Neutropenic fever

• Neutropenic fever is fever arising in a person whose neutrophil count is dangerously low. It is treated as an oncological emergency, because a neutropenic host cannot contain bacteria and fungi at the usual portals of entry.
• The textbook working definition used here is either one oral reading of 38.3 C (101 F) or higher, or a sustained reading of 38.0 C (100.4 F) or higher lasting an hour or more, together with an absolute neutrophil count (ANC) under 500 cells per microlitre. Guidelines differ on the exact threshold used to define the fall in count; the Neutropenia topic in haematology and oncology collects these. ^[3][7]
• In most cases the organism is never identified. When it is, gram-positive pathogens (coagulase-negative staphylococci, Staphylococcus aureus including methicillin-resistant strains, enterococci including vancomycin-resistant strains, viridans streptococci) and drug-resistant gram-negative pathogens (Escherichia coli, Klebsiella species, Enterobacter species, Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia) dominate; with prolonged or profound neutropenia, Candida species and Aspergillus species become the feared pathogens. ^[6]
• Start broad-spectrum antipseudomonal beta-lactam monotherapy within the hour: cefepime, a carbapenem (imipenem-cilastatin or meropenem) or piperacillin-tazobactam is recommended as effective initial monotherapy. ^[1][3][5]
• Risk-stratify with the Multinational Association for Supportive Care in Cancer (MASCC) index (maximum 26; a score of 21 or more predicts low risk of complications) to decide who can be managed as an outpatient on oral antibiotics and who needs hospitalisation and intravenous therapy. ^{[1][7][8] [3]}
• Add antifungal therapy only when fever persists after 4 to 7 days of broad-spectrum antibacterial treatment, or when there is evidence of fungal disease. ^[3][7]
• Colony-stimulating factor is therapeutic rescue for selected high-risk patients, not routine first-line treatment. Prophylaxis in planned chemotherapy follows the risk of febrile neutropenia (20% or more: recommended; 10 to 20%: consider; under 10%: not recommended), though guidelines differ on routine granulocyte-colony stimulating factor in adults. ^{[7][4] [3]}

By the end of this page you should be able to:

1. Define neutropenic fever precisely and explain why a low neutrophil count turns any infection into an emergency.
2. List the organisms most commonly responsible and why prolonged neutropenia changes the list toward Candida and Aspergillus.
3. Carry out the initial assessment, cultures and risk stratification (MASCC and CISNE) of a patient with suspected neutropenic fever.
4. Start the correct empirical antibiotic within the hour, know when to add vancomycin, and know when to escalate to antifungal therapy.
5. Set a treatment duration and stopping rule and know how these differ between IDSA, NICE and ASCO approaches.
6. Outline prophylaxis for patients facing chemotherapy: fluoroquinolones, antifungals, Pneumocystis prophylaxis, vaccines and granulocyte-colony stimulating factor.
7. Adapt the assessment and treatment to low-resource settings.

To use the definition in practice you must calculate the ANC rather than read it off the laboratory report. The ANC is the total white cell count multiplied by the percentage of neutrophils and band forms, divided by 100. A count under 500 cells per microlitre is severe neutropenia and a count under 100 cells per microlitre is profound neutropenia, where the risk of bacteraemia rises sharply. ^[3]

Neutropenic sepsis, the term used in the United Kingdom, is confirmed when the neutrophil count is 0.5 times 10 to the 9 per litre or lower with either a temperature above 38.0 C or other signs or symptoms consistent with clinically significant sepsis. ^[4]

Risk categories matter more than the label. High-risk patients are those in whom severe neutropenia (ANC under 500 cells per microlitre) is expected to last more than 7 days, who have a MASCC score under 21, a CISNE score of 3 or more, active comorbidity, uncontrolled or progressive cancer, hepatic insufficiency, renal insufficiency (creatinine clearance under 30 mL per minute) or who have recently received alemtuzumab or chimeric antigen receptor T-cell therapy. Everyone else, if clinically stable, may be candidates for low-intensity management. ^[3]

Febrile neutropenia is the most common serious complication of cancer therapy; it is uncommon in unselected mixed populations and far more frequent on high-risk myelosuppressive regimens. About half of patients with febrile neutropenia develop a documented infection, and 20% with profound neutropenia develop bacteraemia. ^[3]

Agranulocytosis (an ANC under 200 cells per microlitre) is rare in the general population, and drug-induced neutropenia outside cancer therapy is uncommon. In treated cancer the picture is dominated by myelosuppressive chemotherapy rather than these baseline rates. ^[3]

In solid tumours, common myelosuppressive regimens carry an intermediate to high risk of febrile neutropenia, and the risk is greatest during the first cycle; one review quotes 13 to 21% overall and 23 to 36% in the first cycle, but estimates vary by regimen and population. ^[7]

Almost all febrile neutropenia in oncology is a consequence of myelosuppressive chemotherapy. The depth and duration of the nadir are the dominant determinants of risk: a count under 500 cells per microlitre combined with an expected duration of more than 7 days defines the high-risk episode. ^[3][7]

Other important modifiers increase the chance of an episode developing or progressing:

• Patient factors: age 65 years or older, poor performance status, comorbidity, anaemia, renal insufficiency, liver disease, malnutrition, hypoalbuminaemia, female sex, Asian race. ^[7]
• Treatment factors: prior chemotherapy or radiotherapy, prior febrile neutropenia, prior infection, use of regimens classed as high risk for febrile neutropenia (greater than 20% incidence). ^[7]
• Disease factors: metastatic or uncontrolled cancer, haematological malignancy, haematopoietic stem cell transplantation. ^[6]

The count can fall for other reasons that are easy to confuse with chemotherapy: clozapine, antithyroid drugs, anticonvulsants, sulfonamides, antibiotics, autoimmune neutropenia, vitamin B12 or copper deficiency and viral infection. These are the province of the Neutropenia topic in haematology and oncology, and a medication review is part of every work-up of an unexplained low count. ^[1]

Neutrophils are the first cells to reach a bacterial or fungal focus, where they phagocytose and kill organisms with oxidative burst and proteases. When the circulating count falls, the host loses its ability to contain organisms at the portal of entry: the mucosal lining of the gastrointestinal tract, the sinuses and airways, the skin and any indwelling vascular catheter. ^[3]

Two points determine how ill the patient becomes. First, chemotherapy damages the mucosal barrier, so organisms that normally stay in the bowel (the "febrile mucositis" paradigm) move straight into the bloodstream. Second, neutropenia blunts inflammation, so the classic signs of infection can be absent: a neutropenic patient may have bacterial pneumonia with no sputum, and fever may be the only clue at all. ^[3]

The nadir after myelosuppressive chemotherapy is predictable, which is why patients and staff are taught to take a temperature daily and why national guidelines set a time limit for giving antibiotics. ^[3][4][8]

Presentations range from a well patient who simply has a fever to septic shock. Because inflammation is muted, history and careful examination matter more than the count.

Common presentations and sites of infection include:

• Fever (often the only sign), with or without rigors, is the defining feature.
• Mucositis of the mouth, pharynx and oesophagus causing pain on swallowing.
• Skin and soft tissue: cellulitis, furuncles, wound infection, perianal sepsis.
• Respiratory: sore throat, sinus tenderness, new cough or pleuritic chest pain; lung signs may be absent or appear only as infiltrates on imaging.
• Gastrointestinal: abdominal pain, diarrhoea, neutropenic enterocolitis (typhlitis) in the right lower quadrant.
• Urinary: dysuria may be absent even with significant infection.
• Catheter-related: erythema, tenderness or purulence at a central line insertion site or along the tunnel.
• Fungal: persistent fever with new nodular pulmonary infiltrates, sinus symptoms or hepatic and splenic lesions in prolonged neutropenia.

Red flags that demand the most urgent action include hypotension, tachypnoea, new hypoxia, confusion, an oxygen requirement, a serum lactate raised, a platelet count under 50 000 per microlitre or severe neutropenia (under 100 cells per microlitre) with an expected neutropenia of more than 10 days. ^[7]

Not every fever in a patient on chemotherapy is neutropenic sepsis, and not every neutropenic patient with fever has an infection.

Take cultures before antibiotics whenever this can be done without delaying treatment; "do not let this delay antibiotics" is the principle behind every guideline. ^[4]

• Full blood count with differential to confirm the degree and trend of neutropenia.
• Two sets of blood cultures: one from a peripheral vein and one from any central venous access device, plus additional sets from both sites if the first set was drawn through the catheter. ^{[4] [3]}
• Cultures from any site that could be infected: throat swab, sputum or bronchoalveolar lavage fluid, urine, stool and any skin, catheter or soft-tissue specimen. ^[3][4]
• Serum lactate, renal and liver function, C-reactive protein, albumin. ^[4]
• Urinalysis in all children under 5 years. ^[4]
• Chest radiograph only if clinically indicated. ^[4]
• High-resolution computed tomography of the chest if fever persists, to look for invasive mould disease; galactomannan (serum or bronchoalveolar lavage) and beta-D-glucan as fungal biomarkers where available. ^[3][6]
• Repeat counts to track recovery.

Do not remove a central venous access device as part of initial management. ^[4]

The classical score has seven items, a maximum of 26 points, and identifies patients at low risk of complications when the score is 21 or more. It was derived from more than 1000 episodes in several countries. ^[3][1][7][8]

Two cautions about using it. First, one of its major criteria, the "burden of febrile neutropenia", is subjective and difficult to apply consistently. Second, adding biochemical markers (C-reactive protein, procalcitonin) and using it alongside CISNE improves its performance, and scores under 21 may be used to define high risk. ^{[1][7] [3]}

CISNE is best used in the emergency department to identify patients with apparently stable febrile neutropenia who are at low risk of complications (maximum score 8; a score of 0 is low risk, 1 to 2 intermediate risk and 3 to 8 high risk). It is reported to discriminate better than MASCC in stable outpatients, with a threshold of 3 or more identifying those who should be hospitalised. ^[7]

Its six items are: Eastern Cooperative Oncology Group performance status of 2 or more (2 points); stress-induced hyperglycaemia (2 points); chronic obstructive pulmonary disease (1 point); chronic cardiovascular disease (1 point); monocytes under 200 per microlitre (1 point); and mucositis of grade 2 or higher (1 point). ^[3]

Febrile neutropenia is treated as an acute medical emergency.

The first practical steps are:

1. Triage and vital signs, including assessment for sepsis.
2. Rapid history and examination focusing on the common portals: mouth, pharynx, sinuses, skin, perianal area, catheter sites, abdomen and chest.
3. Cultures as above.
4. Basic bloods: full blood count, renal and liver function, C-reactive protein, lactate.
5. Empirical antibiotics as soon as possible. IDSA and NICE aim for antibiotic delivery within 1 hour of triage, whereas AGIHO (Heinz et al.) sets an outer limit of 2 hours from the onset of fever; delays beyond these targets are associated with complications and decreased survival. ^{[8] [3] [6] [4]}

The core recommendation is shared by IDSA, ASCO, NICE and others: cover Pseudomonas aeruginosa and other serious gram-negative pathogens from the first dose, using a single antipseudomonal beta-lactam. ^[1][4][7]

Monotherapy with an antipseudomonal beta-lactam is as effective as multidrug combinations, and an aminoglycoside should not be added as initial routine therapy, either as monotherapy or dual therapy, without patient-specific or local microbiological indications. ^[1][4]

Children from 2 months upwards can receive cefepime for febrile neutropenia at 50 mg per kilogram per dose every 8 hours. ^{[5] [7]}

Better patient-specific choices are needed when the patient was already taking fluoroquinolone prophylaxis when fever developed: use an antipseudomonal beta-lactam without a fluoroquinolone in these cases, and the empirical regimen should change if the local antibiogram shows rising resistance. ^[2]

Routine addition of vancomycin to the first dose is not recommended even though gram-positive organisms have become the most commonly cultured pathogens. Vancomycin (or another antibiotic with enhanced gram-positive coverage) should be considered when any of the following applies: ^[1][3][4]

• Suspected catheter-related infection, with cellulitis or tenderness along the tunnel.
• Skin or soft-tissue infection.
• Pneumonia.
• Haemodynamic instability.
• Severe mucositis.
• Colonisation with methicillin-resistant Staphylococcus aureus or penicillin-resistant Streptococcus pneumoniae.
• A blood culture growing a gram-positive coccus before final identification.

Do not remove the central line in the first hours, and do not stop the beta-lactam when cultures grow a gram-positive organism.

Piperacillin-tazobactam and carbapenems interfere with fungal biomarker testing (false positives with piperacillin-tazobactam, false negatives with mould-active antifungals), so culture and antigen results must be interpreted in the light of the antibiotics given. ^{[1] [4]}

Summarised from the ASCO and IDSA 2018 update. ^[2]

• Clinical judgment comes first; use clinical criteria or a validated tool such as MASCC.
• Candidates have few or no symptoms, an MASCC score of 21 or more, a stable clinical condition, no haemodynamic instability, no respiratory distress and no evidence of resistant infection; they must have good social support, reliable transport and 24-hour access to emergency care.
• Initial doses of empirical antibacterial therapy within 1 hour of triage, followed by at least 4 hours of observation, remain the standard even for patients who will go home.
• An oral fluoroquinolone plus amoxicillin-clavulanate, or clindamycin if penicillin allergic, is recommended, unless the patient was already on fluoroquinolone prophylaxis before the fever developed.
• Reassess after 2 to 3 days: patients who are still febrile should be re-evaluated and considered for inpatient treatment.

If fever persists or recurs after 72 to 96 hours of broad-spectrum antibacterial treatment, reassess for a resistant or untreated bacterial source and image for invasive fungal infection (computed tomography of the chest and sinuses, plus galactomannan where available). ^[2][7]

Guidelines differ slightly on timing: the 2010 IDSA update and several sources advise empirical antifungal coverage in high-risk patients with persistent fever after 4 to 7 days of broad-spectrum antibacterial therapy with suspicion of fungal infection, while other guidance sets the trigger at 72 to 96 hours. State the difference honestly rather than merging the numbers. ^[1][3][7]

Suitable empirical choices are:

• Caspofungin 70 mg intravenously once, then 50 mg intravenously daily. ^[7]
• Liposomal amphotericin B 3 to 5 mg per kilogram intravenously daily. ^[7]
• Voriconazole or posaconazole where mould-active prophylaxis is not already in use and mould disease is a strong possibility. ^[3][7]

Empirical antifungal treatment may not be needed in a patient with stable febrile neutropenia and no clinical, radiological or antigenic evidence of invasive fungal disease; repeat assessment is what separates unnecessary treatment from undertreatment. ^[7]

Stopping rules vary by guideline, and cross-checking the local protocol matters more than memorising one rule.

• IDSA approach: appropriate antibiotics may be continued until the ANC reaches at least 500 cells per microlitre or the infection is cleared. If the patient remains neutropenic but has recovered clinically and the documented infection has resolved, oral fluoroquinolone prophylaxis may be resumed until bone marrow recovery. ^[3]
• NICE approach: switch from intravenous to oral antibiotics after 48 hours once risk has been reassessed as low, and discontinue empirical antibiotics in patients whose neutropenic sepsis has responded to treatment, irrespective of neutrophil count. ^[4]
• Other centres use local stopping rules that combine defervescence with rising counts and a documented source controlled; published rules differ, so the local oncology and microbiology protocol should be followed. ^[1][4]
• Do not change the initial empirical antibiotic simply because fever persists; change only for clinical deterioration or a microbiological indication. ^[4]

Routine use is not recommended for every febrile neutropenia episode. Reviews agree that therapeutic granulocyte-colony stimulating factor shortens neutrophil recovery and hospital stay but has no proven effect on overall or infection-related mortality, and that the benefit in infection-related mortality is not established. ^[1][7]

Consider it when risk factors for poor outcome are present: age 65 years or older, sepsis syndrome, ANC under 100 cells per microlitre, an expected neutropenia of more than 10 days, pneumonia or other documented infection (especially invasive fungal infection), a low MASCC score (under 21), hospitalisation, a platelet count under 50 000 per microlitre, hypoproteinaemia or a previous episode of febrile neutropenia. ^[7]

Practical rules on top of this: if the patient was already on short-acting prophylactic granulocyte-colony stimulating factor, continue it; if they were on a long-acting (pegylated) form, do not add a short-acting one; if they were on none, decide on the risk factors above. ^[7]

• Septic shock, multi-organ failure and death from gram-negative bacteraemia.
• Invasive fungal infection (candidaemia, invasive aspergillosis) in prolonged and profound neutropenia.
• Neutropenic enterocolitis (typhlitis) and perianal sepsis.
• Mucositis, neutropenic colitis and malnutrition.
• Renal, hepatic and pulmonary dysfunction as part of sepsis.
• Chemotherapy interruption: dose reductions and delays can compromise cancer control, so preventing and treating episodes matters for cancer outcomes as well as immediate survival.

Prognosis depends on the underlying cancer, whether the episode is the first or a recurrent one, the depth and duration of neutropenia and the speed and appropriateness of antibiotic delivery. Patients whose time from triage to antibiotic administration is kept to the guideline target (1 hour under IDSA and NICE guidance, up to 2 hours under AGIHO) have lower rates of complications and death. ^[8][4][6]

Prevention is divided into avoiding infection and raising the neutrophil count.

Avoidance of infection:

• Patient education before starting chemotherapy: recognise fever, take a temperature daily, avoid exposure to people with respiratory infections, avoid crowded places, wear a mask in public when the ANC is under 1000 cells per microlitre. ^[3]
• Standard precautions, hand hygiene, respiratory etiquette; vaccination according to national schedules (yearly influenza vaccination for everyone on chemotherapy; herpes simplex virus prophylaxis for seropositive patients undergoing allogeneic stem cell transplantation or leukaemia induction; Pneumocystis jirovecii prophylaxis where the regimen-associated risk is above 3.5%). ^[3]
• Trimethoprim-sulfamethoxazole covers the five most common infecting pathogens in chronic granulomatous disease and is the standard prophylaxis for Pneumocystis pneumonia in high-risk groups. ^[3]
• Antifungal prophylaxis with an oral triazole for patients with profound neutropenia in leukaemia and stem cell transplantation settings. ^[3]
• Fluoroquinolone prophylaxis (ciprofloxacin) during the expected period of neutropenia for adults with acute leukaemia, stem cell transplants or solid tumours expected to have significant neutropenia, with monitoring of resistance and infection patterns in the unit. ^[4]
• Limiting environmental exposures in hospital: single rooms where feasible, no standing water or live plants, appropriate food handling; details follow local infection control.

Raising the count (granulocyte-colony stimulating factor):

• Risk of febrile neutropenia is assessed before the first cycle and before each subsequent cycle on the basis of the regimen and patient factors. High-risk is a 20% or greater chance of febrile neutropenia, intermediate 10 to 20%, low under 10%. ^[2][7]
• Primary prophylaxis with granulocyte-colony stimulating factor is recommended at 20% or greater risk, should be considered at 10 to 20% where additional risk factors exist, and is generally not used below 10%. ^[7]
• NICE advises that routine granulocyte-colony stimulating factor should not be offered for the prevention of neutropenic sepsis in adults receiving chemotherapy unless it is part of the regimen or needed to maintain dose intensity; anglophone oncology guidance (ASCO and IDSA) and continental guidance differ on this point, so the local and regimen-level decision prevails. ^[2][4][7]
• Granulocyte-colony stimulating factor prophylaxis is typically started 24 to 72 hours after chemotherapy; long-acting (pegylated) forms are given once per cycle. ^[7]

For children specifically, guidance differs in risk scoring and thresholds: the NICE guideline discusses the modified Alexander rule for children under 18 years, but the principles of early assessment and antipseudomonal cover remain the same. ^[4]

• Older adults (65 years or older) have higher risk of both febrile neutropenia and poor outcome and do less predictably on the same drugs. ^[7]
• Pregnancy: treat suspected febrile neutropenia as in any cancer patient with obstetric and haematology input; growth factor decisions are specialist. ^[3]
• Children: most bacterial patterns and sepsis approaches are as in adults, but risk scores, doses and the Modified Alexander rule apply. Dosing above is given for cefepime. ^[3][4][5]
• Allogeneic stem cell transplant and acute leukaemia: these patients are rarely safe for outpatient therapy and have the strongest case for antifungal and antibacterial prophylaxis. ^[6][8]

• The diagnosis rests on a full blood count with differential. Where a Coulter counter is unavailable, a manual white cell count and a differential stain can separate neutrophil depletion from lymphocyte depletion well enough to act.
• Give empirical antipseudomonal coverage as soon as possible: piperacillin-tazobactam if available, otherwise cefepime or a carbapenem; if none of these is available, a broad beta-lactam plus gentamicin is better than nothing, with knowledge of local resistance. The choice should be made by the local microbiology service.
• Blood cultures should be drawn before antibiotics if they can be processed locally; treatment must not wait for them.
• Where granulocyte-colony stimulating factor is unavailable, good supportive care (hydration, source control, the antibiotic above and close observation) is the mainstay.
• Liposomal amphotericin B and mould-active azoles, computed tomography scanning and galactomannan testing are often unavailable; prolonged unexplained fever in a neutropenic patient should prompt the cheapest available imaging and empiric antifungal choice consistent with local supply.
• Where catheter-associated infection or multidrug-resistant gram-negatives are common, ask for local antibiogram data before selecting first-line therapy; national or World Health Organization essential medicines lists can guide which agents are stocked.
• Avoid over-investigation of the underlying cancer's stage once an episode is underway; the emergency is the neutropenia and infection.

• Neutropenic fever is an oral temperature of at least 38.3 C, or at least 38.0 C for an hour or more, with an ANC under 500 cells per microlitre. ^[1][3]
• It is the most common serious complication of cancer therapy, affecting a minority of patients on chemotherapy overall and a far higher proportion on high-risk myelosuppressive regimens. ^[3]
• Infection is never documented in most cases; when documented, gram-positive organisms now dominate (coagulase-negative staphylococci, Staphylococcus aureus, enterococci, viridans streptococci), with drug-resistant gram-negative organisms close behind; prolonged neutropenia brings Candida and Aspergillus to the fore. ^[3][6]
• A neutropenic patient may have no inflammatory signs other than fever, so the examination must be systematic and repeated.
• Start an antipseudomonal beta-lactam within the hour, every time, for high-risk patients. ^[1][4][8]
• Monotherapy with cefepime, a carbapenem or piperacillin-tazobactam is as effective as combinations; do not add vancomycin or an aminoglycoside by default. ^[1][4]
• Use vancomycin or other gram-positive coverage for specific indications (line infection, skin or soft tissue infection, pneumonia, shock, severe mucositis, resistant colonisation). ^[1][3][4]
• Treat persisting fever for 72 to 96 hours before broadening coverage toward Candida and Aspergillus; which guideline number is used should be stated locally. ^[1][3][7]
• Stop treatment when the episode has responded, irrespective of neutrophil count under NICE-style guidance, or continue to neutrophil recovery under IDSA-style guidance; convert intravenous to oral after 48 hours when reassessed as low risk. ^[4][3]
• MASCC 21 or more (out of 26) predicts low risk of complications; CISNE 3 or more identifies unstable low-risk patients who should be hospitalised. ^[1][7]
• Granulocyte-colony stimulating factor for an acute episode is rescue therapy for high-risk patients, not routine treatment. ^[7]
• Prophylaxis: fluoroquinolones during the expected neutropenic window in high-risk adults, antifungal triazoles for profound neutropenia in leukaemia and transplant, granulocyte-colony stimulating factor when the regimen risk is 20% or more, plus education and vaccination. ^[3][4][7]
• Take the one-hour antibiotic target seriously; complications and mortality rise as it slips. ^[8]

Neutropenia (Hematology/Oncology); Sepsis; Candidiasis; Aspergillosis; Pneumocystis pneumonia; Antimicrobial prophylaxis in cancer.