Agranulocytosis

What agranulocytosis means

Granulocytes are white blood cells with granules in them: neutrophils, eosinophils and basophils. Neutrophils make up most of them and are the first responders to bacterial and fungal infection. "Agranulocytosis" literally means an absence of granulocytes.

Agranulocytosis vs neutropenia: neutropenia is any low neutrophil count. Agranulocytosis is the severe end, usually with neutrophils near zero, and in classic use it means a sudden drop caused by a drug while red cells and platelets stay normal. When all three blood cell types fall, the term is pancytopenia, as in aplastic anemia.

Symptoms

Low neutrophils cause no symptoms by themselves. Symptoms come from infection, which can develop quickly:

• sudden fever, often high, with chills or rigors
• severe sore throat, sometimes with ulcers on the tonsils
• painful mouth ulcers and swollen, bleeding gums
• skin infections, abscesses or sores around the anus
• pneumonia, with cough and breathlessness
• feeling very weak and unwell

Because there are so few neutrophils, the usual signs of infection, such as pus or swelling, may be minimal. Fever is often the only sign.

Causes

Medicines (most common)

Drug-induced agranulocytosis is rare but can occur with many medicines. It usually appears within the first 3 months of starting the drug. It may be an immune reaction that destroys neutrophils, or direct toxicity to the bone marrow. Well-known culprits:

• Antithyroid drugs: methimazole, carbimazole and propylthiouracil, used for an overactive thyroid (hyperthyroidism)
• Clozapine: an antipsychotic; regular blood count monitoring is required
• Antibiotics: sulfonamides (co-trimoxazole), beta-lactams in high doses, chloramphenicol
• Sulfasalazine and dapsone
• Metamizole (dipyrone): a painkiller banned in the US and some other countries but used elsewhere
• Deferiprone, used for iron overload
• Anti-seizure drugs: carbamazepine
• Levamisole: often found as a contaminant in illicit cocaine

Chemotherapy causes expected, dose-related neutropenia, which is managed differently (see febrile neutropenia).

Bone marrow disorders

• Leukemia, myelodysplastic syndrome and cancers that spread to the marrow
• Aplastic anemia
• Radiation exposure

Other causes

• Infections: severe sepsis can use up neutrophils; viruses such as HIV, hepatitis, EBV and parvovirus suppress production
• Autoimmune disease: lupus, rheumatoid arthritis with an enlarged spleen (Felty syndrome)
• Nutritional deficiency: severe vitamin B12, folate or copper deficiency
• Congenital conditions: such as severe congenital neutropenia (Kostmann syndrome) and cyclic neutropenia, usually found in childhood

Diagnosis

1. Complete blood count with differential: confirms the neutrophil count and checks red cells and platelets.
2. Blood film: a specialist looks at the cells under a microscope.
3. Medicine review: every medicine started in the past few months, including over-the-counter and herbal products, and recreational drugs.
4. Infection workup when fever is present: blood cultures, urine tests, chest X-ray and swabs.
5. Bone marrow biopsy: if there is no clear drug cause, if other cell lines are low, or if counts do not recover after stopping a drug.
6. Other tests: vitamin B12, folate, HIV and hepatitis tests, and autoimmune screening.

Treatment

Stop the cause

The suspected drug is stopped immediately and should never be restarted. Related drugs may also be avoided. Your doctor will record it as an allergy.

Treat infection urgently

Fever with a very low neutrophil count is treated as febrile neutropenia. Hospitals aim to start broad-spectrum IV antibiotics within about 1 hour of arrival, before culture results are back. Antifungals are added if fever persists.

Help the marrow recover

• Granulocyte colony-stimulating factor (G-CSF) injections such as filgrastim can speed neutrophil recovery in drug-induced and chemotherapy-related cases.
• Bone marrow diseases are treated by a hematologist, sometimes with immune therapy or a stem cell transplant.

Protecting yourself while counts are low

• Wash hands often, and ask visitors to do the same.
• Avoid people with infections and crowded places.
• Keep teeth and gums clean with a soft brush.
• Avoid raw or undercooked meat, eggs and unwashed produce.
• Check your temperature if you feel unwell, and do not take fever-lowering medicine to hide a fever before calling your care team.

Outlook

With prompt drug withdrawal and treatment of infection, most people with drug-induced agranulocytosis recover their neutrophils within 1 to 3 weeks. The risk of death has fallen sharply with modern antibiotics and G-CSF but remains significant in older adults and those with sepsis, kidney failure or other serious illness. Outlook in marrow diseases depends on the underlying condition.

Frequently asked questions

What is agranulocytosis?

Agranulocytosis is a severe drop in granulocytes, especially neutrophils, the white blood cells that fight bacteria and fungi. The neutrophil count is usually below 500 per microliter. It leaves the body almost defenseless against infection, so fever is treated as an emergency.

What drugs cause agranulocytosis?

The most common are antithyroid drugs (methimazole, carbimazole, propylthiouracil), clozapine, sulfasalazine, co-trimoxazole and other sulfonamides, dapsone, carbamazepine, deferiprone and metamizole. Levamisole, a contaminant in cocaine, is another cause. Chemotherapy causes expected drops in neutrophils.

What are the first symptoms of agranulocytosis?

The first signs are usually a sudden fever, chills and a severe sore throat, often with mouth ulcers. Anyone taking a medicine known to cause it should stop the drug and get a same-day blood count if these symptoms appear.

What is the difference between agranulocytosis and neutropenia?

Neutropenia means any neutrophil count below normal, from mild to severe. Agranulocytosis is the most severe form, usually below 500 per microliter, and is classically a sudden, drug-induced drop affecting only white cells. Both raise infection risk, which grows as the count falls.

Can agranulocytosis be reversed?

Yes, in most drug-induced cases. Once the drug is stopped, neutrophils usually recover in 1 to 3 weeks, and G-CSF can speed this up. The same drug should never be taken again. Recovery in bone marrow diseases depends on treating the underlying condition.