Agranulocytosis: Symptoms, Types, Causes and Treatment

Agranulocytosis is a rare but potentially life-threatening condition where the body’s white blood cell count—specifically, neutrophils—drops drastically. Without enough of these immune cells, even minor infections can quickly become severe or fatal. While the condition is uncommon, its sudden onset and rapid progression make understanding its symptoms, types, causes, and treatment vital for patients, caregivers, and healthcare providers alike.

Symptoms of Agranulocytosis

Agranulocytosis often strikes unexpectedly. Because the body's defense against infection is compromised, early symptoms are usually related to infections that the immune system would otherwise contain. Recognizing these warning signs can be lifesaving, as timely medical intervention can prevent severe complications.

Symptom	Description	Frequency/Significance	Source(s)
Fever	Sudden, high-grade	Most common (78–84%)	1 2 3 4 5
Sore throat	Pain, difficulty swallowing	Early symptom (72–83%)	1 2 3 4
Ulcers/Stomatitis	Mouth or throat sores	Common, often with pain	4 5
Weakness	General malaise	Frequent	5
Infections	Sinusitis, bronchitis, pneumonia, sepsis	Major risk, can be severe	5 18

Table 1: Key Symptoms

Recognizing the Warning Signs

Fever and Sore Throat

The most consistent early symptoms of agranulocytosis are fever and sore throat. Studies show that fever is present in about 78–84% of cases, often accompanied by a sore throat in approximately 73–83% of patients at diagnosis 1 2 3 4. These symptoms typically signal a bacterial infection, which the immune system can no longer fight effectively due to neutrophil depletion.

Oral and Throat Ulcers

Ulcerative lesions in the mouth or throat—sometimes called stomatitis—are also common. Patients may develop painful sores, making eating and swallowing difficult. These can be the first clue in patients otherwise feeling only mildly unwell 4 5.

General Weakness and Other Infections

Generalized weakness, fatigue, and malaise are often reported. Because neutrophils help prevent both minor and major infections, patients may develop sinusitis, bronchitis, or even life-threatening infections like pneumonia and sepsis 5 18. In severe cases, the immune system’s inability to fight bacteria leads to rapid clinical deterioration.

The Importance of Early Detection

Unfortunately, routine blood tests may not always predict an impending episode, as some patients develop symptoms abruptly even with recent normal results 2. Delayed recognition and treatment can result in a lower minimum granulocyte count and longer recovery times, emphasizing the need for prompt evaluation whenever these symptoms arise in at-risk individuals 3.

Types of Agranulocytosis

Not all cases of agranulocytosis are the same. Understanding the different types helps clinicians tailor diagnosis and management, and gives patients a clearer sense of what to expect.

Type	Definition/Mechanism	Common Causes	Source(s)
Drug-induced	Sudden drop in neutrophils due to medications	Antithyroid drugs, antibiotics, antipsychotics, others	4 5 7 9 10 11
Immune-mediated	Body's immune system attacks neutrophils	Often triggered by drugs/metabolites	6 7 12
Cytotoxic	Direct toxic effect on bone marrow	Chemotherapy, some drugs	5 6
Idiopathic	Unknown cause	Rare, diagnosis of exclusion	5

Table 2: Types of Agranulocytosis

Drug-Induced Agranulocytosis

The Most Common Type

The majority of agranulocytosis cases are drug-induced, accounting for up to 70% or more in several large studies 10 11. Medications most frequently implicated include antithyroid drugs (like methimazole and propylthiouracil), antibiotics (e.g., penicillins, sulfonamides), antipsychotics (especially clozapine), antiplatelet agents, and certain NSAIDs 5 9 10 11 18.

Mechanisms

Drug-induced agranulocytosis can occur in two main ways:

• Immune-mediated (idiosyncratic): The drug or its metabolite triggers an abnormal immune response, leading the body to attack its own neutrophils or their precursors. This reaction is unpredictable, can occur after days to months of exposure, and is not dose-dependent 6 7 12.
• Direct cytotoxic: Some drugs (notably chemotherapy agents) directly suppress bone marrow function, causing predictable neutrophil depletion 5 6.

Immune-Mediated vs. Cytotoxic

• Immune-mediated agranulocytosis is often sudden in onset and can happen even with normal doses. It is more likely with certain genetic backgrounds and may recur if the same drug is reintroduced 7 12 13.
• Cytotoxic agranulocytosis is usually dose-related, such as with chemotherapy drugs 5 6. It develops more gradually and is easier to predict and monitor.

Idiopathic and Other Types

Rarely, agranulocytosis occurs without a clear cause—termed idiopathic. This diagnosis is made only after excluding drugs, infections, inherited disorders, and bone marrow diseases 5.

Causes of Agranulocytosis

While several factors can lead to agranulocytosis, medications are by far the most common cause. However, genetics, underlying medical conditions, and even infections can play a role.

Cause	Examples/Details	Notes/Significance	Source(s)
Drugs	Antithyroid, antibiotics, antipsychotics, NSAIDs, antiplatelets	Most common cause, up to 70%	5 9 10 11 18
Genetic susceptibility	HLA-B38:02, HLA-DRB108:03	Strongly increases risk	13
Chemotherapy	Alkylating agents, antimetabolites	Direct marrow suppression	5 6
Autoimmune diseases	Lupus, rheumatoid arthritis	Rare, via immune destruction	5
Infections	Viral (rare)	Usually transient	5

Table 3: Common Causes

Medication-Related Agranulocytosis

High-Risk Medications

• Antithyroid drugs: Methimazole, propylthiouracil, and carbimazole are leading culprits, especially in the treatment of hyperthyroidism and Graves' disease 1 2 3 10 11.
• Antipsychotics: Clozapine carries a recognized risk, with modern monitoring programs reducing the incidence and fatality rates 8 16.
• Antibiotics: Penicillins, sulfonamides, and others can trigger the condition 9 10 11.
• Other drugs: NSAIDs, antiplatelet agents (e.g., ticlopidine), and iron chelators like deferiprone have also been linked 9 17 18.

Timing and Risk Factors

The onset of drug-induced agranulocytosis usually occurs within weeks to a few months after starting the offending medication. For antithyroid drugs, approximately 80–90% of cases emerge within the first 2–3 months of therapy 1 2 3.

Additional risk factors include older age, female sex, prior chemotherapy or radiation, malnutrition, and certain genetic markers 5 13 17. For instance, individuals carrying HLA-B38:02 and HLA-DRB108:03 alleles are at dramatically increased risk of antithyroid drug-induced agranulocytosis 13.

Genetics and Susceptibility

Pharmacogenetics plays a crucial role. In some populations, certain HLA types confer a 20- to 40-fold increased risk, and carrying both can make risk even higher 13. This finding suggests that genetic screening may one day help prevent cases among high-risk individuals.

Non-Drug Causes

• Chemotherapy: Cytotoxic agents for cancer almost universally cause neutropenia as a predictable side effect 5 6.
• Autoimmune disorders: Rarely, diseases like lupus can cause immune-mediated destruction of neutrophils.
• Infections: Acute viral illnesses may transiently suppress neutrophil production, but these cases usually resolve without specific treatment 5.

Treatment of Agranulocytosis

Prompt recognition and management of agranulocytosis can be life-saving. The treatment approach varies depending on cause, severity, and presence of infection.

Treatment Step	Purpose/Effect	Notes/Outcomes	Source(s)
Discontinue offending drug	Stops further neutrophil loss	Critical first step	4 5 6 9 18
Broad-spectrum antibiotics	Treats/prevents infection	Initiate even before infection confirmed	18
Hematopoietic growth factors (G-CSF, GM-CSF)	Stimulates neutrophil recovery	Shortens recovery in some cases, not all	1 2 14 15 18
Supportive care	Fluids, monitoring, isolation	Manage complications	5 18
Treat underlying disease	Hyperthyroidism, psychosis, etc.	Adjust therapy as needed	1 8 16

Table 4: Main Treatment Strategies

Immediate Actions: Stop the Offending Drug

Discontinuing the causative medication is the single most important intervention. Ongoing exposure worsens neutrophil destruction and increases the risk of fatal infection 4 5 6 9 18. In polypharmacy cases, careful review and withdrawal of all potential culprits may be necessary.

Infection Control: Broad-Spectrum Antibiotics

Because infection risk is extremely high, most patients are started on empirical (preventive) broad-spectrum antibiotics at the first sign of fever or other infection—even before microbiological confirmation 18. Severe infections, including septicemia and pneumonia, are not uncommon and can progress rapidly 18.

Hematopoietic Growth Factors: G-CSF and GM-CSF

Growth factors like granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are used to accelerate neutrophil recovery. Their effectiveness varies:

• Some studies show a reduction in recovery time, especially in mild or asymptomatic cases 15 18. For example, recovery time was shortened from 5–9 days to 2–5 days in some settings 15.
• However, other studies found little or no benefit in severe cases or those with very low neutrophil counts 1 2 14.
• G-CSF is generally not effective in patients with severe symptoms and neutrophil counts below 0.1 x 10⁹/L; these patients require intensive supportive care 15.
• Modern management protocols recommend selective use of growth factors, primarily in moderate cases or where recovery needs to be expedited 18.

Supportive Care and Monitoring

Hospitalization is often required, especially if the patient is febrile, symptomatic, or severely neutropenic. Supportive care may include:

• Intravenous fluids
• Strict infection control measures (protective isolation)
• Frequent monitoring of blood counts and vital signs
• Management of complications (e.g., sepsis, organ dysfunction) 5 18

Treating the Underlying Condition

If agranulocytosis is secondary to treatment for another medical condition (e.g., hyperthyroidism, psychosis), alternative therapies must be considered. For example, patients with Graves' disease who develop agranulocytosis on antithyroid drugs may be managed with radioiodine (I-131) therapy, which is both effective and safe 1. In psychiatric patients, alternative antipsychotic medications or other strategies may be needed 8.

Prognosis

With prompt recognition and appropriate therapy, the prognosis for drug-induced agranulocytosis is generally good, with survival rates exceeding 95% in modern cohorts 18. However, delays in diagnosis or treatment, severe infections, or very low neutrophil counts increase the risk of complications and mortality 3 9 17.

Conclusion

Agranulocytosis, though rare, is a medical emergency that demands vigilance from both clinicians and patients. Its sudden onset, often triggered by common medications, makes early recognition of symptoms and risk factors essential.

Key Points Covered in This Article:

• Symptoms: Fever, sore throat, and infections are the most frequent and dangerous signs; early detection is crucial.
• Types: Most cases are drug-induced, particularly via immune-mediated or cytotoxic mechanisms; idiopathic cases are rare.
• Causes: Medications—especially antithyroid drugs, antibiotics, and antipsychotics—are most often responsible, with genetic factors and other medical conditions sometimes playing a role.
• Treatment: Discontinuing the offending drug, starting broad-spectrum antibiotics, and using hematopoietic growth factors when appropriate form the cornerstone of management. Supportive care and treatment of underlying diseases are also vital.

Awareness, rapid action, and careful management can dramatically improve outcomes for those affected by agranulocytosis.