Discussion and Conclusions
The concept of maintenance treatment or treatment until progression has entered oncological concepts for improving control of incurable cancers. In the lymphoma field, rituximab has been used for many years. In MCL, rituximab maintenance is frequently administered for 3 years and sometimes even longer. Ibrutinib, another B-cell-depleting agent, has become a relevant medication for MCL; it is typically applied as a single agent in relapsed or refractory disease. Infectious complications have been reported for each of both agents.[2,5,6] Ibrutinib is mostly associated with fungal and bacterial infections. However, serious viral infections also occur. BTK, the molecular target of ibrutinib, is a critical mediator in innate and adaptive immune response. The suggested mechanisms leading to a higher susceptibility for infectious complications in patients treated with ibrutinib are inhibition of B-cell proliferation and impaired macrophage activation and phagocytosis.[8,9] Also, some authors suggest off-target effects on non-BTK Tec family proteins relevant for adequate immune response.
Although synergistic toxicity of combined treatment with rituximab and ibrutinib has not been fully explored, aggravated immunosuppression can be expected. Although other reports have described single-organ manifestations of enterovirus infection associated with rituximab therapy,[11–13] our patient's case is characterized by an unprecedented multiorgan enterovirus disease, which is in line with a profound immunosuppression by a both functional and numerical B-cell depletion. Severe infectious causes are reported in various types of lymphoma but are more often associated with immunosuppressive therapy, especially antibodies against CD20 receptor such as rituximab or obinutuzumab.[11,14,15] Also, individuals with loss of BTK expression are at increased risk for enterovirus infections, although resistance to other viral infections is intact. Dendritic cells of BTK-deficient patients showed impaired maturation and reduced production of certain interferons after in vitro stimulation with enterovirus but a normal response after stimulation with influenza virus. The results suggest these specific deficiencies as one possible cause of severe enterovirus infections in BTK-deficient patients. It appears, therefore, that the combination of two agents known to specifically trigger serious enterovirus infections might have facilitated such a fulminant course of enterovirus infection in our patient.
There is no standard recommendation for the treatment of enterovirus infection. Fortunately, a severe course of the disease is rare even in immunodeficient patients. Only a few small studies with highly heterogeneous cohorts of patients regarding virus subtypes, comorbidities, or clinical manifestations have been published.[11,19] In addition, studies were mainly performed in pediatric patients.[20,21] Treatment usually consisted of IVIG application, antiviral substances, or both. Outcomes ranged from complete recovery to death, with no patient- or virus-related characteristics being predictive of therapeutic success with IVIG or antiviral drugs. Among the latter, the capsid inhibitor pleconaril has been used in studies; however, current experience is limited.[22,23] Echovirus 11 is associated with myocarditis in infants. A specific treatment for this strain has not been established.
In our patient, IVIG treatment was successful with rapid clinical improvement, which is in line with earlier findings. However, the intensity and duration of treatment have not been defined. Treatment decisions are further complicated by the inability to reliably predict and determine the restoration of a protective immune response after cessation of immunosuppressive medication. In order to avoid a potential flare of the infection, we chose tapering of IVIG dosage rather than immediate discontinuation.
In summary, enterovirus infections in immunocompromised patients are a rare but potentially life-threating complication. The combination of rituximab with ibrutinib seems to deepen immunosuppression and might render patients more susceptible to multiorgan manifestations in cases of enterovirus infection, which needs to be considered and requires rigorous treatment. Ongoing combined use of ibrutinib and CD20 antibodies in future oncological therapy will show if these agents increase predisposition to this rare disease. High-dose IVIG therapy showed satisfying outcomes in several cases and should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we consider subtyping essential to identify strain differences in pathogenicity for the development of efficient preventive and therapeutic strategies.
ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BTK: Bruton tyrosine kinase; CK: Creatine kinase; CRP: C-reactive protein; CSF: Cerebrospinal fluid; ECG: Electrocardiography; ECOG: Eastern Cooperative Oncology Group; eGFR: Estimated glomerular filtration rate; IgG: Immunoglobulin G; IVIG: Intravenous immunoglobulins; LDH: Lactate dehydrogenase; MCL: Mantle cell lymphoma; MRI: Magnetic resonance imaging; PCR: Polymerase chain reaction; RNA: Ribonucleic acid
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The patient consented to the presentation of his case under appropriate data protection measures. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
J Med Case Reports. 2020;14(135) © 2020 BioMed Central, Ltd.