A 42-year-old woman is evaluated in the ambulatory clinic due to a three-day history of hi… — USMLE Step 3

A $42$ -year-old woman is evaluated in the ambulatory clinic due to a three-day history of high fever, severe fatigue, and a painful sore throat. Her medical history is notable for Crohn disease, which has been in clinical remission for the past four years on a stable daily dose of azathioprine. She also has a history of recurrent gout. Three weeks ago, her primary care physician initiated febuxostat to better control her serum uric acid levels. Today, her temperature is $39.4^\circ\text{C}$ ( $102.9^\circ\text{F}$ ), blood pressure is $98/60\text{ mmHg}$ , pulse is $112/\text{min}$ , and respirations are $20/\text{min}$ . Physical examination reveals pale conjunctivae and several aphthous ulcers on the buccal mucosa. There is no active joint swelling, erythema, or focal source of infection identified on examination.

Laboratory studies reveal:
Leukocyte count: $1,100/\text{mm}^3$ (Absolute neutrophil count: $400/\text{mm}^3$ )
Hemoglobin: $7.8\text{ g/dL}$
Platelet count: $42,000/\text{mm}^3$

Which of the following is the most appropriate next step in the evaluation and management of this patient?

Admit to the hospital, discontinue azathioprine, and initiate empiric broad-spectrum intravenous antibioticsAnswer
B
Discontinue febuxostat, initiate oral colchicine, and discharge with instructions to repeat the complete blood count in 48 hours
C
Order a computed tomography scan of the neck and chest to identify the source of infection prior to administering antibiotics
D
Schedule an urgent bone marrow aspiration and biopsy to evaluate for a primary hematologic malignancy
E
Obtain thiopurine methyltransferase (TPMT) activity levels and withhold azathioprine pending the results

Answer

Admit to the hospital, discontinue azathioprine, and initiate empiric broad-spectrum intravenous antibiotics.

The correct action is to admit the patient to the hospital, discontinue azathioprine, and initiate empiric broad-spectrum intravenous antibiotics. This patient has febrile neutropenia (defined as a single oral temperature

\ge 38.3^\circ\text{C}

or sustained temperature

\ge 38.0^\circ\text{C}

for

1

hour, coupled with an absolute neutrophil count

< 500/\text{mm}^3

). This is a medical emergency. The underlying etiology is a severe pharmacokinetic interaction: azathioprine is a prodrug converted to

6

-mercaptopurine (

6

-MP).

6

-MP is subsequently degraded into inactive metabolites by the enzyme xanthine oxidase. Febuxostat (like allopurinol) is a xanthine oxidase inhibitor. When co-administered, febuxostat blocks the degradation of

6

-MP, leading to massive intracellular accumulation of active thiopurine nucleotides and profound, life-threatening myelosuppression.

Step-by-Step Solution

Evaluate the clinical presentation and vital signs.

The patient is febrile, tachycardic, hypotensive, and severely neutropenic (absolute neutrophil count

<500/\text{mm}^3

To identify that the patient is experiencing a hematologic emergency known as febrile neutropenia, which carries a high risk of rapid progression to septic shock.

Analyze the patient's medication list for pharmacokinetic interactions.

The patient was recently started on febuxostat while taking a stable dose of azathioprine.

To pinpoint the etiology of the sudden pancytopenia. Azathioprine is metabolized into

6

-mercaptopurine, which is normally inactivated by xanthine oxidase. Febuxostat is a potent xanthine oxidase inhibitor, leading to toxic accumulation of

6

-mercaptopurine and profound myelosuppression.

Determine the most appropriate setting and sequence for treatment evaluation.

Immediate inpatient admission, cessation of the interacting medications, and rapid administration of empiric broad-spectrum intravenous antibiotics are required.

Febrile neutropenia requires emergent stabilization before any further diagnostic workup (like imaging or biopsies) to prevent mortality.

Key Concept

Co-administration of azathioprine and xanthine oxidase inhibitors (such as febuxostat or allopurinol) results in a severe pharmacokinetic interaction leading to toxic accumulation of

6

-mercaptopurine and life-threatening myelosuppression. The resulting febrile neutropenia is a medical emergency requiring immediate hospitalization and empiric broad-spectrum intravenous antibiotics.

Question

Answer

Step-by-Step Solution

Key Concept

Common Mistakes

Topics

More questions from this topic