Agranulocytosis

Etiology

Agranulocytosis can be broadly classified into two distinct categories, inherited and acquired. The hereditary disease is due to genetic mutations in the gene coding for neutrophils elastase or ELA2. The most commonly seen mutations are intronic substitutions that inactivate a splice site in intron 4. Acquired diseases may be due to various medications,[1] chemicals, autoimmune conditions, and infections.

The following are the medications commonly involved with agranulocytosis:

• Cancer chemotherapies
• Analgesic and anti-inflammatory (gold, naproxen, and penicillamine)
• Anti-thyroid (carbimazole, propylthiouracil)[2][3]
• 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)[4]
• Antibiotics (sulphonamides, penicillin, cephalosporins)[5]
• Miscellaneous (cimetidine, ranitidine, chloropropamide, zidovudine)[6]

Infections that can cause agranulocytosis include:

• Bacterial (typhoid fever, shigella enteritis, brucellosis, tularemia, tuberculosis)
• Rickettsial (rickettsialpox, human granulocytic anaplasmosis, Rocky Mountain spotted fever)
• Parasitic (kala-azar, malaria)
• Viral (human immune deficiency, Epstein-Barr virus, cytomegalovirus, hepatitis viruses, human herpesvirus 6)

Autoimmune conditions such as lupus, rheumatoid arthritis, and bone marrow diseases like myelodysplastic and leukemias are also associated with agranulocytosis.

Epidemiology

Agranulocytosis is a rare condition and occurs in all age groups, with a reported incidence ranging from 6 to 8 cases per million population per year.[7] About 70% of the cases are found to be involved with medication usage. It also occurs more frequently in women than in men, either because of increased medication usage in females or due to increased incidence of autoimmune diseases in females. Agranulocytosis has no racial predilection.

Pathophysiology

Two main mechanisms responsible for agranulocytosis include inadequate or ineffective granulopoiesis and accelerated removal or destruction of neutrophils. Inadequate or ineffective granulopoiesis is due to generalized marrow failure. It also occurs in aplastic anemia, varieties of leukemias, myelodysplastic syndromes. Accelerated removal or destruction of neutrophils occurs due to immune-mediated injury to neutrophils or is idiopathic.

Histopathology

Marrow hypercellularity is seen when it results from excessive destruction of the mature neutrophils or ineffective granulopoiesis. In contrast, drugs that suppress granulocytopoiesis are associated with a marked decrease in mature granulocytic precursors in the marrow.[8]

History and Physical

A history of a new medication used or a change in medication, recent exposure to chemical or physical agents, or recent viral or bacterial infection is usually associated with agranulocytosis. A history of autoimmune disease or a strong family history of recurrent infection usually beginning from early childhood may be present. The initial symptoms are often malaise, fever, and chills, or infections, which usually present in the form of ulcers, necrotizing lesions of the gingiva, the floor of the mouth, buccal mucosa, pharynx, or other sites within the oral cavity.[9] Pharyngitis, with difficulty in swallowing and multiple skin abscesses, could be another presentation of the disease. As the onset of agranulocytosis can be abrupt, sepsis can be the presentation. On examination, a fever usually more than 40 degrees Celcius, tachycardia, tachypnea, and hypotension are usually present.

Evaluation

The diagnosis of agranulocytosis requires a high degree of suspicion based on signs and symptoms, medication use, recent exposure to chemical agents, and infections. A complete blood count (CBC) with the differential count is used in the initial workup. An absolute neutrophil count (ANC) of less than 100 neutrophils per microlitre of blood is necessary to diagnose the condition. The peripheral blood smear should assess neutrophil morphology. A Wright-stained peripheral smear will show a 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), and urine analysis can be used in patients with a relevant history. If the patient is febrile, cultures of the blood, urine, sputum and other suspected sites of infection should be taken. No imaging technique is used to diagnose agranulocytosis, but a chest X-ray (CXR) can be used for the initial workup. Further, bone marrow aspiration and biopsy can be used after an initial abnormal blood smear.

Treatment / Management

Agranulocytosis is a serious condition, and prompt treatment for it should be initiated. Once agranulocytosis is documented, any suspected offending medications or agents should be removed regardless of whether the patient is symptomatic or not. If it is due to drugs or offending agents, it usually resolves after one to three weeks after the offending agent is stopped. Meanwhile, general care like oral hygiene to prevent infection of the mucosa and teeth, control of oral and gingival lesion pain with anesthetic gel, and gargles are helpful. Stool softeners can be used in case of constipation. Skin infection and abrasion should be treated promptly.

Hematopoietic growth factors are used to accelerate the production, maturation, migration, and cytotoxicity of the neutrophils.[10] Filgrastim, a granulocyte colony-stimulating factor (G-CSF),[11] sargramostim, a granulocyte-macrophage colony-stimulating factor, pegfilgrastim (a long-acting filgrastim) are the agents used to treat agranulocytosis.(A1)

In case of infection, start specific antibiotic therapy with third-generation cephalosporins or equivalent. Cefepime,[12] carbapenems,[13] (e.g., meropenem, imipenem-cilastatin), or piperacillin-tazobactam can be used. In suspected cases of resistant bacteria, vancomycin or linezolid can be used in methicillin-resistant Staphylococcus aureus (MRSA). Linezolid or daptomycin can be used in cases of vancomycin-resistant enterococcus. Carbapenems can be used in the case of extended-spectrum beta-lactamase (ESBL) producing gram-negative bacteria. If the patient’s fever does not respond within 4-5 days or if the fever recurs with the administration of broad-spectrum antibiotics after an initial afebrile interval, consider adding empiric antifungal coverage with amphotericin B (preferably lipid formulation), a broad-spectrum azole (e.g., voriconazole), or an echinocandin (e.g., caspofungin).(B2)

Differential Diagnosis

Agranulocytosis should be differentiated from other conditions that cause bone marrow failure and leukemias. The following are the differential diagnosis of agranulocytosis:

• Aplastic anemia: Aplastic anemia is a condition of 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): Patients with AML present with signs and symptoms of 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): ALL is a 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 immune deficiency virus (HIV): Patients with HIV can present in any stage of the illness 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: EBV infectious mononucleosis is an infectious disease caused by EBV (human herpes virus-4). It presents with fatigue, malaise, sore throat, pharyngitis, and fever.
• Bacterial sepsis: Sepsis is a life-threatening condition characterized by fever (temperature more than 38 degrees Celcius, or less than 36 degrees Celcius) with or without chills, hypotension, tachypnea, respiratory infections, altered mental status, gastro-intestinal or genito-urinary infections.

Prognosis

A number of factors are associated with adverse prognosis in patients with agranulocytosis. These include:

• Age more than 65 years
• Absolute neutrophil count at the time of diagnosis less than 100/microlitre
• Development of severe intercurrent infection (e.g., septicemia, septic shock)
• Pre-existing comorbidities (e.g., renal, cardiac, respiratory, and systemic inflammatory diseases)

Complications

The main complication of agranulocytosis is infection. The duration and severity of agranulocytosis directly correlate with the incidence of infection. 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 is another major complication of agranulocytosis. Sepsis is a clinical syndrome due to the dysregulated bodily response to infection. As the number of mature granulocytes is severely decreased in agranulocytosis, the body is no longer able to fight the offending agents leading to sepsis, bacteremia, and septic shock. Septic shock is a type of distributive or vasodilatory shock that leads to circulatory and metabolic abnormalities and is associated with a higher rate of mortality.