Life-threatening Disseminated Enterovirus Infection During Combined Rituximab and Ibrutinib Maintenance Treatment for Mantle Cell Lymphoma

A Case Report

Maximilian Higer; Denis Cana; Juergen Podlech; Simin Schadmand-Fischer; Andreas Schwarting; Daniel Teschner; Matthias Theobald; Thomas Wölfel; Georg Hess


J Med Case Reports. 2020;14(135) 

In This Article

Case Presentation

Our patient was a 57-year-old Caucasian man who was diagnosed in July 2017 with MCL stage cS4a (bone marrow and abdominal, cervical and axillary lymph node involvement) and a high-risk Mantle Cell Lymphoma International Prognostic Index score. Besides controlled arterial hypertension and mild neuropathy, the patient had no significant comorbidities. Within a clinical trial, he was treated with induction chemoimmunotherapy of alternating R-CHOP/R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin), resulting in a complete remission. From February 2018, the patient received maintenance therapy with ibrutinib (560 mg once daily) and rituximab (1400 mg subcutaneously every 8 weeks) within the study protocol of the clinical trial. In August 2018, he noticed painful swelling of the calves. Diagnostic workup showed no evidence of deep venous thrombosis or soft tissue infection. Retrospectively, the patient remembered a short episode of gastroenteritis at this time. Diuretic therapy resulted in temporary improvement, but in the following weeks, the patient's symptoms worsened and spread to the upper extremity and proximal trunk muscles. Administration of systemic steroids and transient discontinuation of ibrutinib had no effect. In November 2018, the swelling of the patient's calves worsened, but besides a single slightly enlarged lymph node of the right groin, no other new findings were present on physical examination. Laboratory tests showed elevated lactate dehydrogenase (LDH) and creatine kinase (CK) with a negative result of autoimmune serology. Analgesic treatment with metamizole and tilidine was initiated with limited success. In January 2019, a computed tomographic scan showed no signs of a lymphoma relapse but revealed diffuse subcutaneous edema. Continuous clinical deterioration was noted, with the patient being unable to walk properly. Swelling of the limbs progressed and eventually led to hospitalization. On admission, the patient was experiencing generalized muscle pain, and his performance score deteriorated to Eastern Cooperative Oncology Group 3 (ECOG 3). Massive generalized edema was present, especially of the lower extremities, accompanied by a slight erythema. Muscles of the trunk and the extremities were extremely palpation-sensitive and painful. Besides a weak symmetric fist closure and shoulder lift, no neurological deficit was apparent.

Initial findings were consistent with myositis of unknown cause. Differential diagnoses included autoimmune myositis either idiopathic or paraneoplastic due to undetected lymphoma relapse, therapy-related side effects, neurological disease or infectious disease such as lues or borreliosis. Because therapy-related side effects could not be ruled out, ibrutinib and rituximab were discontinued.

Initial laboratory testing revealed a distinct inflammatory constellation and slightly elevated transaminases (Table 1). The patient's plasma protein and albumin levels as well as immunoglobulin G were decreased. His CK was elevated. Additional myositis panel testing did not indicate an autoimmune reaction, and analysis of bone marrow aspirate showed no evidence of lymphoma relapse. Further neurological diagnostics only confirmed mild neuropathy.

Magnetic resonance imaging (MRI) of the thighs was consistent with myositis (Figure 1) and confirmed by muscle biopsy (Figure 2). The patient rapidly developed acute kidney injury accompanied by further increase in uric acid, LDH, CK, leukocyte count, and myoglobin (Table 1). A diagnosis of rhabdomyolysis with consecutive kidney injury was made and treated symptomatically. At this time, a rise of troponin I level was noted, and electrocardiography (ECG) revealed a newly acquired right bundle branch block and disturbance of repolarization. Subsequently, the patient developed atrial fibrillation. Cardiac MRI confirmed the diagnosis of a myocarditis.

Figure 1.

Magnetic resonance imaging (MRI) indicating myositis. Diffuse high intramuscular and extramuscular signals showing edema consistent with myositis (MRI short tau inversion recovery sequence, axial views)

Figure 2.

Biopsy revealed signs of viral myositis. Biopsy from the leg abductors showing vast interstitial and perivascular infiltrations by T cells and macrophages as well as the characteristic alterations in muscle fibers such as variation in size, centrally located nuclei, and stages of necrosis and regeneration (hematoxylin and eosin staining, original magnification × 100)

In parallel, increasing sleepiness and changes in personality became evident. MRI of the brain was inconspicuous, but a hyperintense lesion was detected in the spinal cord, which was highly suspicious for myelitis. Cerebrospinal fluid (CSF) analysis showed increased leukocyte counts as well as increased lactate and protein levels (Table 2). Extended microbiological and virological screening revealed a positive enterovirus polymerase chain reaction (PCR) in the CSF. Subsequently, enterovirus RNA was also found in the patient's serum, stool samples, and muscle biopsy, whereas no antienterovirus antibodies were detectable in the serum. Further subtyping identified the virus as echovirus 11.

Taken together, a multiorgan enterovirus infection with myositis, gastroenteritis, myocarditis, encephalitis, and hepatitis was diagnosed. Retrospectively, the gastroenteric symptoms in August 2018 are likely to indicate the primary enterovirus infection.

Treatment with high-dose intravenous immunoglobulin (IVIG; 2 g/kg body weight daily over 4 days followed by 0.5 g/kg once weekly) was initiated to restore humoral immunity. The clinical condition of the patient improved rapidly. His laboratory parameters and ECG normalized. One week after the first IVIG infusion, antienterovirus antibodies were detected in the serum. Moreover, enterovirus PCR in the patient's CSF became negative, and the virus burden in his stool was reduced after 2 weeks. His neurologic symptoms also regressed, and he was discharged 6 weeks after admission.

At his latest follow-up visit, the patient's clinical condition was found to have further improved to ECOG 1. Analgesic treatment could be reduced to low dosage with only occasional and mild pain attacks. The patient's MCL was still in remission without any further antilymphoma treatment. IVIG treatment was continued at lower doses and with prolonged intervals.