Lessons from practice
Volume 197 - Issue 8
Listeria monocytogenes infection in Crohn’s disease treated with adalimumab
Authors: Kaspar J Willson, Antony Jacob, Mohit P Shetti, Rajesh Bhatia, Kwang Yee and William Osler
Med J Aust 2012; 197 (8): 466-467. || doi: 10.5694/mja11.10521
Published online: 15 October 2012
Published online: 15 October 2012
Clinical record
A 58-year-old man with a history of Crohn’s disease presented to the emergency department of a peripheral hospital in March 2011. He had been ill for the past day,
with confusion, fluctuating expressive dysphasia, frontal headache and fever, preceded by 12 hours of lethargy
and myalgia.
The patient had been diagnosed with Crohn’s disease 2 years earlier after a colonoscopy for profuse bloody stools, which revealed extensive ...
Clinical record
A 58-year-old man with a history of Crohn’s disease presented to the emergency department of a peripheral hospital in March 2011. He had been ill for the past day, with confusion, fluctuating expressive dysphasia, frontal headache and fever, preceded by 12 hours of lethargy and myalgia.
The patient had been diagnosed with Crohn’s disease 2 years earlier after a colonoscopy for profuse bloody stools, which revealed extensive colitis with limited ileal involvement. Early improvement was achieved with corticosteroids; however, he developed hepatitis with azathioprine. Treatment with azathioprine was stopped and mercaptopurine was subsequently used, with the dose limited to 50 mg/day because leukopenia occurred at higher doses. Red cell thiopurine methyltransferase levels were normal. Since his diagnosis, he had been taking prednisolone continuously in varying doses until he had a severe flare 3 months before presentation, at which point he started taking adalimumab (a tumour necrosis factor-alpha antagonist). At the time of presentation he was taking mercaptopurine (50 mg daily), a weaning dose of prednisolone (15 mg daily) and adalimumab (40 mg fortnightly) for his Crohn’s disease. He reported stable symptoms of 2–3 stools per day with frequent blood while taking these medications. He worked as an information technology consultant and had no history of recent overseas or interstate travel, camping, extended bush exposure or insect bites. On examination, he was tachycardic and febrile with a temperature of 39.7°C. Examination was otherwise unremarkable except for mild confusion with fluctuating expressive dysphasia and some clotted blood on digital rectal examination. A non-contrast computed tomography scan of the brain revealed a subtle low-density lesion in the right basal ganglia, which was thought to represent an old lacunar infarct.
The initial treating team suspected a transient ischaemic attack (TIA) in addition to a flare of Crohn’s disease, and started treatment with aspirin–dipyridamole for the TIA and intravenous corticosteroids and intravenous metronidazole for the flare of Crohn’s disease.
Over the next 3 days the patient remained intermittently febrile and his antibiotic therapy was escalated to ticarcillin–clavulanate. No improvement was noted and he was transferred to a tertiary referral hospital. After the transfer, a lumbar puncture was performed, which showed a high lymphocyte count (115 × 106/L; reference interval [RI], < 1 × 106/L), high protein (0.67 g/L; RI, 0.15–0.45 g/L) and low glucose (1.9 mmol/L; RI, 2.2–3.9 mmol/L). The Gram stain was unremarkable. The preliminary results of the blood cultures yielded gram-positive rods consistent with Listeria monocytogenes. High-dose intravenous benzylpenicillin and trimethoprim–sulfamethoxazole (co-trimoxazole) were substituted for ticarcillin–clavulanate. He was no longer given mercaptopurine and adalimumab, and his dose of prednisolone was tapered.
In the following days, his headache improved and he became afebrile. Cultures of blood and cerebrospinal fluid confirmed L. monocytogenes. Intravenous co-trimoxazole was no longer administered after 3 days of clinical improvement, and benzylpenicillin monotherapy was continued. A follow-up magnetic resonance imaging scan on Day 14 after admission revealed no evidence of the basal ganglia lesion and was normal. He was given oral co-trimoxazole 3 weeks after admission to complete a 6-week course.
Public health services were notified and conducted an investigation. L. monocytogenes was isolated from leg ham in the patient’s fridge, but this was not thought to be the source of his infection. The pathogenic isolate was of serotype 4b, one of three serotypes responsible for the majority of all cases.1 No other cases were identified. The patient made a full recovery, with a final diagnosis of listeriosis with probable resolved basal ganglia abscess.
Invasive listeriosis is an uncommon cause of meningitis associated with the intracellular gram-positive rod Listeria monocytogenes. L. monocytogenes is widely distributed in the environment and is a common isolate from soil, vegetation and animals. Primarily a foodborne pathogen, L. monocytogenes is able to grow at refrigeration temperatures and is associated with uncooked refrigerated goods such as coleslaw, pâté, soft cheeses and delicatessen foods.2-2 Infection can either be non-invasive, with a self-limiting febrile gastroenteritis, or invasive, with either frank sepsis (often with central nervous system infection in adults) or pregnancy-associated infection resulting in stillbirth, miscarriage or neonatal disease.2 L. monocytogenes invades the host via enterocyte and macrophage phagocytosis, whereby it continues to spread intracellularly and during bacteraemia after cell lysis.3 Through cell-to-cell spread, it avoids the humoral immune system; and hence, an intact cell-mediated immunity is critical to host defence. Circumstances where cell-mediated immunity is impaired, such as with treatment with prednisolone or fludarabine, are well documented predisposing factors.4 In recent years, case reports have also implicated monoclonal antibodies against tumour necrosis factor-alpha (TNF-α), including infliximab, etanercept and adalimumab. TNF-α stimulates macrophage differentiation, phagocytosis and bacterial killing, and has been shown in mice to be critical to the early immune response.3 Accordingly, epidemiological studies have described the rate of listeriosis in those taking infliximab and etanercept to be 20–30 times and three times greater than that in the general population, respectively.5 Five cases of listeriosis in patients who were taking or had recently been taking adalimumab have been reported, three in patients with rheumatoid arthritis and two in patients with Crohn’s disease.6-10 Additionally, most reported cases have occurred in patients receiving concurrent immunotherapy with steroids, methotrexate, azathioprine and/or mercaptopurine.9,11 Highlighting the emerging evidence of association between TNF-α antagonists and listeriosis, the United States Food and Drug Administration updated the Boxed Warning on the entire class in 2010 to include the risk of infection with L. monocytogenes.12
Lessons from practice
Fever and confusion in patients receiving anti-tumour necrosis factor (TNF)-α therapy should prompt a thorough evaluation for infection, including taking blood cultures and performing a lumbar puncture if neurological signs are evident.
All anti-TNF-α antibodies predispose to Listeria monocytogenes infection, particularly in combination with other immunosuppressive agents such as steroids, methotrexate, azathioprine or mercaptopurine.
Patients receiving anti-TNF-α therapy should be made aware of the risk of listeriosis, and that an adjustment in their diet might mitigate this risk.
The Food Standards Australia New Zealand guidelines on Listeria are available at: http://www.health.gov.au/internet/main/publishing.nsf/Content/ageing-clinicians-type.htm/$File/Listeria.pdf
Diagnosis is most often made with positive results from cultures from either blood or cerebrospinal fluid, with Gram stain usually unhelpful. Empirical treatment for meningitis in adults when listeriosis is suspected is ceftriaxone or cefotaxime and benzylpenicillin, which can be reduced to benzylpenicillin alone when listeriosis is confirmed. L. monocytogenes is intrinsically resistant to all cephalosporins; therefore, intravenous co-trimoxazole is used for patients with penicillin allergy. Treatment usually continues for 3 weeks in immunocompetent patients and 6 weeks in immunocompromised patients, with oral co-trimoxazole substituted for the last 3 weeks if the initial response is good.13
Competing interests
No relevant disclosures.
References
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