Neutropenic fever

Petersdorf and Beeson 1961

The term "febrile neutropenia" or "neutropenic fever" are replacement terms for severe febrile neutropenic infections of unknown origin during or after chemotherapy. Nine out of ten tumour patients develop neutropenia under chemotherapy. If the number of granulocytes falls below a critical value (< 500/µl), the risk of fever and life-threatening infections increases significantly (Mulders-Manders C et al. 2015).

A febrile neutropenia (FN) is defined by temperature increases in neutropenia:

• oral temperature is once above 38.3 °C; neutrophil count < 500/µl
• oral temperature is above 38 °C for 2 times > 1 hour; neutrophil count < 500/µl
• oral temperature is twice > 38 °C within 12 h; neutrophil count < 500/µl.

In 50% of the cases the genesis remains unexplained. Until proven otherwise, the cause is assumed to be an infection (staphylococci, streptococci, gram-negative bacteria, possibly fungi). The cause may also be neoplastic, rheumatological or inflammatory diseases (Chusid J et al. 2017; Beresford RW et al. 2016).

adults and also children (Chien YL et al. 2017)

The therapy must start within 2 hours. The diagnostics must not delay the start of therapy.

1-7h:

• initial monotherapy with Meropenem 3x1g/day i.v;
• alternatively: piperacillin/tazobactam 3x4.5g i.v.
• alternative: Ceftazdim 3x2g/day i.v.

72-96h:

• Persistent fever is an indication of resistant pathogens (e.g. St. Aureus or problem germs), a systemic fungal infection (e.g. Aspergillus fumigatus) an infection with P. jiroveci or CMV.
• Extend antibiotic therapy: additionally vancomycin 2x1g/day i.v. as short infusion and/or aminoglycoside
• In case of proven P. jiroveci pneumonia: high dosage of Cotrimoxazol
• For Pseudomonas: Ceftazidim 3x2g/day i.v. + gentamicin 1x5mg/kgKG as short infusion

>9h

• Additional antimycotic therapy for:
• Especially Candida infection: Fluconazole initial 1x400-800mg/day i.v.
• Alternative: Caspofungion, voriconazole

Mainly aspergillosis: voriconazole 2x6mg/kgkgkgkg i.v. (as loading dose), then 2-4mg/kgkgkgkg i.v. per day. After improvement oralization of the therapy (e.g. 200mg/day p.o.).

Mainly VZV-infection: Aciclovir 1,5g/m2 spread over 3 doses (every 8 h)

Mainly HSV infection: Aciclovir 3x(every 8 h) 5-10mg/kgKG as short infusion

In the longer term, neutropenia often forces the patient to reduce the dose of cancer drugs or postpone the next chemotherapy cycle. An alternative is the prophylactic administration of antibiotics and/or bone marrow growth factors such as granulocyte and granulocyte-macrophage colony stimulating factors (G- and GM-CSF). Filgrastim, the pegylated form Pegfilgrastim and Lenograstim are available. All of them could approximately halve the risk of FN. Dose dense therapy regimens with shortened intervals, for example when applied every 14 days, are only possible with G-CSF support.

A study with > 40 000 patients who were hospitalized for FN under chemotherapy showed a general mortality of 9.5 percent. If complications such as sepsis, pneumonia, leukaemia or pulmonary embolism occurred, 20% of the patients died. Neutropenia is not only a precursor for bacterial pathogens, but also for invasive mycoses. It is the main risk factor for aspergillosis. Invasive mycoses have a high mortality rate.

Prophylaxis or early administration of bone marrow growth factors can stop the disease.

1. Beresford RW et al (2016) Pyrexia of unknown origin: causes, investigation and management. Intern Med J 46:1011-1016
2. Chusid J et al (2017) Fever of Unknown Origin in Childhood. Pediatr Clin North Am 64: 205-230
3. Chien YL et al.(2017) Clinical approach to fever of unknown origin in children. J Microbiol Immunol Infect 50: 893-898Cunha
   BA, et al. (2015) Fever of unknown origin: a clinical approach. Am J Med 128: 1138.e1-1138.e15 Mulders-Manders C et al (2015) Fever of unknown origin. Clin Med (Lond) 15: 280-284.
4. Unger M et al.(2016) Fever of unknown origin (FUO) revised. Wien Klin Wochenschr 128: 796-801