You’re working as the Paeds registrar overnight at a regional centre when ED phones you about an incoming patient – Josef, 8 – who’s in a delayed intensification cycle of his treatment for ALL and has a fever of 38.6oC. Josef’s last chemotherapy was last week, and an FBC done 2 days ago showed WCC 4.0×109/L with an absolute neutrophil count 0.9×109/L.
Bottom Line
Fever in the setting of neutropaenia may be the only herald of a severe, potentially life-threatening infection.
Febrile neutropenia is an oncologic emergency.
A thorough history and physical examination are essential in cases of febrile neutropaenia.
Find and follow your local protocol and discuss it with a senior early.
Isolate the child to reduce the chances of further infection.
Why is fever in an oncology patient dangerous?
Febrile neutropaenia may be the only feature of a life-threatening infection, a major cause of morbidity and mortality in paediatric oncology patients. A 2005 study of over 12000 children established a mortality rate as high as 3%. Around 1 in 5 children will have microbiologic evidence of infection during induction chemotherapy, and this number jumps to ~40% if the fever returns upon ceasing antibiotic therapy.
You move Josef to a resus bay with isolation (and cytotoxic) procedures in place. He is febrile to 38.6oC, mildly tachycardic but normotensive. You do not identify an immediate threat to life after considering shock, overwhelming sepsis, or respiratory compromise. You take a thorough history and examine Josef.
What are the criteria for febrile neutropenia?
Fever is any temperature >38.5°C or >38.0°C for one hour.
Neutropenia is an absolute neutrophil count <0.5×109/L, or <1×109/L, with a predicted decline to less than 0.5×109/L within 48 hours.
What are the specific features of the history?
What is the child’s oncology diagnosis, and where are they in their treatment course? Different chemotherapeutic agents have stronger myeloablative effects, leading to more fulminant and predictable neutropenia. As chemo agents vary with diagnosis and cycle, it’s important to clarify which medications have been given and the number of days since the last cycle of chemotherapy.
Compliant with antifungal and pneumocystis prophylaxis? Think about PCP pneumonia in any oncology child presenting with work of breathing.
What kind of central venous access +/—was last accessed? Central venous access is a double-edged sword—it is essential for chemo that allows a reduction in the number of peripheral venipunctures, but it is also the most common source of bacterial infection in chemo kids.
Sick contacts? Remember, just because your patient has an oncology diagnosis doesn’t mean they don’t catch other age-appropriate illnesses like gastroenteritis, upper respiratory infections, etc. Of course, they’re often more severe, but it’s important to look!
Specific features on examination?
Examine for signs of dehydration, sepsis and anaemia.
Examine the central line site. A good time to look is when the line is accessed for cultures. Check the age of the dressing and note any erythema or cracks in the line.
Look at the skin all over.
Examine as for a fever without source.
Have a good look in the mouth – mucositis is common and a possible entry site.
Likewise, the perianal area is susceptible to skin breakdown, with or without perianal abscesses.
Take particular note of any areas of erythema.
Why is skin erythema significant?
It’s worth considering the pathophysiology of erythema; local inflammatory mediators (IL-1, IL-6, TNFa) signal neutrophils to marginate, roll, and undergo diapedesis to the area of action. But in the absence of a full neutrophil response, any localized erythema will likely be reduced, and pus will not form in the usual volume.
Thus, the smallest area of erythema should be considered as a possible source for infection, especially around central access sites or surgical wounds.
Which investigations are indicated?
FBC (are they actually neutropaenic?)
Blood culture (central lines/PICC)
Urea & electrolytes, consider calcium, magnesium, and phosphate (dehydration, renal dysfunction, tumour lysis syndrome)
Liver function tests (liver dysfunction secondary to chemotherapy agents)
CXR if increased work of breathing, poor SpO2
Nasopharyngeal aspirate if rhinorrhoea (make sure the PLT >50×109/L beforehand)
Consider coagulation profile
Focused investigations as per history and examination
Stool sample if diarrhoea, with C. difficile toxin if on recent antibiotics
IV access is gained via Josef’s tunnelled central line by an experienced staff member. Bloods are sent for FBC, culture and UEG, LFT, Ca/Mg/PO4, and coags.
What is the management?
Most hospitals have well-established protocols for treating febrile neutropenia. Be aware of where to find yours and the choice of anti-infective agents.
Start antibiotic treatment promptly; it may be life-saving. This is not a time to faff about waiting for the results of investigations, as antibiotics are the treatment irrespective of any preliminary results.
Some protocols advise anti-fungal treatment in addition to antibiotics. These protocols will vary between centres and over time with changing resistance patterns.
Remember to discuss your patient with the oncologist on call; these kids will usually need admission and, on occasion, transfer to the tertiary oncology centre.
Antibiotics are the mainstay of treatment in febrile neutropaenia. Miadema and her Dutch colleagues are undertaking a Cochrane Review of intravenous vs oral empiric treatment of febrile neutropaenia.
The Therapeutic Guidelines currently recommend:
Piperacillin+tazobactam 100+12.5mg/kg (Max 4+0.5g) IV q8h
OR
Cefipime 50mg/kg (Max 2g) IV q8h
OR
Ceftazidime 50mg/kg (Max 2g) IV q8h
If you suspect MRSA, central line infection, or hemodynamic instability, add vancomycin. Gentamicin or amikacin may also be indicated.
Treat dehydration with the appropriate fluids, and if the child is nauseated or vomiting, use antiemetics.
References
RCH Melbourne CPG – Febrile Neutropenia
Management of Fever in the Paediatric Oncology Patient v3.0 17102012 Febrile Neutropenia Protocol QPHON QCCC
Miadema et al. [Protocol] Empirical antibiotic therapy for febrile neutropenia in pediatric cancer patients. Cochrane Library.
