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Multi-fungal sepsis and mucormycosis of the central nervous system in a patient treated with ibrutinib, a case report and review of the literature.

ABSTRACT: We report the case of a 71 years old patient with chronic lymphocytic leukemia (CLL), who developed a rapidly progressing multi-fungal infection including mucormycosis of the central nervous system (CNS) during treatment with ibrutinib. On autopsy mucorales species were demonstrated intravascularly by histomorphology of several organs and lymph nodes and were characterized as Rhizomucor pusillus by polymerase-chain reaction (PCR) - analysis. In addition, invasive pulmonary Aspergillus fumigatus was found and also confirmed by PCR. To the best of our knowledge, this is the first confirmation of a multi-fungal sepsis and invasive CNS-infection with mucorales species under ibrutinib. Knowing the risk for invasive fungal disease in patients under ibrutinib, identifying the pathogen and early initiation of specific treatment is crucial for a good clinical outcome especially in mucormycosis.

SUBMITTER: Fehr M

PROVIDER: S-EPMC6926283 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Multi-fungal sepsis and mucormycosis of the central nervous system in a patient treated with ibrutinib, a case report and review of the literature.

Fehr Martin M Cathomas Gieri G Graber Anne A Makert Eva E Gaus Elisabeth E Boggian Katia K

Medical mycology case reports 20191203

We report the case of a 71 years old patient with chronic lymphocytic leukemia (CLL), who developed a rapidly progressing multi-fungal infection including mucormycosis of the central nervous system (CNS) during treatment with ibrutinib. On autopsy mucorales species were demonstrated intravascularly by histomorphology of several organs and lymph nodes and were characterized as <i>Rhizomucor pusillus</i> by polymerase-chain reaction (PCR) - analysis. In addition, invasive pulmonary <i>Aspergillus ...[more]

PMID: 31890489

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Project description:BackgroundLPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient's presentation with a reviewed synthesis of the available literature.Case presentationsThe younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic-clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla. His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions.ConclusionsNeurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.

Project description:Central nervous system (CNS) involvement of graft versus host disease (GvHD) is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic CNS GvHD symptoms are heterogeneous and include cerebrovascular manifestations, demyelinating disease and immune-mediated encephalitis. CNS-Acute GvHD is not formally defined in literature.We report 7 cases of CNS-GvHD among which two had histological-proven disease. We reviewed 32 additional cases of CNS GvHD published in literature since 1990. In this cohort, 34 patients were transplanted for hematologic malignancies, and 5 for non-malignant hematopoiesis disorders. Of these patients, 25 had a history of chronic GvHD and immunosuppressive treatment had been decreased or discontinued in 14 patients before neurological symptoms onset. Median neurological disorder onset was 385 days [7-7320]. Patients had stroke-like episodes (n?=?7), lacunar syndromes (n?=?3), multiple sclerosis-like presentations (n?=?7), acute demyelinating encephalomyelitis-like symptoms (n?=?4), encephalitis (n?=?14), mass syndrome (n?=?1), and 3 had non-specific symptoms. Median neurological symptoms onset was 81.5 days [7-1095] for patients without chronic GVHD history versus 549 days [11-7300] for patients with chronic GVHD (P?=?0.001). Patients with early involvement of CNS after allo-HSCT and no chronic GVHD symptoms were more frequently suffering from encephalitis (64% versus 28%, P?=?0.07), whereas stroke-like episodes and lacunar symptoms were less frequent (9% versus 36%, P?=?0.13).34 patients with CNS-GvHD were treated with immunosuppressive therapy, including corticosteroids for 31 of them. Other treatments were intravenous immunoglobulin, plasmapheresis, cyclophosphamide, calcineurin inhibitors, mycophenolic acid, methotrexate and etoposide.27 patients achieved a response: 10 complete responses, 15 partial responses and 2 transient responses. Of 25 patients with sufficient follow-up, 7 were alive and 18 patients deceased after CNS-GvHD diagnosis.CNS-related GvHD is a rare cause of CNS disorders after allo-HSCT and is associated with a poor prognosis.

Project description:BackgroundCentral nervous system (CNS) mucormycosis is insidious and difficult to diagnose. It progresses rapidly and causes high mortality. Rare cases have been reported during ibrutinib use, which have poor prognosis. Through this case, we share the experience of successful diagnosis and treatment. We also emphasize the importance of focusing on high-risk groups, early diagnosis and prompt management.Case descriptionIn this case, a 52-year-old patient was diagnosed with chronic lymphocytic leukemia (CLL) for more than 5 years. He was in remission after rituximab plus fludarabine and cyclophosphamide (RFC) regimen, and relapsed in the fourth year. During the ibrutinib monotherapy, the patient presented with sudden headache. Cranial imaging examination revealed a definite right occipitoparietal lobe mass with extensive edema. A rapid diagnosis of mucormycosis infection was made using metagenomic next-generation sequencing (mNGS). The patient at that time didn't have neutropenia, but he had hypogammaglobulinemia. The infection was treated with amphotericin B cholesteryl sulfate complex, posaconazole, and interventional surgery, and the treatment was successful. At the same time, we considered the control of disease progression in this relapsed patient with, as well as to the drug interaction with posaconazole. We chose the next generation Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib as the treatment, whose safety has been identified. As of the submission date, the patient has been followed up for nearly 1 year, and his disease is stable.ConclusionsWhen new clinical problems arise in recurrent CLL patients, it is important to identify multiple factors, especially the insidious fungal infections. In particular, the immunocompromised patients should be concerned. CNS mucormycosis is extremely deadly, the early diagnosis will improve the prognosis. In clinical practice, the gold standard diagnosis of mucormycosis is difficult to obtain through pathology. In this case, mNGS was applied to quickly diagnose mucormycosis, enabling earlier treatment and ameliorating the prognosis. Thus, it will help us to early detect this group of people who may be potentially infected. Current guidelines do not recommend the prophylactic use of antifungal agents in treated CLL patients. However, in patients with prior severe infection or hypogammaglobulinemia, intravenous immunoglobulin is recommended to reduce the associated infection rate.

Dataset Information

Multi-fungal sepsis and mucormycosis of the central nervous system in a patient treated with ibrutinib, a case report and review of the literature.

Publications

Multi-fungal sepsis and mucormycosis of the central nervous system in a patient treated with ibrutinib, a case report and review of the literature.

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