Clozapine Neutropenia and the Coronavirus

Dr Chiara Buhagiar (Psychiatry Trainee)
Dr Rupa Ramesh (Consultant Psychiatrist)

Abstract

COVID-19 is a new virus that affects the full blood count, generally causing a lymphopenia, while the white blood cell count and neutrophil count remain unchanged. Clozapine is a drug well known for causing neutropenia and low white cell counts but has no effect on lymphocytes. Not much is known about how COVID-19 and clozapine would interact. The following describes such a case, and one can see the effect on the patient’s blood results as well as consider various other implications of this case.

Introduction

Neutropenia is a relatively common adverse side effect of clozapine treatment, affecting up to 2.7% of patients within the first 18 weeks of treatment.1 COVID-19 has been shown to cause lymphopenia.2 The white cell count can be either within normal range, slightly decreased in mild disease, or elevated in severe disease.3 Neutrophils are within normal range or elevated.4 The following case report describes a patient who, shortly after starting clozapine treatment, became both neutropenic and infected with COVID-19.

Methods

A 40-year-old gentleman was admitted to an acute inpatient ward after being arrested for criminal damage – arson to his own accommodation – due to a relapse and deterioration of his mental health. He had been well known to mental health services since 2001, initially due to cannabis induced psychosis, with established diagnoses of paranoid schizophrenia (diagnosed in 2013) and poly-substance misuse (diagnosed in 2012). He was aggressive, paranoid, and thought-disordered with persecutory delusional ideation. He also had a history of non-concordance with medication and multiple previous admissions, the last of which had been two months earlier. He had no known medical history, other than a having had a seizure in the past.

After 3 months on an acute inpatient unit he was discharged to a rehabilitation ward on olanzapine depot 300mg every 2 weeks and semi-sodium valproate 1000mg in the morning and 750mg at night. After a week on the rehab ward his mental health appeared to deteriorate once more, and he had a relapse where he was aggressive to staff. The rehabilitation ward was unable to support his behaviour. He was therefore transferred back to the acute ward.

Given the relapsing and remitting nature of his illness, and the fact that he had previously tried aripiprazole, risperidone, paliperidone and olanzapine (which had seemed to be the most effective for him), it was felt that clozapine was a better option moving forward. The patient had, in the past, been reluctant to switch to clozapine. On this occasion, however, he agreed, in order to try to prevent further relapses with their attendant readmissions to hospital.

Prior to clozapine initiation, his baseline bloods showed a total white blood cell (WBC) count of 7.9 x109/L, with a neutrophil count of 4.3 x109/L and lymphocytes of 2.6 x109/L (see Table 1, along with the reference ranges).

11/11/201901/04/2020
(pre-Clozapine)
08/04/2020
Clozapine Day 4
12/04/202013/04/2020
Clozapine stopped
14/04/202015/04/202021/04/202029/04/2020UnitsNormal Range
WBC7.37.94.92.72.9336.66.510^9/L4.0 - 11.0
Automated Neutrophil Count5.14.32.11.21.61.41.54.13.410^9/L2.0 - 7.0
Automated Lymphocyte Count1.62.61.710.91.11.21.62.310^9/L1.0 - 4.0

Table 1: Table showing the patient’s blood results for white blood cells (WBC), neutrophils and lymphocytes

On day 4 after starting clozapine, his bloods were taken and showed that his WBC had dropped to 4.9 x109/L, neutrophils to 1.6 x109/L and lymphocytes to 1.7 x109/L. Although there was a clear drop in his white cell and neutrophil counts, it was still considered safe to continue with clozapine treatment (CPMS) (see Table 2).

Date Blood
Taken
WBC
(x 109/L)
NC
(x 109/L)
PLTS
(x 109/L)
EOS
(x 109/L)
MXD
(x 109/L)
Total Daily
Dose (mg)
Name of
Laboratory
Blood
Alert
10/12/20188.504.802120.100Darent Valley Hospital DA2 8DAGreen
01/04/20207.904.301870.200Darent Valley Hospital DA2 8DAGreen
08/04/20204.902.101490.10Darent Valley Hospital DA2 8DAGreen
13/04/20202.901.601340.00Darent Valley Hospital DA2 8DARed
14/04/20203.001.401460.00Darent Valley Hospital DA2 8DARed
15/04/20203.001.501520.00Darent Valley Hospital DA2 8DAAmber
21/04/20206.604.10347Darent Valley Hospital DA2 8DAGreen
16/05/20207.803.702000.60Darent Valley Hospital DA2 8DAGreen

Table 2: Table from the Clozapine Monitoring Service (CPMS) showing the safe green results and red alerts

On day 8 of treatment, the patient developed a fever (38.1oC). At the time, the differential diagnosis was neutropenic sepsis or COVID-19, so bloods and a COVID-19 swab were done to investigate further. His bloods showed a CRP of 7mg/L (Ref. range <10), WBC 2.7 x109/L, neutrophils 1.2 x109/L and lymphocytes 1.0 x109/L. His COVID-19 swab came back positive and he was therefore diagnosed with coronavirus. Neutropenic sepsis was ruled out due to his low CRP and the clinical presentation (he presented only with a fever and no other signs of sepsis). Due to the neutropenia (neutrophils <1.5) his clozapine was withheld and his blood counts were monitored daily (see Table 1). The following day (13/4/20) repeat tests showed total WBC 2.9 x109/L, neutrophils 1.6 x109/L and lymphocytes 0.9 x109/L and he had a red alert from CPMS (Table 2).

The patient was restarted on olanzapine. He remained in isolation, taking regular paracetamol to control his fever, and was transferred to the COVID-19 ward. His bloods began to normalise, as seen in the tables, and, 3 to 8 days after cessation of clozapine, they had returned to his admission levels. His only symptom from the virus was a fever. 15 days after the start of his isolation period, he was transferred back to his acute ward, being symptom-free and testing negative on a repeat swab.

Case Discussion

Neutropenia is an uncommon (between 0.1% and < 1%) side effect of olanzapine.5 The risk of agranulocytosis is significantly lower with olanzapine than with clozapine. The exact mechanisms by which olanzapine causes neutropenia are not well established but are thought to be similar to those of clozapine.5 In this case the patient had been on olanzapine for over ten years and during that time there had been no documentation or evidence of neutropenia. Also, neutropenia did not persist once the patient was restarted on olanzapine; in fact, his blood results resolved to pre-clozapine levels.

The patient had also been on semi-sodium valproate since 2018, and previously between 2014-2016. It had been stopped in the first instance as it was felt that he did not need to be on both valproate and olanzapine as his mental state had been stable. Throughout the time that he was taking valproate, there were no haematological changes noted on his blood tests. The main haematological side effect that valproate is known to cause is thrombocytopenia. This occurs in 5 to 18% of patients on valproate, with females and the elderly being at increased risk.6 Leucopenia, and by extension neutropenia, is also a rare side effect of sodium valproate;7 however his blood levels were well within range throughout. It should be noted, however, that concurrent use of valproate increases the risk of, and has been associated with, clozapine induced neutropenia.8

Graph depicting the neutrophil count

Graph 1: Graph depicting the neutrophil count

Clozapine carries a significantly increased risk of neutropenia compared to olanzapine, affecting close to 3% of patients.1 Although still unclear, a number of mechanisms for this effect have been postulated, including direct bone marrow suppression, toxicity by the drug itself or its metabolites, or by causing immune-mediated destruction of the granulocyte line.1 Risk factors include having a lower baseline white cell count, being Afro-Caribbean, and being younger in age. This patient did not have any of the risk factors; however, he did become neutropenic within the first 18 weeks of treatment, which is the most common time to get this side effect.1
A policy has been released to show that patients on clozapine who develop a low WBC count in the context of COVID-19 infection can generally continue their treatment with the drug, as the low count is due to the virus causing a decrease in the lymphocytes while neutrophils generally remain within range.7

This case, however, described a neutropenia which is out of keeping with the blood picture of COVID-19 and is more consistent with the usual adverse reaction of agranulocytosis that clozapine is known to cause. 9

It is important to note that this patient’s lymphocytes were also on a downward trend; however, they were only below normal range (1.0-4.0 x109/L) on one occasion (0.9 x109/L). Lymphopenia has been reported in most studies of COVID-19, in up to 85% of patients.10 It is likely that this downward trajectory of the lymphocyte count is a result of the viral infection as clozapine is not known to affect lymphocyte count.11

Graph depicting the comparison between WBC, neutrophil count and lymphocyte count

Graph 2: Graph depicting the comparison between WBC, neutrophil count and lymphocyte count

In this case it was highly important to rule out neutropenic sepsis as up to 60% of patients with severe drug induced neutropenia can develop septicaemia.12 His bloods were monitored daily as close monitoring of blood counts has been found to reduce the incidence of fatal neutropenia to 0.03% during clozapine treatment.12 Any neutropenic patient who presents with signs and symptoms of septicaemia or who is at high risk of infection should be treated aggressively and broad-spectrum antibiotics should be initiated empirically.13 This patient presented with a fever only and was not septic. Although the patient did have a high fever and a positive COVID-19 swab, he did not have a severe illness. The degree of lymphopenia, which has been linked to disease severity in COVID-19, was only mild and his CRP was normal.

Another independent marker of severity, morbidity and mortality found in association with the coronavirus is the neutrophil-to-lymphocyte ratio (NLR).14 An increased NLR holds a worse prognosis for the positive COVID-19 patient and, even given what we have seen with our patient, it would be important to keep this in mind in the future with patients whose medication, such as clozapine, may be affecting their blood levels.15

The authors of this case report acknowledge that a false positive swab test for COVID-19 cannot be ruled out and, in the future, when accurate antibody testing is more widely available, this can be looked into.

This case also reveals the potential to detect neutropenia at an earlier stage than is routinely practised. This patient went from a situation of 2 acceptable (green) results from CPMS to an established state of neutropenia (red result). This happened in the middle of the COVID-19 epidemic and, fortunately, his immuno-compromised state did not translate into any opportunistic overwhelming infection. We propose that had greater attention been paid to the initial drop in the neutrophil count, then an earlier follow-up FBC could have been performed, allowing for earlier cessation of the clozapine therapy. This may require the introduction of a delta-neutrophil count by CPMS, a simple estimation akin to the standard practice of the estimation of delta-cardiac troponin in the detection of acute coronary syndrome.16

With the benefit of hindsight, the drop of the neutrophil count to 37% of its former value within days of starting clozapine is a significant result that should have alerted closer monitoring.

References

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[16] Calculating Serial Change Values (Delta) for High-Sensitivity Cardiac Troponin Assays [Internet]. International Federation of Clinical Chemistry and Laboratory Medicine. Available from: https://www.ifcc.org/media/259735/201405_TF_CB_IFCC_practice%20Extended%20document.pdf