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Case 043: Fever, chills, gum pain, sore throat.

Authors: David C Chung MD, FRCPC

Thomas YK Chan MD, PhD, FRCP
Affiliation: The Chinese University of Hong Kong

A 58-year-old minibus driver with good past health was diagnosed to have
hyperthyroidism and put on carbimazole. His hyperthyroid symptoms improved when
he was reviewed in the out-patient clinic 6 weeks later but he presented to his doctor
another month later with a 2 day history of swinging fever, chills and rigor, gum pain,
sore throat, and epigastric pain. Physical examination revealed an ill-looking patient
with raw gum margins, inflamed tonsils and pharynx, and tenderness over the right
upper quadrant. Laboratory investigations revealed an absolute neutrophil count of
0.14 X 109/L; alkaline phosphatase was elevated at 279 IU/L; CT of abdomen
showed micro-abscesses in the liver.

1. What can account for this patient’s neutropenia (agranulocytosis)?

This patient’s absolute neutrophils count was 0.14 X 109/L. An absolute

neutrophil count of < 1.5 X 109/L is termed neutropenia and an absolute
neutrophil count of < 0.2 X 109/L is called agranulocytosis. This patient’s
agranulocytosis is carbimazole induced. It is a rare but potentially fatal
complication that appears within the first 3 months of therapy and affects
approximately 3 – 10 per 10,000 patients. An uneventful previous exposure does
not guarantee a complication-free subsequent exposure. The mechanism
underlying this complication is unclear: Both a toxic process interfering with cell
replication and an immune-mediated suppression of granulocyte formation have
been proposed. Toxicity is reversible upon discontinuation of the drug. Similar
drug-induced agranulocytosis has been reported with the other anti-thyroid drugs,
propylthiouracil and methimazole.
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2. What is the clinical significance of neutropenia (agranulocytosis)?

Neutropenia or agranulocytosis increases a patient’s vulnerability to infection by

gram-positive and gram-negative bacteria and by fungi. The risk increases with
the severity of neutropenia and a stepwise approach to management of the
patient is advised:

Neutropenia Clinical significance Management

1 – 1.5 X 109/L Guarded Monitor for febrile illness
0.5 – 1 X 109/L Slight increase in Treat febrile illness with antibiotics
vulnerability
0.2 – 0.5 X 109/L Significant increase in Treat febrile illness with antibiotics
vulnerability and start granulocyte colony
stimulating factor (G-CSF) therapy
< 0.2 X 109/L Extremely vulnerable Treat febrile illness aggressively
with antibiotics and start G-CSF
therapy
Adapted from Newburger PE. Neutropenia. In Rakel: Conn’s Current Therapy, 58th edition. Saunders; 2006.

3. What is granulocyte colony stimulating factor (G-CSF)?

Human G-CSF (Neupogen) is a glycoprotein produced in E. coli using

recombinant technology. It is a myeloid growth factor that has been shown to
improve neutrophil count in a diverse number of congenital and acquired
conditions associated with neutropenia, thus decreasing the risk of bacterial and
fungal infections in these conditions.

4. How should carbimazole-induced neutropenia be managed?

o First and foremost, carbimazole should be discontinued. Spontaneous

recovery generally occurs within 2 weeks after stoppage of the drug. In
general it is safe to switch the patient to propylthiouracil—or vice versa if
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propylthiouracil is the offending drug—because the chance of developing

neutropenia or agranulocytosis with a second anti-thyroid drug is only
occasional. If anti-thyroid drug is stopped completely, the patient should be
monitored for the development of thyroid storm and treated accordingly. (See
“Thyroid Storm” in Case 021 on http://www.medicine-on-line.com.)
o Start antibiotic and G-CSF therapy according to the stepwise approach listed
in the table under Question 2. Ideally the choice of antibiotic should be based
on culture and sensitivity results. However, this practice would cause
unnecessary delay. A more pragmatic approach is to send samples for culture
and sensitivity studies but start broad spectrum antibiotic therapy immediately
afterwards, with its choice based on the prevailing identity and susceptibility of
micro-organisms in the local community or the institution.

5. How should patients on anti-thyroid drugs be monitored for

neutropenia?

Neutropenia usually develops within the first 3 months of starting anti-thyroid drug
therapy. Regular periodic white blood count is not helpful in monitoring because
neutropenia is a rare complication that develops erratically and rapidly. The best
approach is to instruct the patient to seek medical advice on the first signs of sore
throat, gum pain, or febrile illness.

Further readings

Newburger PE. Neutropenia. In Rakel: Conn’s Current Therapy, 58th edition.

Saunders; 2006.

Tajiri J et al. Antithyroid drug-induced agranulocytosis: how has granulocyte colony-

stimulating factor changed therapy? Thyroid 2005;15:292-7.