Neutropenic Fever Syndrome

Neutropenic Fever Syndrome

The story of Carl Wunderlich, his dedication to determine average body temperature, and his not so accurate thermometer is well known among the medical fraternity. Like any other physiological parameter, the average temperature should be looked at as a range and not a number. There are certain instances when a temperature above 0.5-degree centigrade of average is too hot for an ER doctor. Let us talk about one such condition today.

Cancer patients being treated with anti-neoplastics are at risk of neutropenic fever syndrome (NFS). An overly simplistic, and hence super helpful way of looking at NFS is: anti-neoplastics damage gastrointestinal mucosa, help bugs translocate into the bloodstream, and at the same time damage our white blood cells. All this happens in the background of malignancy, already an immunocompromised status.

Eighty percent of identified infections in NFS arise from endogenous flora. Well, that backs up my oversimplification. Now I can confidently tell you this statistic; infectious sources are only found in up to 30% of the cases.

NFS is a disease of acute leukemia patients. Up to 95% of leukemia patients, 25% of non-leukemic patients with hematologic malignancies, and 10 percent of patients with solid tumors get NFS after being started on cytotoxic therapy.

Fever in neutropenic [Absolute Neutrophil Count (ANC) <500] patients is a single temperature of 101F or a temperature of 100.4° F over one hour.

How would you calculate ANC?

Total leukocyte X (% of neutrophils + % of band neutrophils)

How do you measure temperature?

Neutropenia is one of the two common instances when a rectal temperature is wrong; the other is thrombocytopenic patients. Oral temperature is adequate; make sure they don’t have oral mucositis that can falsely increase the reading in the patient’s thermometer and your head at the same time.

To make it even more complicated, guess what most patients on cancer chemotherapy are taking? Glucocorticoids! Also, remember, they are neutropenic, meaning they don’t have an adequate inflammatory response. Infections in neutropenic can present without elevated temperature, so be aware of SIRS: tachycardia, tachypnea, hypotension.

There are scoring systems to stratify NFS patients in high and low risk; CISNE and MASCC scores are examples, but none are comprehensive and hence are underused.

The management’s holy grail is antibiotics, but with such diverse and elite targets, where do you shoot? Let us try and oversimplify this: If the bugs are coming from our gut, they better be gram-negative rods (Pseudomonas aeruginosa!) That was so very true back in the day. Now, with the introduction to long-term indwelling central venous catheters, the empiric antibiotics to cover P. aeruginosa, and other gram negatives (Ciprofloxacin)– Staphylococcus epidermidis is winning the race. The gram-negatives are catching up; 60:40 is the score currently.

Fungi are not frequently the cause of the first febrile episode, but candida from the gut (of course!) and aspergillus from the lungs are culprits in long-term invasive fungal infections.

Here is another one for those who like analogies; Remember how there is a time-dependent door to needle approach in treating STEMI or acute stroke? There is one for NFS, sort of; 60 mins, some agree, some don’t! The unanimous consensus is to do it fast!

The problems like time for confirmation of neutropenia, a protocol for what to cover, and where to start antibiotics are yet to be discussed and solved. Studies have been done to demonstrate that mortality increases with every hour delay in administering antibiotics. A good rule of thumb to follow is administering antibiotics right after you draw blood for culture and before you send it.
They pose one last problem while recovering from neutropenia. Myeloid reconstitution syndrome is fever and a new inflammatory focus while neutrophil numbers go up. That is vaguely reminiscent of immune reconstitution syndrome in newly started HAART patients.

Next time you see a patient being treated for leukemia with a temperature of 100.4° F being triaged to a green zone in your ER, know that green has different shades.

Cite this article as: Sajan Acharya, Nepal, "Neutropenic Fever Syndrome," in International Emergency Medicine Education Project, January 18, 2021,, date accessed: October 1, 2023

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