Clozapine-induced pneumonitis

To the Editor

Clozapine is an effective treatment for treatment-resistant psychotic patients (Stoppe et al., 1992). Allergic reactions to clozapine have been described before but are rare and usually cutaneous (Stoppe et al., 1992), often with eosinophilia (Benning, 1998). A number of drugs can cause various forms of interstitial lung disease including interstitial pneumonia, alveolitis and occasionally vasculitis (Camus et al., 2004). The diagnosis relies upon: (a) association between exposure and the subsequent development of symptoms; (b) lung infiltrates; (c) exclusion of other causes; and (d) symptom resolution once the agent is withdrawn (Camus et al., 2004). Here we present a case of clozapine-induced pneumonitis without eosinophilia.

A 77-year-old man with a long history of treatment-resistant schizophrenia was admitted for medication adjustment due to persistent, distressing psychotic symptoms and extrapyramidal side effects. His past medical history was negative apart from chronic constipation, but on admission paroxysmal atrial flutter and a new heart murmur were noted. An echocardiogram showed moderate mitral regurgitation with preserved left ventricular function. He had previously been treated with several antipsychotic drugs with limited success. On admission he was taking fortnightly long-acting risperidone injections but experiencing significant akathisia and incomplete resolution of psychotic symptoms.

Clozapine was initiated at 12.5 mg daily and was titrated to 250 mg per day over 3 weeks. Risperidone was continued during initial clozapine titration, aiming to prevent exacerbation of psychotic symptoms during the changeover.

On the second day of treatment, tachycardia was noted; however, this resolved when clozapine was withheld for 24 hours and did not recur on reintroduction.

On day 20, the patient became non-specifically unwell with low blood pressure and unsteady gait. The following day he deteriorated with fever, tachycardia, dyspnoea, cough and feelings of panic. Clinical signs included lower limb oedema and bi-basal crackles with intermittent low blood pressure. A chest X-ray was consistent with congestive heart failure and pneumonia. Initially he responded well to antibiotics but then became more short of breath and his oxygen requirements increased.

There was no eosinophilia at any point and only mild neutrophilia. Daily troponins were essentially normal, but brain natriuretic peptide (BNP) was mildly raised and C-reactive protein (CRP) rose to 100. An electrocardiogram (ECG) showed persistent atrial fibrillation rather than intermittent flutter, but was otherwise unchanged. Myocarditis with associated heart failure was suspected, but cardiology opinion was that this was unlikely given the normal troponin.

A repeat chest X-ray 1 week after the initial onset of symptoms showed bilateral upper lobe shadowing and pleural effusions consistent with right heart failure and pneumonitis. The patient was transferred to a general medical ward for further investigation. Computed tomographic pulmonary angiography (CTPA) was negative for pulmonary embolism (PE) but did show reticulonodular shadowing typically seen in intrinsic allergic alveolitis and large effusions bilaterally. An anti-neutrophil cytoplasmic auto-antibody (ANCA) test was positive with positive anti-proteinase 3 antibodies (highly predictive of small vessel necrotising vasculitis). The patient declined a diagnostic aspirate.

The clozapine serum level taken on day 22 (on a daily dose of 250 mg) was above the therapeutic range at 2650 nmol/l. In response, the dose was reduced and then stopped altogether. Notwithstanding this, the serum level rose further (3320 nmol/l on day 28) then subsequently declined.

The consensus diagnosis was clozapine-induced pneumonitis, although vasculitis could not be ruled out. Heart failure was also clearly part of the picture but a repeat echocardiogram showed no functional change.

Five months after withdrawal of clozapine steady improvement has been seen but the patient continues to require treatment for cardiac failure and has not yet returned to his pre-morbid physical state. He continues to report exertional dyspnoea and impaired stamina, and has developed a new problem of atypical anxiety attacks, which are being investigated for a possible cardiological cause. His schizophrenia is currently being treated with a combination of risperidone and quetiapine, but psychotic symptoms remain prominent and distressing.

Allergic reactions to clozapine have been previously described, involving a number of organ systems (Benning, 1998); however, they are rare and usually associated with eosinophilia (Benning, 1998). A literature review indicates three other case reports of clozapine-induced alveolitis (Arias et al., 2011; Benning, 1998; Vanfletern et al., 2011) with one case reporting a normal eosinophil count (Arias et al., 2011). In two of these cases, the symptomatic manifestations were surprisingly mild, considering the diffuse infiltrates and pulmonary effusions seen on radiology (Arias et al., 2011; Benning, 1998). The third case was of fatal interstitial pneumonia with high serum levels of clozapine (Vanfletern et al., 2011).

This case highlights the importance of very careful medical monitoring during clozapine initiation. Pyrexia and tachycardia, although often benign, do warrant early investigation and should signal clinical suspicion for serious cardio-respiratory complications.