Pure white cell aplasia induced by mesalazine in a patient with ulcerative colitis

Abstract

Objectives and importance

Mesalazine is a widely used and generally safe drug for the treatment of chronic inflammatory bowel diseases. Neutropenia rarely complicates this treatment and very few cases have been reported in the literature.

Clinical presentation

We report here the case of a patient with ulcerative colitis who developed a severe febrile neutropenia during treatment with mesalazine.

Intervention

Drug withdrawal and treatment with granulocyte colony-stimulating factor resulted in a complete and durable remission of cytopenia.

Conclusion headings

We recommend periodic blood count monitoring in all patients undergoing treatment with mesalazine.

Keywords:

• Neutropenia
• Mesalazine
• Cytopenia
• Ulcerative colitis
• Pure white cell aplasia

Introduction

Neutropenia is an extremely rare occurrence during treatment with mesalazine and only a very few cases have been reported in the literature: it has not been demonstrated whether this event is related to direct toxicity to stem cells or to immune-mediated destruction of peripheral blood cells.

Here, we report the case of severe febrile neutropenia caused by pure white cell aplasia secondary to the use of mesalazine in a 64-year-old patient with ulcerative colitis who had been receiving mesalazine treatment for about 14 months. The neutropenia responded poorly to treatment with granulocyte colony-stimulating factor (G-CSF) and resolved slowly after suspension of mesalazine.

Case report

A 64-year-old woman was admitted to hospital because of a 20-day history of persistent fever with phlegm, not responsive to treatment with oral amoxicillin or, subsequently, intramuscular ceftriaxone, both given at home. She had a history of pancolitis due to ulcerative colitis, which, with about 14 months of treatment with mesalazine, was in clinical and histological remission. She also had hypothyroidism for which she was receiving levothyroxine.

On admission, the patient had a septic-type fever with a temperature higher than 38°C, grade 3 mucositis according to the World Health Organization classification and submandibular swelling. Blood-chemistry tests showed a hemoglobin concentration of 12.5 g/dl with normal-sized red cells, a platelet count of 329 000/mm³, a leukocyte count of 800/mm³, a neutrophil count of 10/mm³, liver and kidney function within the norm, and a C-reactive protein level of 203. The patient was admitted to the ENT ward and then, in the light of the septic picture and the severe neutropenia, transferred to the infectious diseases ward. After having taken samples for blood cultures, empirical broad-spectrum antibiotic therapy was started with clindamycin and levofloxacin, without benefit. Following isolation of a multiresistant Streptococcus oralis from the blood culture, the treatment was charged to amikacin, fluconazole, and vancomycin, which led to stable defervescence. Given the isolated grade 4 neutropenia, G-CSF (Filgrastim) was given together with the antibiotic treatment, but initially produced only a partial response, inducing a peak neutrophil count of 1600/mm³ after more than 20 days of treatment; furthermore, this modest rise was not maintained after withdrawal of the G-CSF (neutrophils 80/mm³ 10 days after the patient's discharge when the acute infectious episode had resolved). In order to exclude a primary blood disease, before starting the G-CSF treatment, a bone marrow aspirate and biopsy had been performed which showed pure white cell aplasia, with normal erythro poiesis and megakaryopoiesis. We also noted a significant polyclonal lymphoplasmacytic infiltrate, in some cases organized in nodules. After having excluded other possible causes of neutropenia (Anti-neutrophil cytoplasmic antibody, anti-nuclear antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, extractable nuclear antigen negative; serological tests for cytomegalovirus, Epstein–Barr virus, Parvovirus B19, hepatitis C virus, hepatitis B virus infection, and human immunodeficiency virus negative; galactomannan assay negative, no vitamin deficiencies, normal thyroid function on current treatment), it was hypothesized that the woman had iatrogenic neutropenia, which was initially attributed to the antibiotic treatment that she had taken at home before her admission to hospital. The patient was, therefore, discharged from hospital after 24 days: she was afebrile, in a good general condition and had the following laboratory values: hemoglobin 11 g/dl; white blood cell count 3960/mm³ (of which neutrophils 1590/mm³), and platelet counts 410 000/mm³. Following discharge, the patient was monitored with weekly full blood counts: after the suspension of the G-CSF, her neutrophil count gradually decreased and, after 10 days, was again below 100/mm³. Since the patient was only taking levothyroxine and mesalazine at home (drug which she had been taking throughout her period in hospital), we considered whether the agranulocytosis could be being caused by mesalazine, an event that is known to be possible, albeit extremely rare. In the light of the clinical remission of the woman's ulcerative colitis, and in accordance with the gastroenterologist, the drug was withdrawn. A new bone marrow assessment immediately after suspension of the drug showed a picture compatible with the diagnosis. About 20 days after suspension of the drug (in association with a very brief cycle of G-CSF treatment for 2 days given because of the onset of a sore throat and low-grade fever), the woman had complete, stable normalization of her neutrophil count (2500/mm³), which has remained normal until the time of writing, 9 months later.

Discussion and conclusions

Mesalazine, or 5-aminosalicylic acid, is an anti-inflammatory drug very frequently used in patients with chronic bowel disorders and is generally well tolerated; indeed, over time it has replaced sulphasalazine since it has fewer side effects.¹ The most common side effects of mesalazine, such as gastrointestinal disturbances, headache, joint pain, and skin rashes, are usually of modest entity and transitory.^1,2 Severe hematological toxicity is very rare, but there have been reports of thrombocytopenia, aplastic anemia, pancytopenia, and leukopenia/agranulocytosis.^3–7 Individual case reports in the literature also include some episodes of neutropenia developing in adult patients.^8–11 The hematological recovery is generally reported to be fairly slow: in one case the neutrophil count returned to normal after only 4 months (albeit without the use of G-CSF)¹¹; in another case recovery occurred after 15 days of treatment with G-CSF, with the dose doubled because of lack of efficacy of the standard dose.⁹ Our patient showed the same trend, obtaining a partial and only transitory response to G-CSF, with the response being durable only after suspension of the mesalazine. In our opinion, this trend, the histological demonstration of pure white cell aplasia and, above all, the documentation of a significant lymphoplasmacytic infiltrate support the hypothesis of an immune-mediated toxicity of myeloid precursors. Curiously, in our case the neutropenia developed just a little more than 1 year after starting treatment with mesalazine, whereas the onset of cytopenias in the other reported cases was usually earlier (2 weeks – 3 months, up to 1 year).^3–7,9,11

Mesalazine is a widely used and generally well-tolerated drug for the treatment of chronic inflammatory bowel diseases. In the light of our experience, this drug can cause severe hematological toxicity, even in patients who have been under treatment for more than 12 months. Hematological recovery is generally rather slow, probably because of the central, immune-mediated mechanism of toxicity, and can be complicated by severe infections. For this reason, in situations of particular risk, such as during pure white cell aplasia, only withdrawing the mesalazine could be inadequate. It is, therefore, essential that all patients receiving mesalazine undergo periodic monitoring through blood counts, even after prolonged use of the drug.