Fever and elevated CRP-related to clozapine dose

To the Editor

Benign fever is a common reported side effect of treatment with clozapine, reported in up to 50% of cases. However, descriptions of concomitant clozapine-induced elevations in serum C-reactive protein (CRP) are rare, with only two previous descriptions in literature (Löffler et al., 2010; Štuhec, 2013). Although clozapine-induced fever remains a diagnosis of exclusion, we present this case to heighten clinicians’ awareness of the issue and suggest further research be directed at the dose-dependency of this effect.

A 57-year-old was admitted to the inpatient psychiatry unit for management of schizoaffective disorder. She had no other medical history and took quetiapine 200 mg daily and clonazepam 300 mg daily.

She was commenced on clozapine 12.5 mg daily, titrating up by 12.5 mg each day. On day 12, she was noted to be febrile. The clozapine trough level was found to be markedly elevated at 3280 nmol/L. After 3 days of persistent fever, she was admitted to general medicine. She complained of left iliac fossa tenderness. Examination revealed a temperature of 38.6 degrees and a pulse of 110 beats per minute. A complete systems examination was normal.

A full bloodwork panel most noticeably revealed a CRP of 211 mg/L (0–5 mg/L). Prior to starting clozapine, her CRP was 3 mg/L. A computerised tomography scan of her abdomen revealed only faecal impaction. Other investigations including frontal chest radiograph, full blood count, creatine kinase, troponin, blood cultures, electrocardiogram (ECG) and echocardiogram were normal.

Empirical cefuroxime was commenced. Bowels improved with laxatives. Despite this, fevers continued to a maximum of 39.5 degrees. Antibiotics were stopped after 3 days and clozapine-associated side effect was considered. Clozapine was reduced to 150 mg daily, with the follow-up trough 1740 nmol/L and CRP at this reduced dose of 11 mg/L. The temperature normalised after 1 day.

While benign fever is a well-documented adverse effect of clozapine, there is very little evidence about the significance of CRP. Traditional teaching indicates that a CRP > 100 mg/L can indicate a severe bacterial infection, and higher CRP values increase this probability due to the increased specificity associated with higher thresholds (Melbye and Stocks, 2006). The risk factors for developing fever on clozapine are not well understood, and there is conflicting evidence as to whether there is a dose-dependent effect. However, we hypothesise that our patient’s CRP, the highest reported in literature due to clozapine, could be partially attributed to a dose-dependent effect, with the peak corresponding to the high clozapine level and remission corresponding to down titration. Future research needs to be directed at this thought.