Neutropenic Sepsis

1. Definition

Neutropenic sepsis is a life-threatening medical emergency characterized by sepsis occurring in a patient with neutropenia, typically defined as:

Absolute neutrophil count (ANC) < 0.5 × 10⁹/L, or
< 1.0 × 10⁹/L and expected to fall below 0.5 × 10⁹/L

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3 criteria: an increase in SOFA score ≥ 2).

2. Causes

Iatrogenic: Chemotherapy-induced myelosuppression (most common)
Radiotherapy: Bone marrow suppression
Hematologic malignancies: AML, ALL, MDS, lymphoma
Bone marrow failure syndromes: Aplastic anemia
Immunosuppressive therapies: Post-transplant or autoimmune conditions

3. Risk Factors

Risk Factor	Description
Recent chemotherapy	Within the past 6 weeks
Profound neutropenia (<0.1 × 10⁹/L)	Higher risk of invasive infections
Mucositis or GI mucosal injury	Portal of bacterial/fungal translocation
Central venous catheters	Risk for bloodstream infections
Indwelling urinary catheters or drains	Increases local infection risk
Recent hospitalization or surgery	Nosocomial pathogen exposure
Corticosteroid use	Blunts immune response

4. Types / Classifications

By Neutropenia Severity:

Classification	ANC (× 10⁹/L)
Mild	1.0 – 1.5
Moderate	0.5 – 0.9
Severe	< 0.5
Profound	< 0.1

By Sepsis Criteria (Sepsis-3):

Sepsis: Suspected infection + ≥2-point increase in SOFA score
Septic shock: Persistent hypotension requiring vasopressors + serum lactate >2 mmol/L despite fluid resuscitation

5. Pathogenesis

Neutropenia impairs innate immunity, particularly phagocytic activity.
Disruption of mucosal barriers (oral, GI, respiratory) allows translocation of bacteria/fungi.
Dysregulated immune response → uncontrolled cytokine release → organ dysfunction.
Delayed recognition and treatment leads to progression to septic shock, multiorgan failure, and death.

6. Clinical Presentation

Symptoms:

Fever (>38.0°C or a single spike >38.3°C)
Chills, rigors
Malaise, fatigue
Diarrhea, mucositis
Localized symptoms often absent due to immune suppression

Signs:

Hypotension, tachycardia
Tachypnea or hypoxia
Oliguria
Altered mental status
No focal signs of infection in many cases

Physical Exam:

May be unrevealing; requires high index of suspicion
Look for mucositis, line infections, skin breakdown, perianal tenderness

7. Organ & System Complications

System	Complication
Cardiovascular	Septic shock
Respiratory	ARDS, pneumonia
Renal	Acute kidney injury
Hematologic	DIC, thrombocytopenia
Gastrointestinal	Mucositis, enterocolitis
Neurologic	Delirium, encephalopathy

8. Diagnostic Investigations

Investigation	Purpose
CBC with differential	Confirms neutropenia
Blood cultures (×2)	From peripheral vein and central line
CRP / procalcitonin	Inflammatory markers
Serum lactate	Marker of tissue hypoperfusion
Renal & liver panel	Assess end-organ dysfunction
Chest X-ray / CT	Rule out pneumonia or occult infection
Urinalysis & urine culture	Evaluate for UTI

9. Other Relevant Investigations

Fungal markers: Galactomannan, β-D-glucan (in prolonged neutropenia)
Viral PCRs: CMV, EBV, HSV (if clinically indicated)
Line tip cultures: If catheter removal is needed
Stool cultures: If diarrhea present
SOFA score: For sepsis severity

10. Treatment

Neutropenic sepsis is a medical emergency. Start antibiotics within 60 minutes of presentation.

Curative:

Treat underlying infection (bacterial/fungal/viral)
Reverse neutropenia (if possible, via G-CSF in select cases)

Empirical:

Start broad-spectrum IV antibiotics immediately:

First-line (UK & MY guidelines):
- Piperacillin-tazobactam 4.5 g IV Q6H
- If penicillin allergy: Meropenem or Cefepime ± Vancomycin (if line infection or MRSA risk)

Supportive:

IV fluids for sepsis resuscitation
Oxygen supplementation or ventilation support
Vasopressors (if hypotension persists)
Antifungals: if no response within 4–7 days or suggestive signs
Blood products for cytopenias

Palliative:

For end-stage malignancy or poor prognosis patients, consider goals-of-care and comfort measures

11. Long-Term Effects / Complications of Treatment

Treatment	Potential Complication	Monitoring
Broad-spectrum antibiotics	C. difficile infection	Stool studies if diarrhea develops
G-CSF	Bone pain, leukocytosis	CBC monitoring
Prolonged hospitalization	Deconditioning, nosocomial infections	Nutritional and mobility assessment
Line removal	Bleeding, thrombosis	Line site monitoring

12. Surveillance for the Disease

Measure	Frequency
Vital signs & fluid balance	Hourly in acute phase
CBC	Daily or more frequent if unstable
Blood cultures	Repeated if fever persists >48–72 hrs
CRP / procalcitonin	Serial to assess response
Fungal markers	If fever persists despite antibiotics
Review for de-escalation	Once patient afebrile and cultures negative

References

NHS/UK Guidelines:
- NICE NG151: Neutropenic Sepsis: prevention and management in cancer patients
  - https://www.nice.org.uk/guidance/ng151
- UK Sepsis Trust Toolkit: https://sepsistrust.org
Malaysia Clinical Practice Guidelines:
- Ministry of Health Malaysia, CPG: Management of Neutropenic Sepsis in Adults, 2nd Edition, 2019
  - https://www.moh.gov.my
UpToDate:
- "Evaluation and management of fever in patients with cancer and neutropenia"
- "Initial management of sepsis and septic shock in adults"