key: cord-0996403-z6xzij2b
authors: Iannetta, Marco; Cesta, Novella; Stingone, Christof; Malagnino, Vincenzo; Teti, Elisabetta; Vitale, Pietro; De Simone, Giuseppe; Rossi, Benedetta; Ansaldo, Lorenzo; Compagno, Mirko; Spalliera, Ilaria; Lorenzo, Andrea Di; Landi, Doriana; Nicoletti, Carolina Gabri; Marfia, Girolama Alessandra; Andreoni, Massimo; Sarmati, Loredana
title: Mild clinical manifestations of SARS-CoV-2 related pneumonia in two patients with multiple sclerosis under treatment with ocrelizumab
date: 2020-08-04
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2020.102442
sha: a84d25ab98158a2e8d51742d7e3e4be30d940b69
doc_id: 996403
cord_uid: z6xzij2b

Backgrund: Recently SARS-CoV-2 has spread worldwide causing a pandemic. Little is known about disease severity in immunocompromised hosts and people receiving disease modifying therapies (DMTs). In the last decades DMTs have been widely employed, and ocrelizumab represents one of the newest therapies for the relapsing remitting and progressive forms of multiple sclerosis (MS). Objectives: to describe SARS-CoV-2 related pneumonia in two MS patients under ocrelizumab treatment. Methods: Case series. Results: Patients showed a mild clinical course of SARS-CoV-2 related pneumonia without complications or sequelae. Conclusion: Ocrelizumab treatment is not necessarily associated to increased severity in MS patients with SARS-CoV-2 infection.

Backgrund: Recently SARS-CoV-2 has spread worldwide causing a pandemic. Little is known about disease severity in immunocompromised hosts and people receiving disease modifying therapies (DMTs). In the last decades DMTs have been widely employed, and ocrelizumab represents one of the newest therapies for the relapsing remitting and progressive forms of multiple sclerosis (MS).

Objectives: to describe SARS-CoV-2 related pneumonia in two MS patients under ocrelizumab treatment.

Results: Patients showed a mild clinical course of SARS-CoV-2 related pneumonia without complications or sequelae.

Ocrelizumab treatment is not necessarily associated to increased severity in MS patients with SARS-CoV-2 infection.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-COV-2) is currently causing a pandemic. A few reports on multiple sclerosis (MS) patients receiving disease-modifying therapies (DMTs) are described, so far Borriello and Ianniello, 2020; Foerch et al., 2020; Ghajarzadeh et al., 2020; Hughes et al., 2020; Meca-Lallana et al., 2020; Montero-Escribano et al., 2020; Novi et al., 2020; Suwanwongse and Shabarek, 2020) . Here we analyze the cases of two patients affected by MS under ocrelizumab treatment, who experienced SARS-CoV-2 pneumonia, with a mild clinical course.

Demographic and clinical data were directly registered from patients' clinical folders, while laboratory findings were extracted from the central laboratory electronic software.

Concerning SARS-CoV-2 testing, real time reverse transcription-polymerase chain reaction (RT-PCR) for SARS-CoV-2, targeting three distinct regions in the envelope (E), nucleoprotein (N) and RNA dependent RNA polymerase (RdRP) genes (Allplex TM 2019-nCoV Assay, Seegene) was performed on nasopharyngeal (Nph) swabs. SARS-CoV-2 serology was assessed either with a lateral flow immunoassay (detecting specific IgG and IgM), or with a quantitative chemiluminescent immunosorbent assay (CLIA) from DiaSorin TM (IgG only, cutoff: >15 AU/ml).

A 36-year-old Caucasian woman was admitted to Tor Vergata Hospital in Rome on March 29 th , 2020, because of 4-day fever with dry cough and coryza. Her husband was previously Plaquenil 200 mg twice daily for 10 days and lopinavir/ritonavir 400/100 mg twice daily for from hospitalization (+12 days from symptom onset), showing bilateral ground-glass opacities of the lungs (figure 1B). Notably, D-dimers peaked concomitantly with the worsening of lung infiltrates and tended to normalize with the resolution of pneumonia. No oxygen therapy was needed during hospitalization and the patient was discharged in good clinical condition and unremarkable arterial blood gases, on room air. Two negative NPh swabs for SARS-CoV-2 RT-PCR were obtained after 19 days from symptoms onset. IgG and IgM were undetectable up to 27 days from symptom onset. Follow-up chest CT-scan was performed 27 days after symptom onset and showed the complete resolution of lung ground glass opacities (figure 1C).

A 54-year-old Caucasian man was admitted to Tor Vergata Hospital in Rome on April 4 th , 2020, because of 5-day fever. Before hospital admission, the patient was living in a nursing home, where other cases of COVID-19 have been diagnosed. His past medical history was 

Ocrelizumab is an anti CD20 monoclonal antibody causing B-cell depletion, and is currently used for the treatment of MS (Hauser et al., 2017) . Considering that the incidence of upper respiratory tract infection was increased in ocrelizumab registration studies (Hauser et al., 2017) , there are some concerns about the risk of severe SARS-CoV-2 infection in MS patients treated with ocrelizumab. In our cases, besides the presence of comorbidities and high disability, representing additional risk factors for COVID-19 severity, clinical presentation was mild, IL-6 levels remained within normal ranges and patients did not require oxygen support. No changes in the EDSS or neurological symptoms and signs were observed during patients' hospitalization. Our findings reflect the preliminary results of an Italian study in MS patients, in which only 5% of 232 cases of SARS-CoV-2 related infections were defined as severe or critical (Sormani, 2020) . In a pharmacovigilance case series, reporting disease severity and outcomes of 100 suspected case (74 confirmed) of COVID-19, Hughes et al. concluded that there was no evidence of a more severe course of the disease in ocrelizumab-treated MS patients (Hughes et al., 2020) . Furthermore, several authors have reported cases of SARS-CoV-2 related pneumonia in MS patients under ocrelizumab treatment, with a favorable outcome, in the absence of serious complications (Ghajarzadeh et al., 2020; Montero-Escribano et al., 2020; Suwanwongse and Shabarek, 2020) . In a case series of 7 MS patients under anti CD20 therapies (1 rituximab and 6 ocrelizumab), only 2 patients showed a severe disease, while all patients recovered from SARS-CoV-2 infection (Meca-Lallana et al., 2020) . Considering the documented CD19+ lymphocyte depletion observed in our two patients, B-cell mediated immunity seems to be not essential to recover from SARS-CoV-2 infection. However, B cell impairment could impact on virusspecific serum antibody production, as demonstrated in rituximab long-term treated patients, who can develop hypogammaglobulinemia and show an increased rate of upper respiratory tract infections (Tallantyre et al., 2018) . Some reports have already demonstrated an attenuated antibody response to SARS-CoV-2 in patients under ocrelizumab treatment, characterized by the undetectability of specific immunoglobulin G (IgG), several weeks after symptoms' onset (Conte, 2020; Lucchini et al., 2020; Thornton and Harel, 2020) . Very little is known about the effect of anti-CD20 treatment on secretory IgA production in the bronchial mucosa and its associated lymphoid tissue. One case report showed the presence of anti-SARS-CoV-2 specific IgA, despite the absence of IgG, indicating that the mucosal-associated lymphoid tissue (MALT) could be less influenced by ocrelizumab, thus sparing IgA response (Lucchini et al., 2020) . Accordingly, in our two patients, serum specific IgG to SARS-CoV-2 were undetectable up to 27 days from symptom onset in case 1, and slightly detectable after 28 days from symptom onset, in case 2.

B-cell depleting therapies are able to reduce IL-6 production, thus modulating inflammation and T-cell activation (Barr et al., 2012) . Consequently, we could speculate that ocrelizumab could have contributed to modulate IL-6 production in our two patients, despite the absence of specific anti-IL6 receptor treatment, such as tocilizumab and sarilumab, which have been administered in SARS-CoV-2 infected patients (Lu et al., 2020) .

In conclusion, ocrelizumab is not necessarily associated to increased severity in MS patients White blood cell (WBC), neutrophils, total lymphocyte (upper panels) and subsets (middle panels) absolute counts, fibrinogen (normal range 200-400 mg/dl), D-dimers (normal range 0-500 ng/ml), C-reactive Protein (CRP, normal range 0-5 mg/l) and IL-6 levels (normal range 0-50 pg/ml) (lower panels) in the two MS patients (case 1 on the left, case 2 on the right), before ocrelizumab first administration (BO), during ocrelizumab treatment prior to SARS-CoV-2 infection (AO) and during hospitalization for SARS-CoV-2 infection are represented.

Dashed vertical lines indicate the time of symptom onset. SARS-CoV-2 RT-PCR results on nasopharyngeal swabs and specific serology are reported in the grid, below the lower panels. SARS-CoV-2 IgG and IgM were detected with a lateral flow immunoassay in patient 1 and in patient 2 at +18 days from symptom onset, while a quantitative chemiluminescent immunosorbent assay (CLIA) from DiaSorin TM (asterisk) was employed in patient 2 at +28 days from symptom onset, detecting specific IgG at a very low concentration (17,9 AU/ml, cutoff: >15 AU/ml). IgM test was not available (NA). E: Envelope, N: nucleoprotein, RdRP:

RNA dependent RNA polymerase.

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