Febrile Neutropenia

Definition and Classification of Neutropenia

• Neutropenia is strictly defined as a decrease in the absolute number of circulating segmented neutrophils and bands in the peripheral blood.
• The absolute neutrophil count (ANC) is calculated by multiplying the total white blood cell (WBC) count by the percentage of segmented neutrophils plus bands.
• The lower limit of normal for ANC varies by race and age: for White children older than 12 months, it is 1,500 cells/$\mu$L; for Black children older than 12 months, it is 1,200 cells/$\mu$L.
• The relative lower normal limit in Black individuals is attributed to the prevalence of the Duffy negative (Fy−/−) blood group.
• Mild neutropenia is categorized as an ANC between 1,000 and 1,500 cells/$\mu$L.
• Moderate neutropenia is categorized as an ANC between 500 and 1,000 cells/$\mu$L.
• Severe neutropenia is defined as an ANC less than 500 cells/$\mu$L, and agranulocytosis is defined as an ANC less than 200 cells/$\mu$L.
• Patients face a substantial risk of developing life-threatening pyogenic infections primarily when they have severe neutropenia (ANC <500 cells/$\mu$L) resulting from disorders of bone marrow production,.

Etiology of Neutropenia

Acquired Causes

• Transient neutropenia accompanying or following viral infections is the most frequent cause of acute neutropenia in childhood.
• Implicated viruses include influenza A and B, SARS-CoV-2, adenovirus, respiratory syncytial virus, enteroviruses, human herpesvirus 6, measles, rubella, varicella, and Epstein-Barr virus,.
• Viral-associated acute neutropenia typically occurs during the first 24 to 48 hours of illness and persists for 3 to 8 days, related to a virus-induced redistribution of neutrophils from the circulating to the marginating pool.
• Severe bacterial infections (e.g., sepsis, Brucella, Salmonella, Shigella, disseminated tuberculosis), protozoal, rickettsial, and fungal infections can also provoke significant neutropenia,,.
• Drug-induced neutropenia is common and can arise from antimicrobial agents (e.g., penicillins, sulfonamides), antithyroid drugs, antipsychotics, and antiepileptics via immune-mediated, toxic, idiosyncratic, or hypersensitivity mechanisms,,.
• Cytotoxic anticancer drugs and radiotherapy predictably cause profound severe neutropenia by exerting cytotoxic effects on rapidly replicating myeloid precursors,.
• Immune-mediated neutropenias include alloimmune neonatal neutropenia (caused by transplacental transfer of maternal alloantibodies against fetal neutrophil antigens) and autoimmune neutropenia of infancy (where the child creates antineutrophil antibodies during a mild viral inflammatory episode),.
• Acquired nutritional deficiencies of copper, vitamin B12, or folic acid, as well as starvation and marasmus, can cause ineffective myelopoiesis resulting in neutropenia.

Inherited Causes

• Cyclic neutropenia is an autosomal dominant disorder characterized by regular 21-day oscillations with the ANC dropping below 200 cells/$\mu$L, almost invariably caused by pathogenic variants in the neutrophil elastase gene (ELANE).
• Severe congenital neutropenia (SCN) is characterized by a marrow arrest at the promyelocyte stage, consistently yielding ANCs less than 200 cells/$\mu$L.
• SCN exhibits genetic heterogeneity, presenting as an autosomal dominant trait (primarily ELANE variants) or an autosomal recessive trait (e.g., HAX1 variants causing Kostmann disease, or G6PC3 variants),.
• Shwachman-Diamond syndrome is an autosomal recessive disorder featuring neutropenia, exocrine pancreatic insufficiency, and metaphyseal dysostosis, most commonly caused by variants in the SBDS gene.
• Chédiak-Higashi syndrome is a rare autosomal recessive defect (LYST gene) causing giant cytoplasmic granules, progressive neutropenia, partial albinism, and impaired neutrophil degranulation,.
• Glycogen storage disease type Ib is caused by variants in G6PT1, which inhibits glucose transport and results in defective neutrophil motility, increased apoptosis, neutropenia, and recurrent bacterial infections.

Clinical Manifestations and Pathogens in Febrile Neutropenia

• The most common clinical presentation of profound neutropenia includes fever, frequent infections, aphthous stomatitis, and severe gingivitis.
• Focal infections highly associated with febrile neutropenia include cellulitis, furunculosis, perirectal inflammation, colitis, sinusitis, otitis media, pneumonia, deep tissue abscesses, and sepsis.
• In patients with profound neutropenia, the classic signs of local inflammation—such as exudate, fluctuance, and regional lymphadenopathy—may be severely diminished or absent because of the inability to form pus.
• Despite the absence of visible pus or focal inflammatory swelling, neutropenic patients with active infections still experience fever and feel localized pain at the sites of inflammation.
• The most common pathogens causing infections in neutropenic patients are Staphylococcus aureus and gram-negative bacteria derived from both endogenous flora and nosocomial sources,.
• Specific highly virulent gram-negative organisms like Escherichia coli and Pseudomonas species frequently cause severe infections that disseminate to the blood, meninges, and peritoneum.
• During the neutropenic nadir, patients with cyclic neutropenia are specifically at risk for intestinal perforation with peritonitis, which can lead to life-threatening clostridial sepsis.
• Isolated absolute neutropenia primarily increases the patient's susceptibility to bacterial and fungal pathogens, but it does not generally heighten susceptibility to parasitic or viral infections, nor to bacterial meningitis.

Evaluation of Febrile Neutropenia

Risk Stratification

• A validated risk stratification strategy must be adopted by clinicians and systematically incorporated into the routine management of pediatric febrile neutropenia.
• Patients are stratified as being at high risk for invasive fungal disease (IFD) if they have acute myeloid leukemia (AML), high-risk acute lymphoblastic leukemia (ALL), relapsed acute leukemia, or are undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
• Children experiencing prolonged neutropenia and children receiving high-dose corticosteroids are additionally categorized as high risk for IFD,.
• All other pediatric patients presenting with febrile neutropenia should be categorized as low risk for IFD.

Initial Diagnostic Workup

• Blood cultures must be obtained immediately at the onset of febrile neutropenia from all lumens of any indwelling central venous catheters.
• Clinicians should consider obtaining peripheral blood cultures concurrently with the central venous catheter cultures.
• A urinalysis and urine culture should be considered for patients from whom a clean-catch, midstream urine specimen is readily obtainable.
• Chest radiography should not be performed routinely; it should be obtained exclusively in patients exhibiting specific respiratory signs or symptoms.

Management of Febrile Neutropenia

Initial Empirical Antibacterial Therapy

• For patients with high-risk febrile neutropenia, monotherapy utilizing an antipseudomonal $\beta$-lactam, a fourth-generation cephalosporin, or a carbapenem must be initiated as the empirical therapy.
• The addition of a second gram-negative agent or an empirical glycopeptide (such as vancomycin) is strictly reserved for patients who are clinically unstable, when a highly resistant infection is suspected, or in centers documenting a high local rate of resistant pathogens.
• For patients with low-risk febrile neutropenia, initial or step-down outpatient management may be strongly considered provided the necessary infrastructure is in place to ensure careful monitoring and follow-up.
• Oral antibiotic administration may be considered in the low-risk febrile neutropenia cohort if the child is able to tolerate the oral route reliably.

Ongoing Management and Modification of Therapy

• In patients who are clinically responding to the initial empirical antibiotic therapy, any double coverage for gram-negative infections or empirical glycopeptides (if initiated) must be discontinued after 24 to 72 hours, provided there is no specific microbiologic indication to continue combination therapy.
• The initial empirical antibacterial regimen should not be modified based solely on the persistence of fever, as long as the child remains clinically stable.
• If a child with persistent fever becomes clinically unstable, the initial empirical antibacterial regimen must be rapidly escalated to include broad coverage for resistant gram-negative, gram-positive, and anaerobic bacteria.

Cessation of Antibacterial Therapy

• In all risk categories, empirical antibiotics must be discontinued if blood cultures remain negative at 48 hours, the patient has been completely afebrile for at least 24 hours, and there is clear laboratory evidence of bone marrow recovery.
• In patients specifically categorized with low-risk febrile neutropenia, the discontinuation of empirical antibiotics at 72 hours can be considered if blood cultures are negative and the patient has been afebrile for at least 24 hours.
• This low-risk cessation at 72 hours may be performed irrespective of the patient's marrow recovery status, provided that careful outpatient follow-up is ensured.

Empirical Antifungal Therapy in Prolonged Febrile Neutropenia

Evaluation for Invasive Fungal Disease (IFD)

• High-risk patients experiencing prolonged febrile neutropenia (defined as persisting $\ge$ 96 hours) must be systematically evaluated for IFD, which is most commonly caused by Aspergillus and Candida species,.
• A computed tomography (CT) scan of the lungs must be performed as part of the evaluation for prolonged febrile neutropenia in IFD high-risk patients.
• Imaging of the abdomen should be considered in these patients if they completely lack localizing signs or symptoms.
• Routine CT imaging of the sinuses should generally not be performed in patients who lack specific localizing signs or symptoms.
• Regarding the use of fungal biomarkers to guide empirical antifungal management, clinicians should consider not utilizing serum galactomannan (GM) assays.
• The use of $\beta$-D-glucan assays and fungal polymerase chain reaction (PCR) testing in the blood is explicitly not recommended and should not be used for this evaluation,.

Antifungal Treatment Strategies

• In IFD high-risk patients who experience prolonged febrile neutropenia ($\ge$ 96 hours) that is completely unresponsive to broad-spectrum antibacterial agents, empirical antifungal therapy must be initiated.
• The strongly recommended agents for initiating empirical antifungal therapy in this unresponsive, high-risk setting are caspofungin or liposomal amphotericin B.
• Conversely, in IFD low-risk patients who experience prolonged febrile neutropenia ($\ge$ 96 hours), clinicians should safely consider withholding empirical antifungal therapy.