Introduction

Infection is a major cause of death in children with haematological malignancies following bone marrow or solid organ transplantation, iatrogenic immunosuppression, and chemotherapy. The major factor predisposing to infection in these patients is neutropenia, which is defined as decreased circulating neutrophils in the peripheral blood. The normal reference range for neutrophil counts varies with the age of the child, being highest in the neonatal period. In infants, the normal threshold is 1000 neutrophils per mL; the usual value is 1500 neutrophils per mL up to 10 years of age, with an adult threshold of 1800 neutrophils per mL applied thereafter.¹ Neutropenia is defined as ≤500 neutrophils per mL or an anticipated decline from 1000 to ≤500 neutrophils per mL. Infection risk increases when the neutrophil count is ≤500 neutrophils per mL and is highest when ≤100 neutrophils per mL. Febrile neutropenia requires an associated fever ≥38.3°C, or ≥38.0°C for at least 1 hour.² This chapter focuses on neutropenia associated with paediatric cancer or its treatment as this is the more frequent type encountered in the emergency department (ED).

Neutropenic children receiving chemotherapy for leukaemia or undergoing bone-marrow transplantation (BMT) are at significant risk from Gram-negative sepsis, including Pseudomonas aeruginosa and Escherichia coli. In BMT patients, half the infections are bacterial, evenly split between Gram-positives (such as Staphylococcus aureus) and Gram-negative organisms; 40% are due to viruses like cytomegalovirus; and 10% due to fungi, with up to a third of episodes due to systemic fungaemia being life threatening.¹ Vascular catheter-related infections are usually related to Gram-positive skin organisms. Although the overall mortality rate due to neutropenia-associated infection is 1%, children undergoing BMT with febrile neutropenia have a startling mortality up to 80%.¹

Management priorities are:

Presentation

Young children compensate for impending shock and remain normotensive in the early stages of systemic sepsis. The earliest reliable sign of vascular redistribution is delayed capillary return, because tachycardia and tachypnoea can be secondary to the fever. Neutropenic or immunosuppressed children may have attenuated or altered signs of infection. The absence of neutrophils to localise an infection makes it difficult to determine the source of infection by physical examination alone. Pay special attention to body regions vulnerable to bacterial infection, such as oropharynx, ears, skin, and perianal area. Evidence of respiratory, circulatory, renal, and metabolic derangement indicates severe sepsis.

Investigations

Microbiological samples from potential infection sources such as blood, urine, cerebrospinal fluid, throat, skin, and central access devices should ideally be obtained prior to, but not delay, treatment. Similarly, radiological investigation to localise infection source should not delay treatment commencement. Although no microbiological source is identified in one-half of febrile neutropenic children with cancer, a high proportion have culture-positive bacteraemia, respiratory tract infections and central access device infections.¹ Full blood count with white cell differential confirms neutropenia, and when followed serially tracks progress of neutrophil recovery. Thrombocytopenia and coagulopathy are early markers of disseminated intravenous coagulation. Chest X-ray may indicate lower respiratory involvement or cardiac decompensation.

Treatment

IV fluid resuscitation and vasopressor support may be required in septic shock. Urgent empiric intravenous therapy with combination broad-spectrum antimicrobials that have excellent Gram-negative cover is essential in febrile neutropenia. The pattern and severity of infection varies according to location, clinical context, and level of immune suppression. Regularly reviewed institution- and scenario-specific treatment protocols, developed in conjunction with infectious diseases physicians and microbiologists, that take into account local patterns of infection and their susceptibilities help to deliver and standardise optimal treatment.

The Victorian Drug Committee’s Therapeutic Guidelines for Antibiotics³ is an excellent resource for centres that do not have their own febrile neutropenia protocols but should ideally be adapted to local requirements. The recommended regimen in eTG 2010 includes: cefepime or ceftazidime 2 g (child: 50 mg kg⁻¹ up to 2 g) IV, 8-hourly or piperacillin + tazobactam 4 + 0.5 g (child: 100 + 12.5 mg kg⁻¹ up to 4 + 0.5 g) IV, 8-hourly in children with no immediate hypersensitivity to penicillin. Gram-positive bacteraemia from infected intravascular devices require addition of IV vancomycin (<12 years: 30 mg kg⁻¹ up to 1.5 g IV, 12-hourly concentration monitoring) only if the child is shocked, known to be previously colonised with MRSA or has catheter-related infection in a treatment environment with high incidence of MRSA infection. Vancomycin is also indicated if a Gram-positive organism resistant to other drugs is isolated from blood cultures or the child worsens clinically despite broad spectrum antibacterials for 48 h.

If fevers persist in high-risk children after 96 hours of antibacterial therapy, consider empirically adding antifungal therapy after consultation with a paediatric infectious diseases physician. Antibiotics can be discontinued if there is clinical improvement, no proven infection, cultures remain negative, and neutrophil count improves to ≥500 mL⁻¹; this typically occurs at 3 to 7 days. Although inpatient management is associated with an excellent outcome, carefully selected children who are clinically well, with low-risk criteria, could be considered for early discharge or outpatient management with daily intravenous ceftriaxone or oral ciprofloxacin and daily reviews.^2,4–6

Bone-marrow stimulation with colony-stimulating factors reduces the severity and duration of neutropenia and fever, and antibiotic requirements in children undergoing BMT, and may be effective in premature infants at high risk of infection as well as children with severe neutropenia and Gram-negative sepsis. Corticosteroids are effective in Pneumocystis carinii pneumonia and have been used in conjunction with immunoglobulin to treat immune-mediated neutropenia.⁷

Controversies and challenges

Early goal-directed therapy, directed at optimising cardiac preload, afterload and contractility to balance oxygen delivery with oxygen demand as part of a sepsis bundle multimodal algorithm, was associated with reduced mortality in adults in a single-centre study which did not include children;⁸ as such, it may not be relevant in septic children requiring further care in ICU.

Granulocyte infusions are no longer used because of questionable efficacy but may have a role in refractory neonatal sepsis.

Although colony-stimulating factor does not affect overall mortality in children with cancer-related febrile neutropenia, it is known to reduce length of hospital stay, infection rate and neutrophil recovery period.^9,10

The emergence of highly resistant and virulent organisms is increasingly recognised as a barrier to improved outcomes, especially in the context of immunosuppression.