Neutropenic sepsis

Neutropenic sepsis is a common medical emergency of cancer therapy. It usually occurs with patients undergoing chemotherapy. Most commonly, it happens due to catching a bacterial infection 7-14 days post-chemotherapy. This is because many chemotherapeutic drugs cause bone marrow suppression leading to neutropenia.

Neutropenia is defined as having a neutrophil count <0.5 x 10⁹/L. The normal range is 2-7 x 10⁹/L.

Neutropenic sepsis is considered in any patient who is being treated for cancer and has one of the following:

• Temperature >38ºC
• Signs and symptoms consistent with the clinical findings of sepsis

Pathophysiology

Neutrophils are produced in the bone marrow through the process of granulopoiesis - a process regulated by haematopoietic stem cells (HSCs) that undergo differentiation by various growth factors (especially granulocyte colony-stimulating factor (G-CSF). These neutrophils are then released into the blood stream once mature.

Chemotherapy drugs target cells that are rapidly dividing (a characteristic trait of malignant cells). However, as bone marrow cells are also rapidly dividing they become susceptible to the cytotoxic effects of chemotherapy drugs → bone marrow suppression and subsequent anaemia, thrombocytopenia and neutropenia.

Neutropenia, when severe (<500/µL), increases the risk of opportunistic infections, making early identification and management crucial, particularly in chemotherapy patients who are at high risk for febrile neutropenia and sepsis.

Although chemotherapy is the most common cause of neutropenia, other causes of neutropenia include:

• Malignant bone marrow infiltration
• Extensive radiotherapy
• Bone marrow failure - secondary to non-malignant disease (e.g. aplastic anaemia)
• Hypersplenism
• Infections - such as HIV and EBV (which causes transient bone marrow suppression)
• Megaloblastic anaemia
• Drug-induced (e.g. clozapine)

💡 A rare but potentially life-threatening side-effect of clozapine is neutropenia and agranulocytosis.

🦠 Causative agent

Neutropenic sepsis is predominantly of bacterial aetiology, however, it is important to consider fungal infections (especially Candida species) in immunocompromised individuals.

💡 It is important to note that only 1/3rd of patients with febrile neutropenia have an identified causative organism.

😷 Presentation

• Febrile neutropenia - this is when there is an isolated pyrexia as the only evidence of infection.

Neutropenic sepsis may also present without fever in some patients, including older patients and those taking immunosuppressive medications such as steroids. Therefore, neutropenic sepsis should be considered in any patient at risk of neutropenia who presents unwell, irrespective of temperature.

Symptoms of neutropenic sepsis may be non-specific symptoms of sepsis or reflect the underlying source of infection. But due a decreased ability to mount an inflammatory response, many patients with febrile neutropenia related to a deep-seated focus of infection fail to demonstrate typical localising signs or symptoms.

General, non-specific symptoms of sepsis include:

• Fatigue
• Feeling warm or cold
• Rigors or shaking
• Feeling sweaty or clammy
• Palpitations
• Dizziness
• Confusion or disorientation

Symptoms that reflect a specific infective source include:

• Chest source - shortness of breath, cough, chest pain, sore throat.
• Urine source - dysuria, increased frequency, urgency or any other lower urinary tract symptoms (LUTS).
• Skin source - rashes, blisters, pain.
• Gastrointestinal source - diarrhoea, nausea, vomiting, rectal bleeding, abdominal pain, sore mouth (due to mucositis which is secondary to chemotherapy).
• Indwelling line source - pain around the line or rigors after use of the line.

🔢 Grading

Severity of neutropenia and its duration are correlated with the risk of developing neutropenic sepsis. The Common Terminology Criteria for Adverse Events (CTCAE) grading system can be used to grade the severity of neutropenia:

🔍 Investigations

• ABCDE approach to examination:

General clinical findings in neutropenic sepsis may include:

1. Haemodynamic instability
2. Fever
3. Reduced urine output
4. Altered conscious level or confusion
5. Mottled appearance
• The examination should progress to focus more specifically on identifying a source:
• Chest - increased work of breathing, crepitations, dullness to percussion, reduced air entry.
• Urinary - suprapubic or flank pain, cloudy urine in catheter bag (if applicable).
• Skin - rashes, blistering, tenderness.
• Gastrointestinal - abdominal tenderness, dehydration (if reporting vomiting or diarrhoea), evidence of oral mucositis, jaundice.
• Indwelling line - surrounding erythema, tenderness on palpation, pain or rigors on flushing.
• Investigations may include:
• ECG
• Urinalysis
• Blood glucose - to exclude hypoglycaemia
• Baseline bloods
• Blood cultures - at least two sets from a peripheral vein plus a set from an indwelling line if present to look for a causative organism.
• Lactate
• ABG
• Microbiological cultures - wounds, urine, stool, sputum, and line tip (if indwelling line infection suspected).
• Imaging
• Broncheoalveolar lavage - if suspecting pneumocystis jirovecii pneumonia.

🧰 Management

🚨 Complications

• Single or multi-organ failure - such as renal failure, heart failure and acute respiratory distress syndrome)
• VTE - such as pulmonary embolism or DVT.
• DIC
• Opportunistic or hospital-acquired infections
• Delirium
• Psychological complications - such as anxiety regarding future infections and chemotherapy treatment.
• Delays in chemotherapy - leading to worse cancer outcomes