Dengue fever in a multiple sclerosis patient taking Ocrelizumab

Introduction

Dengue fever (DF) is an endemic infectious disease of tropical and subtropical regions. ¹ It is a mosquito-borne disease and is primarily transmitted to humans by the female Aedes mosquito. Incidence of dengue has increased 30 fold in the last five decades with 390 million cases of dengue infection annually. ¹ The severity of the disease varies from mild fever to severe conditions of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). ² Multiple sclerosis (MS) is an inflammatory demyelinating disease of central nervous system (CNS) and is the common cause of disability in young adults. Disease-modifying therapies (DMTs) have shown to be able to alter the disease course in MS patients, but some of the DMTs are associated with an increased infection risk and require a specific surveillance program. ³ Ocrelizumab is a humanized monoclonal antibody that targets the CD20 antigen on B cells, which is approved for the treatment of both relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS). ⁴ We report the case of a young woman with RRMS treated with Ocrelizumab who contracted dengue infection.

MS course and dengue infection

Our patient is a 40 years old woman, who was diagnosed with RRMS in September 2013 after an episode of optic neuritis. In May 2014, she started the first DMT, the intramuscular interferon beta-1a, which was discontinued due a confirmed pregnancy in January 2019. After the delivery, she presented a recurrence of clinical and radiological disease activity, therefore, it was decided to start Ocrelizumab. The first two doses of 300 mg Ocrelizumab, 2 weeks apart, were administered in February 2020. The first full dose of 600 mg was administered in September 2020.

In December 2020, the patient went to Barbados, in the Caribbean region of North America, where she had already traveled several times for personal reasons. In January 2021, she started complaining flu-like symptoms: sudden-onset high fever (maximum temperature: 39.5°C), muscles and joints pain, severe headache, bilateral retro-ocular pain, asthenia, and a skin rash with red spots. She was clinically diagnosed with DF by a local physician and she received oral rehydration and paracetamol plus codeine for pain management. Blood sample examination, 3 days after the high fever onset, reported elevated serum levels of liver enzymes (alanine aminotransferase, ALT: 79 (normal range (nr): 3–48) IU/L and aspartate transaminase, AST: 101 (nr: 12–45) IU/L), normal platelet count and the presence of dengue nonstructural protein 1 (NS1), negative IgM, and positive IgG dengue serological tests. The immunoglobulin assay techniques were performed by the clinical analysis laboratory with an IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) and the commercial Panbio® Dengue IgG Indirect ELISA kit (Panbio Diagnostics, Australia).

The infection did not progress to DHF or DSS, but symptoms lasted about 3 weeks. During the convalescence, she reported the persistence of late dengue symptoms with hair loss and peeling of skin. ⁵

Discussion

We describe the favorable clinical outcome of DF in an RRMS patient treated with Ocrelizumab, an anti-CD-20 immunosuppressive therapy which depletes B cells with different patterns. ⁶

Although the role of B cells during dengue infection still remain not completely defined, a rapid and massive expansion of plasmablasts, almost entirely dengue virus (DENV)-specific IgG-secreting cells, is associated with severe disease symptoms and a worst outcome. ⁷ The secondary dengue infection is defined by IgM-negative/IgG-positive or IgM-positive/IgG-positive in serum. ⁸ In our patient, the presence of IgG positivity and of NS1 confirmed the DF diagnosis. Probably, according to her serostatus, an asymptomatic or a paucisintomatic primary infection during her past journeys in this area has occurred. Antibodies against yellow fever virus generated by the yellow fever vaccine or by the infection could interfere in the specificity of DENV IgG ELISA tests. ⁹ However, our patient did not report symptoms of other flavivirus infections in the last few years, nor she has been vaccinated against flavivirus, such as yellow fever virus, in the previous 10 years.

Several epidemiological studies suggest that prior exposure and preexisting antibody for DENV may represent a risk factor for a severe disease course. ⁷ Despite that, our patient neither presented hemorrhagic or systemic shock symptoms nor reported neurological worsening. ¹⁰ To our knowledge, this is the first case reported of DF in a patient treated with Ocrelizumab. In a previous study, patients with DF undergoing biological therapies, including anti-CD20 (Rituximab), similarly did not show a severe outcome. ² Same results were shown in a cohort of MS patients, treated with Fingolimod or Natalizumab, where no complications of DF or exacerbations of MS were reported. ¹¹

In conclusion, Ocrelizumab treatment in our patient was not correlated with an unusually severe outcome of DF. However, a close vigilance should be exercised in MS patients treated with immunosuppressive therapies and transiting through regions at greatest risk of tropical diseases.