic anaplasmosis, Rocky Mountain spotted fever)
- Parasitic (kala-azar, malaria)
Two main mechanisms responsible for agranulocytosis include inadequate or ineffective granulopoiesis and accelerated removal or destruction of neutrophils.
- Inadequate/ineffective granulopoiesis: Due to generalized marrow failure.
- Occurs in aplastic anemia, varieties of leukemias, myelodysplastic syndromes.
- Accelerated removal/destruction of neutrophils: Due to immune-mediated injury to neutrophils or is idiopathic.
Onset of agranulocytosis can be abrupt, sepsis can be the presentation. On examination, a fever usually > 40C, tachycardia, tachypnea, and hypotension are usually present.
- Initial symptoms: Malaise, fever, and chills
- Common presentation: High fever and sore throat
- Acute pharyngitis and other infections in the oral cavity are the most common clinical diagnoses at presentation
- Infection (primary complication): Ulcers, necrotizing lesions of the gingiva, the floor of the mouth, buccal mucosa, pharynx, or other sites within the oral cavity.
- When the ANC remains lower than 100 cells per microlitre of blood for longer than 3-4 weeks, the incidence of infection approaches 100%.
- Sepsis: Clinical syndrome due to the dysregulated bodily response to infection.
- Septic shock: Distributive/vasodilatory shock that leads to circulatory and metabolic abnormalities and is associated with a higher rate of mortality.
The diagnosis of agranulocytosis requires a high degree of suspicion based on signs and symptoms, medication use, recent exposure to chemical agents, and infections.
Laboratory studies:Diagnosis is established by an absolute neutrophil count (ANC) < 500/μl in the context of the clinical picture presented above.
- Complete blood count (CBC) with the differential count is used in the initial workup.
- Absolute neutrophil count (ANC) < 100 neutrophils/microlitre of blood
- Wright-stained peripheral blood smear (PBS): Marked decrease and absence of neutrophils.
- Erythrocyte sedimentation rate (ESR), C reactive protein (CRP)
- Coagulation studies (prothrombin time, partial thromboplastin time, D-dimer)
- Lactate dehydrogenase (LDH), antinuclear antibody (ANA), rheumatoid factor (RF)
- Liver function tests (LFT), renal function tests (RFT)
Bone marrow examination:Exclude malignancy, determine cellularity and assess myeloid maturation.
- Selective reduction/absence of granulocytic precursors with normal?increased erythropoiesis
- Megakaryocyte proliferation or left-shifted granulopoiesis with few/no mature granulocytes beyond myelocytes
Differential diagnosis:Other conditions that cause bone marrow failure and leukemias.
- Aplastic anemia: Bone marrow failure characterized by features of pancytopenia. It includes signs and symptoms of anemia (pallor, fatigue, dizziness, murmur), petechial rashes, gingival bleeding, infections, and ulcerations.
- Acute myeloid leukemia (AML): Present with bone marrow failure and organ infiltration. Bone marrow failure results in signs and symptoms of pancytopenia like pallor, fatigue, gingival bleeding, rashes, and infections.
- Acute lymphoblastic leukemia (ALL): Malignant disease of the bone marrow presenting with pancytopenia. It is the most common type of cancer and leukemia in children characterized by fever, pallor, fatigue, dizziness, bleeding, blood clots, lymphadenopathy, infections (pneumonia, and urinary tract infection).
- Human immunodeficiency virus (HIV): Can present in any stage with flu-like illness, fever, malaise, rash, oral ulceration, and severe infections. A detailed history can help differentiate it from agranulocytosis.
- Epstein-Barr virus (EBV) infectious mononucleosis: Presents with fatigue, malaise, sore throat, pharyngitis, and fever.
- Bacterial sepsis: Life-threatening condition characterized by fever with/without chills, hypotension, tachypnea, respiratory infections, altered mental status, gastro-intestinal or genito-urinary infections.
Treatment starts with the identification and immediate discontinuation of the causative agent to prevent further damage.
- IV broad-spectrum antibiotics (mainstay of treatment)
- Granulocyte-colony stimulation factors (G-CSFs) (hematopoietic growth factors): Reduce the time to hematological recovery, duration of antibiotic therapy and hospitalization and global costs
Preventive measures recommended: Good hygiene in high-risk areas such as the mouth, skin and perineum.