Agranulocytosis

Agranulocytosis, also termed agranulosis or granulopenia, is a severe haematological disorder characterised by a critically low white blood cell count, particularly affecting neutrophils. As a result, affected individuals develop profound neutropenia and are highly susceptible to bacterial and fungal infections. The condition represents an acute form of immunodeficiency and requires urgent clinical attention.

Clinical Features

Agranulocytosis may initially be asymptomatic, but symptoms frequently appear abruptly. Common signs include sudden fever, rigors and sore throat. Infections affecting any organ system—such as pneumonia or urinary tract infections—can progress rapidly due to the absence of adequate neutrophil-mediated immune responses. Sepsis can develop quickly in untreated cases. Laboratory findings typically show granulocyte concentrations below 200 cells per mm³, whereas other blood cell lines remain within normal ranges.

Aetiology

Agranulocytosis is most often induced by medications. A wide variety of drugs have been implicated, including:

• Antiepileptics: carbamazepine, valproate.
• Antithyroid agents: carbimazole, thiamazole, propylthiouracil.
• Antibiotics: penicillin, chloramphenicol, trimethoprim–sulfamethoxazole.
• H₂-receptor antagonists: cimetidine, famotidine, nizatidine, ranitidine.
• ACE inhibitors: benazepril.
• Cytotoxic drugs and gold salts.
• Analgesics and anti-inflammatory agents: aminophenazone, indomethacin, naproxen, phenylbutazone, metamizole.
• Other agents: mebendazole, allopurinol, and certain antidepressants such as mianserin and mirtazapine.
• Antipsychotics, particularly clozapine, which requires mandatory blood monitoring due to the risk of severe neutropenia.

Illicit drug contamination has also been linked to outbreaks. Cocaine adulterated with levamisole—an antihelminthic veterinary drug—has caused numerous cases in North America. The reason for its addition is not fully established, but similarities in melting point and physical appearance may contribute.
The reaction is generally idiosyncratic rather than dose-dependent. For this reason, patients prescribed high-risk medications are routinely advised to report early signs of infection, especially fever and sore throat.

Diagnosis

Diagnosis relies primarily on a complete blood count, which reveals an absolute neutrophil count (ANC) below 500 cells per microlitre, and in severe cases approaching zero. To confirm agranulocytosis and exclude conditions with similar presentations—such as aplastic anaemia, myelodysplastic syndromes, paroxysmal nocturnal haemoglobinuria and various leukaemias—a bone marrow examination is often required. In agranulocytosis, marrow cellularity is typically normal, but granulocytic precursors such as promyelocytes fail to mature, accounting for the deficit in circulating granulocytes.

Terminology and Classification

The term derives from Greek: a (“without”), granulocyte (a granule-containing white blood cell) and -osis (“condition”). Although it literally suggests a complete absence of granulocytes, this is not strictly required for diagnosis. The terminology surrounding granulocyte deficiencies includes:

• Granulocytopenia: a general reduction in granulocyte numbers; etymologically more precise.
• Neutropenia: a reduction in neutrophils specifically and the term most often used in clinical practice.
• Agranulocytosis: typically reserved for the most extreme form, with ANC < 100 cells per microlitre.

The condition may involve:

• Neutropenia (most common).
• Eosinopenia (uncommon).
• Basopenia (rare).

Pathogenesis

Mechanisms leading to agranulocytosis can be grouped into two broad categories:
1. Impaired granulocyte production

• Bone marrow failure as seen in aplastic anaemia, leukaemia or following chemotherapy.
• Selective suppression of granulocytic precursors, sometimes due to aberrant immune-cell activity such as cytotoxic T-cell or natural killer cell proliferation.

2. Accelerated destruction or utilisation

• Immune-mediated destruction of neutrophils triggered by drugs.
• Splenic sequestration in cases of splenomegaly.
• High rates of neutrophil consumption during overwhelming infection.

These pathways result in insufficient circulating neutrophils to mount an effective immune response.

Management and Treatment

In the absence of active infection, treatment centres on:

• Stopping the causative drug.
• Close monitoring through serial blood counts.
• Patient education regarding the importance of seeking urgent care with fever onset.