Clozapine-associated pneumonia: Under-recognised morbidity and mortality risk

To the Editor

There is emerging evidence of increased risk of clozapine-associated pneumonia, which is currently under-recognised (Chang et al., 2020; De Leon et al., 2020; Stoecker et al., 2017).

Mr X is a 19-year-old man, who has treatment resistant schizophrenia and was admitted due to persecutory delusions. He had no significant medical comorbidity, nil alcohol and smoking consumption. Clozapine was initiated and on the seventh day (100 mg dose), he was tachycardic and afebrile. He had rhinorrhoea, and no breathlessness, sialorrhoea, over-sedation or abnormalities on physical examination. Electrocardiogram (ECG) showed sinus tachycardia (120), echocardiogram was normal, C-reactive protein (CRP) was 8.9 mg/L (normal < 8) increasing to 29.3 mg/L by day 9 and clozapine levels were 237 ug/L. Differential diagnoses investigated were myocarditis, pulmonary embolus, clozapine-induced tachycardia and pneumonia. Chest X ray (CXR) was normal but computed tomography (CT) pulmonary angiogram revealed patchy opacities consistent with atypical pneumonia. Amoxycillin/clavulanic acid in combination with doxycycline was commenced on day 13 with response noted within 3 days. He was discharged 9 weeks later on clozapine 350 mg, with resolution of psychosis and no pneumonia recurrence.

The potential for clozapine-associated pneumonia is currently under-recognised and appears dose-dependent (De Leon et al., 2020; Stoecker et al., 2017). In a 25-month retrospective study pneumonia occurred in 34% of clozapine patients (odds ratio = 4.07 compared to general population) with no increased pneumonia-risk related to risperidone (Stoecker et al., 2017). Pneumonia was the leading cause of medical admissions for clozapine patients in a 12-year study (De Leon et al., 2020). While recognising clozapine fatalities due to myocarditis and agranulocytosis, we under-recognise potential for clozapine-associated pneumonia fatalities. A World Health Organization pharmacovigilance database study identified that most clozapine-associated fatalities were pneumonia-related (1577), compared to 943 fatalities for cardiac arrest, 212 fatalities for agranulocytosis and 144 fatalities for myocarditis (De Leon et al., 2020). Pneumonia fatalities are particularly increased within 2 months of clozapine initiation (De Leon et al., 2020). This case presentation highlights the importance of considering pneumonia, despite few overt symptoms and signs.

The mechanisms of clozapine-associated pneumonia include sedation, sialorrhoea, decreased oropharyngeal/oesophageal motility, increasing aspiration risk (De Leon et al., 2020; Stoecker et al., 2017). Clozapine has complex immune system effects possibly increasing pneumonia risk (De Leon et al., 2020; Stoecker et al., 2017). We recommend increased clinician awareness of clozapine-associated pneumonia morbidity /mortality, accompanied by patient/carer psychoeducation to recognise potential signs of infection earlier. Vigilance is required particularly for patients with medical comorbidity, smoking history and signs of upper respiratory tract infection, which can progress to pneumonia (Chang et al., 2020; Stoecker et al., 2017). Given the pneumonia fatality-risk (higher fatalities than myocarditis and agranulocytosis), respiratory symptoms need to be taken seriously, particularly during clozapine initiation. Once pneumonia is identified, promptly reducing or withholding clozapine should be considered (Chang et al., 2020; De Leon et al., 2020). Further research is required and we should consider establishing specific pneumonia monitoring guidelines for clozapine patients.