Neutropenic Sepsis

Introduction

Neutropenic sepsis is the commonest life-threatening complication of anti-cancer treatment, and one of the few genuine emergencies in oncology where the actions of a foundation doctor in the first hour change survival. Reported mortality ranges from around 2% in a fit patient with a solid tumour to over 20% in patients with haematological malignancy, prolonged neutropenia or established organ dysfunction.^1,4

The diagnostic problem is that the usual signs of infection are generated by neutrophils. Without them there is little pus, little consolidation on a chest radiograph, and often only faint erythema at an infected line site. Fever may be the only abnormality, and in patients on corticosteroids or paracetamol even that may be absent. The safe approach is therefore not to look for convincing evidence of infection, but to assume it.

The whole of NICE CG151 can be summarised in one sentence: treat first, investigate second. Waiting for the full blood count before starting antibiotics is the classic error, and it is what examiners test.

Definitions

NICE defines neutropenic sepsis in patients having anti-cancer treatment as a neutrophil count of 0.5 x10^9/L or lower together with either a temperature higher than 38 °C, or other signs or symptoms consistent with clinically significant sepsis.¹

Two features of that definition are easily missed. First, the temperature criterion and the clinical criterion are alternatives, not both required - a hypotensive, confused, hypothermic patient with a neutrophil count of 0.2 x10^9/L has neutropenic sepsis whatever their temperature. Second, in practice treatment starts before the count is known, on the basis of recent chemotherapy alone.

Pathophysiology and microbiology

Chemotherapy damages both the bone marrow, removing the effector cells, and the mucosal barriers of the mouth and gut, creating the portal of entry. Most episodes are therefore caused by the patient's own flora translocating across damaged gut or oral mucosa, or entering through an indwelling central venous catheter. In more than half of episodes no organism is ever identified, which does not mean the episode was not infective.

• Gram-positive organisms now cause the majority of documented bacteraemias, reflecting the widespread use of central lines and the effect of quinolone prophylaxis. Coagulase-negative staphylococci from lines are common but rarely fulminant; Staphylococcus aureus and viridans group streptococci (from oral mucositis) are more dangerous.
• Gram-negative organisms - Escherichia coli, Klebsiella, Pseudomonas aeruginosa - are less frequent but cause the most rapid deterioration and the highest mortality. This is why empirical cover must always include anti-pseudomonal activity.
• Fungi - Candida species, and Aspergillus in prolonged profound neutropenia. These typically appear as persistent fever after 4 to 7 days of broad-spectrum antibiotics rather than at presentation.
• Viruses - herpes simplex reactivation causing oral ulceration, varicella zoster, and respiratory viruses
• Pneumocystis jirovecii - in patients on prolonged corticosteroids or specific regimens, which is why co-trimoxazole prophylaxis is prescribed for some

Risk factors

• The regimen - risk is highest with regimens for acute leukaemia and lymphoma, conditioning for stem cell transplant, and intensive solid tumour regimens such as docetaxel-based combinations and platinum-etoposide
• Time since the last cycle - the nadir at 7 to 14 days, though it can occur any time up to 6 weeks
• A previous episode of febrile neutropenia on the same regimen
• Age over 60, poor performance status, and significant comorbidity
• Mucositis - the more severe, the greater the bacterial translocation
• An indwelling central line, Hickman line or PICC
• Bone marrow involvement by tumour, or prior extensive radiotherapy to marrow-bearing bone
• Corticosteroids - both immunosuppressive and masking of fever
• Low serum albumin, renal or hepatic impairment, and advanced disease

Clinical features and assessment

The presentation is often unimpressive at first and then deteriorates quickly. Patients or families ringing the 24-hour helpline typically describe feeling shivery, generally unwell, or simply "not right", and the UKONS triage tool used by chemotherapy helplines is deliberately low-threshold for these calls.⁶

• Fever, rigors or sweats - the commonest presenting feature, but its absence does not exclude the diagnosis
• Non-specific malaise, confusion or drowsiness, particularly in older patients
• Haemodynamic changes - tachycardia, tachypnoea, hypotension, prolonged capillary refill. Hypotension is a late sign and indicates septic shock.
• Hypothermia - a poor prognostic sign that is frequently misread as reassuring
• Localising symptoms - sore mouth, sore throat, cough, dysuria, diarrhoea, perianal pain, line site discomfort, skin lesions

Examination

Assess with an ABCDE approach and calculate a NEWS2 score, then examine specifically for a source. Every site must be looked at, because the signs are subtle:

• Mouth and throat - mucositis, candidiasis, herpetic ulceration
• Central line and all exit sites - erythema, tenderness, discharge, tunnel tenderness
• Chest - often normal on auscultation despite pneumonia
• Abdomen - tenderness in the right iliac fossa raises the possibility of neutropenic enterocolitis (typhlitis)
• Perineum and perianal area - inspect, but do not perform a digital rectal examination
• Skin - a careful whole-body look for cellulitis, ecthyma gangrenosum (a necrotic lesion suggesting Pseudomonas), or a vasculitic rash

Investigations

Investigations are taken alongside, and must never delay, the first dose of antibiotics.

• Blood cultures - peripherally and from every lumen of any central venous catheter, labelled by source, so that differential time to positivity can identify a line infection
• FBC - to confirm the neutrophil count, and to identify anaemia and thrombocytopenia
• U&Es, LFTs, CRP, clotting screen, and a venous or arterial lactate
• Urinalysis and urine culture - note that pyuria may be absent without neutrophils
• Chest radiograph - if there are respiratory symptoms or signs, remembering it may be normal
• Swabs and cultures of any suspicious site, including line exit sites, wounds and mouth
• Stool culture with C. difficile toxin if there is diarrhoea
• Respiratory viral PCR where relevant, and consider CT chest if fever persists

CRP and other inflammatory markers are unreliable early on and must not be used to decide whether to treat. A normal CRP in the first hours of neutropenic sepsis is common and is not evidence against the diagnosis.

Management

The first hour

Antibiotic choice

NICE recommends piperacillin-tazobactam monotherapy as initial empirical therapy for suspected neutropenic sepsis, and advises against routinely adding an aminoglycoside unless there are patient-specific or local microbiological reasons.¹ Every trust has a local policy that reflects its own resistance patterns, and you should follow it - the principle is broad-spectrum cover that includes Pseudomonas.⁷

Continuing management

• Daily senior review with reassessment of the source, culture results and response, aiming to de-escalate to a narrower agent once an organism is identified
• Do not stop antibiotics simply because the neutrophil count has recovered if the patient remains unwell; conversely, NICE supports discontinuing antibiotics in patients who have responded, regardless of whether the count has recovered, provided the risk assessment allows
• Source control - remove the central line if there is tunnel infection, persistent bacteraemia despite appropriate antibiotics, or infection with Staphylococcus aureus, Pseudomonas, Candida or atypical mycobacteria
• G-CSF is not given routinely in established febrile neutropenia; it is considered where neutropenia is expected to be prolonged and the patient is severely unwell
• Supportive care - antipyretics, mouth care, nutritional support, VTE assessment, and transfusion for symptomatic anaemia or significant thrombocytopenia
• Review the chemotherapy plan - subsequent cycles usually require a dose reduction, a delay, or the addition of primary G-CSF prophylaxis

Prevention

• Primary G-CSF prophylaxis - pegfilgrastim or filgrastim after each cycle where the regimen carries a febrile neutropenia risk above roughly 20%, or above 10% with additional patient risk factors. It shortens the neutropenic period and allows dose intensity to be maintained.
• Antibiotic prophylaxis - NICE recommends a fluoroquinolone during the expected neutropenic period for patients with acute leukaemia, stem cell transplants or solid tumours expected to have significant neutropenia
• Antifungal and antiviral prophylaxis - in prolonged neutropenia and transplant patients, typically an azole and aciclovir
• Pneumocystis prophylaxis with co-trimoxazole in patients on prolonged corticosteroids or specific regimens
• Patient education - a thermometer, an alert card, the 24-hour helpline number, and clear instructions to ring immediately with fever, rigors or feeling unwell rather than waiting for a GP appointment
• Vaccination - annual influenza and pneumococcal vaccination, avoiding live vaccines
• Dose reduction or regimen change after a severe episode

Complications

Progression to septic shock with multi-organ failure is the principal danger, and can occur within hours of an apparently mild presentation. Acute kidney injury, ARDS and disseminated intravascular coagulation all follow the usual sepsis pathways, compounded by the thrombocytopenia that accompanies marrow suppression.

Neutropenic enterocolitis (typhlitis) deserves specific mention: right iliac fossa pain, fever and diarrhoea in a neutropenic patient, with caecal wall thickening on CT. It is managed medically with bowel rest, broad-spectrum antibiotics including anaerobic cover, and correction of coagulopathy; surgery is reserved for perforation or uncontrolled haemorrhage, since operating on a neutropenic bowel carries high mortality.

Beyond the acute episode, the consequences for cancer treatment matter. An episode of febrile neutropenia commonly leads to dose reduction or delay in subsequent cycles, which reduces dose intensity and, in curative regimens, can compromise the chance of cure. This is one of the arguments for G-CSF prophylaxis in high-risk regimens rather than reacting after the first episode.

Red flags

Prognosis

Outcome depends chiefly on how quickly antibiotics are given, the depth and expected duration of neutropenia, and the presence of organ dysfunction at presentation. Fit patients with solid tumours and short-lived neutropenia who receive antibiotics promptly generally recover fully within days, and mortality is low. Patients with haematological malignancy, prolonged profound neutropenia or established shock have a substantially worse outlook.⁴

Every hour of delay in antibiotic administration is associated with increased mortality, which is the entire justification for the one-hour standard and for the door-to-needle audits that most cancer centres run. It is also why chemotherapy alert cards, direct-access pathways that bypass triage queues, and pre-prescribed antibiotics on the acute unit exist.

Finally, an episode of neutropenic sepsis is an appropriate trigger to revisit the goals of treatment. In a patient having palliative chemotherapy with declining performance status, a severe episode is often the point at which continuing systemic therapy stops being in their interest, and that conversation should happen while they are recovering rather than at the next crisis.