Management of febrile neutropenia in immunocompetent children and youth

Abstract

Febrile neutropenia is a common clinical presentation in children that can be associated with invasive bacterial infection (IBI). However, in otherwise healthy children and youth with fever and neutropenia, the risk for IBI is low, with most cases being caused by viral infections. Well-appearing, non-oncologic, and presumed immunocompetent children aged 6 months to 18 years experiencing a first episode of neutropenia, with no additional risk factors, typically do not require empiric antibiotics. However, a thorough assessment, including complete history and physical exam, is indicated, and a blood culture should be performed when the absolute neutrophil count is <0.5 × 10⁹/L. Close follow-up, a repeat complete blood count, and strong anticipatory guidance are recommended.

BACKGROUND

Febrile neutropenia in paediatrics is commonly encountered from primary through tertiary care. Clinical presentation can vary from mild transient illness to severe life-threatening conditions (1). Clinicians are most concerned about the risk of invasive bacterial infections (IBI) such as bacteremia and meningitis, particularly when neutropenia is severe. Immunosuppressed children and youth, such as those with malignancy, are at high risk of IBI, with a bacterial pathogen identified in up to 30% of cases (2,3). There is limited information regarding the rates of IBI in otherwise healthy paediatric patients with febrile neutropenia (4,5), though the rate of IBI does not appear to be increased compared to non-neutropenic children, and positive blood cultures are rare (1,6–12). The most common causes of neutropenia in well-appearing, immunocompetent patients older than 3 months are viral illnesses (1,9–12) or common bacterial infections (7,8). Other etiologies may include recent antibiotic use, anticonvulsant therapy, autoimmune disorders such as autoimmune neutropenia, and vitamin B12 or folate deficiency. In most, the neutropenia is transient and resolves within a few weeks (6–8). Established guidelines recommend intravenous (IV) antibiotics and hospital admission for most paediatric oncologic patients with febrile neutropenia. Given the paucity of evidence in the non-oncologic population, recommendations for healthy children with neutropenia are less established.

This practice point proposes that less aggressive management is often appropriate in otherwise healthy children and youth with no additional risk factors (4–7,13). It applies to well-appearing, non-oncologic, and presumed immunocompetent individuals 6 months to 18 years of age who experience a first episode of febrile neutropenia. Management aims to ensure safe patient care while contributing to resource stewardship, considers illness severity and risk tolerance, and emphasizes shared decision-making between clinicians and parents or caregivers. Supplementary Figure 1 summarizes best practice points.

DEFINITIONS

The conventional definition of neutropenia is an absolute neutrophil count (ANC) <1.5 × 10⁹/L, including all neutrophils, bands, myelocytes, and metamyelocytes. Severe neutropenia is typically defined as an ANC <0.5 × 10⁹/L, moderate neutropenia as an ANC 0.5 to <1.0 × 10⁹/L, and mild neutropenia as an ANC 1.0 to <1.5 × 10⁹/L (1,14).

A temperature measurement >38°C is typically considered a fever (15). The Infectious Disease Society of America defines fever in neutropenic oncologic patients as a single oral temperature ≥38.3°C or a temperature ≥38°C sustained over 1 hour (16). However, there is no clear definition of fever in presumed immunocompetent children with neutropenia. Rectal temperature-taking is not recommended for children with severe neutropenia. Axillary or oral measurements (in cooperative children older than 5 years of age) should be obtained (15).

BEST PRACTICE POINTS

Assessment for IBI

• Perform a complete history and physical examination, paying particular attention to risk factors for IBI (Table 1). Children with any one risk factor are considered high risk, and individualized care is warranted in such cases.

• Document general state and vital signs, including a repeat temperature if a measurement has not been taken recently. Ill-appearing children with neutropenia are at higher risk for IBI. Assess the ABCs—airway, breathing, and circulation—and stabilize (17) as needed. Ensure that a recent complete blood count (CBC) and differential, reticulocytes, and a peripheral blood smear, have been obtained in all patients with suspected or known neutropenia. For individuals with thrombocytopenia, lymphopenia, or unexplained anemia in addition to neutropenia, consider other etiologies such as leukemia or bone marrow failure.

Table 1.

Risk factors associated with invasive bacterial infections in children and youth with neutropenia

Risk factors
Medical history:
Immunocompromised status
• Malignancy or post-transplant
• Primary immunodeficiency
• Immunosuppressant therapy (including chronic steroid use)
• Aplastic anemia or other bone marrow failure
History of neutropenia
• Prior episodes
• Congenital or cyclic neutropenia
• Autoimmune neutropenia
Previous severe or recurrent infection (e.g., meningitis, severe pneumonia, sepsis, recurrent abscesses, osteomyelitis, cellulitis)
Intravascular device
Significant co-morbidities
• Chronic medical condition (e.g., sickle cell disease, chronic lung disease, cardiomyopathy)
• Known or suspected genetic condition
• Failure to thrive or short stature
Vaccines for encapsulated bacteria not up-to-date (i.e., pneumococcal, meningococcal, Haemophilus influenzae type b)
Family history
• Known immunodeficiency
• Chronic neutropenia
• Bone marrow failure
• Leukemia
Physical exam:
Ill-appearing
Hepatosplenomegaly or diffuse lymphadenopathy
Dysmorphic features or congenital abnormalities
Investigations:
Suppression of other cell lines (thrombocytopenia, lymphopenia, or unexplained anemia)
High mean corpuscular volume

Children and youth with neutropenia AT RISK for IBI (Table 1):

• If ill-appearing, obtain blood culture and do not delay starting broad-spectrum empiric antibiotics. Refer to this CPS practice point on the diagnosis and management of sepsis for guidance (18).

• If well-appearing, management should be individualized, preferably in consultation with a paediatric specialist. IV antibiotics are typically required, and these children are either admitted or discharged home with close out-patient follow-up.

Children and youth with isolated neutropenia, NOT AT RISK for IBI:

• Individuals with an ANC ≥1.0 × 10⁹/L can be managed as per those with normal ANC.

• Paediatric patients with an ANC 0.5 to <1.0 × 10⁹/L do not routinely require empiric antibiotics. Their health care provider (HCP) should order a repeat CBC in 1 to 3 months (5,7).

• For individuals with severe neutropenia (ANC <0.5 × 10⁹/L):

  • Ensure peripheral blood culture has been obtained. Consider performing a urinalysis or urine culture in incontinent children (generally <24 months old), and for those with symptoms or risk factors for urinary tract infection (19). Based on clinical presentation, also consider investigations such as chest x-ray or respiratory viral polymerase chain reaction testing.

  • Well-appearing children with an ANC <0.5 × 10⁹/L and no risk factors for IBI (Table 1) are considered low risk. Empiric antibiotics are usually not indicated, but may be considered when the child’s ANC is 0 to 0.2 × 10⁹/L. Organize close out-patient follow-up within 24 to 48 hours. Provide clear discharge instructions and consider consulting with a paediatrician or paediatric hematologist.

  • Out-patient referral to a paediatrician or paediatric hematologist should be organized at 4 to 6 weeks if a child’s ANC remains <0.5 × 10⁹/L, and earlier if interim evaluation reveals other cell line abnormalities. Until severe neutropenia resolves, a child who develops a new fever should be assessed urgently by an HCP.

  • Educate parents, alternate care providers, and the patient (if appropriate) before discharge. They should ­understand the signs and symptoms of sepsis (e.g., pallor, lethargy or low level of consciousness, confusion, persistent vomiting, persistent fever) and the reasons for seeking urgent medical attention.

CONCLUSION

Well-appearing, otherwise healthy, immunocompetent patients aged 6 months to 18 years experiencing their first episode of fever and neutropenia are at low risk for IBI and do not typically require empiric antibiotics. However, a thorough assessment including a focused history, physical exam, and blood culture is needed if neutropenia is severe. Children and youth with any one additional risk factor should receive individualized management, which may include IV antibiotics with admission, or close out-patient follow-up. Individuals without risk factors for IBI can be managed conservatively, with close follow-up. Youth and the parents of younger children should receive strong anticipatory guidance.

Correspondence: Canadian Paediatric Society, 100–2305 St Laurent Blvd, Ottawa, Ontario K1G 4J8, Canada. Telephone 613-526-9397, fax 613-526-3332, e-mail info@cps.ca, website www.cps.ca

All Canadian Paediatric Society position statements and practice points are reviewed regularly and revised as needed. Consult the Position Statements section of the CPS website www.cps.ca/en/documents for the most current version. Retired statements and practice points are removed from the website.

FUNDING

There is no funding to declare.

POTENTIAL CONFLICTS OF INTEREST

CEB declares funded grants or clinical trials: CIHR (collaborator); Paediatric Consultants Partnership (Department of Paediatrics, The Hospital for Sick Children; PI and co-investigator); Physician Services Incorporated Foundation Grant (collaborator). There are no other disclosures to declare.

CANADIAN PAEDIATRIC SOCIETY ACUTE CARE COMMITTEE (2021-2022)

Members: Carolyn E. Beck MD MSc, Kevin Chan MD (Chair), Kimberly Dow MD (Board Representative), Karen Gripp MD (Past Member), Marie-Pier Lirette MBChB (Resident Member), Jonathan Sniderman MD, Evelyne D.Trottier MD, Troy Turner MD

Liaisons: Laurel Chauvin-Kimoff MD (Past Chair 2012-2019), CPS Paediatric Emergency Medicine Section; Sidd Thakore MD, CPS Hospital Paediatrics Section

Principal authors: Marie-Pier Lirette MBChB, Nicola Wright MD MSc, Evelyne D.Trottier MD, Carolyn E. Beck MD MSc