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.
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, respiratory compromise. You take a thorough history and examine Josef.
What is 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 in the treatment course are they? Different chemotherapeutic agents have relatively 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 many days since last 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 +/- last accessed? Central venous access is a double-edged sword – an essential access for chemo that allows a reduction in the number of peripheral venipuncture, but 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 and the like. 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 being 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 importan?
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 not formed 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, phosphate (dehydration, renal dysfunction, tumor 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 tunneled central line, by an experienced staff member. Bloods are sent for FBC, culture and UEG, LFT, Ca/Mg/PO4, coags.
What is the management?
Most hospitals have well-established protocols for the treatment of 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 presently undertaking a Cochrane Review of intravenous vs oral empiric treatment of febrile neutropaenia.
The Therapeutic Guidelines currently recommends:
Piperacillin+tazobactam 100+12.5mg/kg (Max 4+0.5g) IV q8h
Cefipime 50mg/kg (Max 2g) IV q8h
Ceftazidime 50mg/kg (Max 2g) IV q8h
If you have a suspicion of MRSA, central line infection or haemodynamically unstable, add vancomycin. Gentamicin or amikacin may be indicated.
Treat dehydration with the appropriate fluids and if the child is nauseated or vomiting, antiemetics.
Basu, K et al. Length of stay and mortality associated with febrile neutropenia among children with cancer. J Clin Oncol. 2005 Nov 1;23(31):7958-66.
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.
Lehrnbecher, T. Guideline for the Management of Fever and Neutropenia in Children With Cancer and/or Undergoing Haematopoetic Stem-Cell Transplantation. JCO Dec 10, 2012, vol. 30, no 35 4427-4438
Afzal, S. et al. Risk Factors for Infection-Related Outcomes During Induction Therapy for Childhood Acute Lymphoblastic Leukemia, The Pediatric Infectious Disease Journal • Volume 28, Number 12, December 2009 pp 1064-68
Therapeutic Guidelines : Antibiotic. Severe Sepsis: empirical therapy (no obvious source of infection): febrile neutropenic patients. Therapeutic Guidelines Group. Revised June 2010. (etg40 July 2013)