key: cord-0915469-mn62chw0 authors: Gibson, Elena G; Pender, Melissa; Angerbauer, Michael; Cook, Craig; Jones, Barbara; Spivak, Adam M; Swaminathan, Sankar; Spivak, Emily S title: Prolonged SARS CoV-2 Illness in a Patient Receiving Ocrelizumab for Multiple Sclerosis date: 2021-04-08 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofab176 sha: db074b75366499b2ff7de768a86cbb5648e7782e doc_id: 915469 cord_uid: mn62chw0 We describe a case of prolonged SARS CoV-2 infection in a patient receiving ocrelizumab for multiple sclerosis. Viral RNA shedding, signs, and symptoms persisted for 69 days with resolution after administration of convalescent plasma and antiviral therapy. This case suggests risk for persistent SARS CoV-2 infection in patients treated with anti-CD-20 monoclonal antibodies and supports a role for humoral immunity in disease resolution. M a n u s c r i p t 4 A 46-year-old female with relapsing remitting multiple sclerosis (RRMS) on ocrelizumab presented to the emergency department with an approximate 9-week history of daily fevers and dyspnea. Symptom onset began 65 days earlier with upper respiratory symptoms, fever, and cough. On day 2 of illness, she was diagnosed with COVID-19 as demonstrated by a positive SARS CoV-2 nasopharyngeal swab antigen immunoassay. She did not require hospitalization, supplemental oxygen, or additional treatment. She continued to have daily fevers and significant dyspnea with minimal exertion after her initial ten-day isolation period. The clinical course is outlined in Figure 1 . On day 28, she received a routine infusion of ocrelizumab scheduled every six months for RRMS despite remaining symptomatic. Symptoms did not improve over several weeks, and she returned to outpatient clinics for evaluation on four occasions. She received three empiric courses of antibiotics (azithromycin once and amoxicillin-clavulanate twice) and steroids (two courses of prednisone 40mg daily for 5 days) for presumed superimposed bacterial pneumonia following SARS CoV-2. Pneumonia was diagnosed based on symptoms and radiographic findings. She did not experience clinical improvement with any of these interventions. On day 66 of illness, she presented to the emergency department with prolonged fevers and dyspnea. Vital signs were notable for an oxygen saturation of 93% on room air, a heart rate of 105, temperature of 38.5 °C and a blood pressure of 98/60. Her past medical history included RRMS, hypothyroidism, celiac disease, and fibromuscular dysplasia. She had no history of underlying lung disease. The patient's medication list included ocrelizumab infusion every 6 months, levothyroxine, dalfampridine, modafinil, and acetaminophen. She had no known allergies. Her social history was notable for occupation in social services at a school and hospital, no tobacco or alcohol use, and no recent travel. She had no known sick A c c e p t e d M a n u s c r i p t 5 contacts and no relevant family medical history. There were no other known medical risk factors for prolonged SARS CoV-2 infection. On exam, she was dyspneic with conversation and minimal exertion. She had tachycardia and a dry cough with diminished bibasilar breath sounds and crackles. Her abdominal exam was tender to palpation throughout. She had normal neurologic, musculoskeletal, and skin exams. A chest radiograph revealed bilateral patchy opacities (Fig. 1 ). Initial inpatient laboratory testing revealed a hemoglobin of 11.9, a leukocyte count of 9.8 (x10³/μL) with a normal differential, thrombocytosis with a platelet count of 470 (×10³/μL), and normal renal and hepatic function. A CT pulmonary angiogram identified multifocal patchy ground-glass opacities without evidence of a focal pneumonia, pulmonary abscess, or pulmonary embolism ( Fig. 1 ). Blood cultures, sputum cultures, respiratory viral PCR panel and serum fungal biomarkers did not reveal any superimposed bacterial, fungal or viral infection. Serum immunoglobulin A (51 mg/dL), G (445 mg/dL), and M (26mg/dL) levels were low. A nasopharyngeal swab for SARS CoV-2 by nucleic acid amplification and COVID-19 serology by enzyme-linked immunoassay (ELISA) were negative. Refer to Supplemental Table 1 for details regarding specific testing and results. The patient remained febrile with daily fevers to a maximum temperature of 39.4°C. Given concern for prolonged COVID-19 infection, an induced sputum sample was obtained and SARS CoV-2 RNA was detected by a Hologic PCR assay with a cycle threshold (Ct) (https://clades.nextstrain.org: v0.14.0) (Supplemental Table 2 For most immunocompetent patients, infectious SARS CoV-2 replication is cleared between 10 to 20 days, with the possibility of prolonged nonviable viral shedding for up to A c c e p t e d M a n u s c r i p t 7 three months 6, 7 . However, time to recovery in immunocompromised patients is not as well defined, and infectious viral shedding for greater than two months has been demonstrated in patients with severe immunosuppression 2, 8 . Immunocompromised patients may also maintain prolonged viral replication in the lower respiratory tract despite negative results from nasopharyngeal PCR swabs 2 . In this case, COVID-19 antibodies were not identified ten weeks after initial infection, suggesting an inadequate humoral response to COVID-19 in the setting of ocrelizumab treatment. Anti-CD20 antibodies have been associated with inadequate antibody production to SARS-CoV-2 in patients with MS 9,10 . Following treatment, different anti-CD20 antibodies result in variable times to B cell repletion with the longest occurring up to 18 months following ocrelizumab 11 . This suggests the need to consider medication specific effects on antibody production that could have implications in vaccine responsiveness. The patient improved rapidly after one dose of CCP and initiation of remdesivir 12,13 . Since both treatments were initiated as soon as available after admission, either or both may have contributed to the patient's rapid improvement. Since SARS CoV-2 antibody titers of CCP available at the time were not measured, the negative qualitative test of patient serum after administration may have been due to low anti-SARS CoV-2 titers in the infused plasma or to in vivo dilution. Remdesivir was started one day following CCP administration to avoid confusion about immediate adverse reactions. among patients with humoral immune deficiencies related to CLL, lymphoma, and chemoimmunotherapy have also been described 1, 2, 5 . Together, these reports support the potential importance of humoral responses for SARS CoV-2 clearance and illness resolution. Patients treated with therapy that suppresses the humoral immune response may be at particular risk for prolonged illness and viral shedding beyond 20 days and warrant close monitoring if they contract COVID-19. Prophylaxis or treatment soon after COVID-19 diagnosis with long-lasting anti-SARS CoV-2 monoclonal antibodies, currently under development, may be a consideration for patients on anti-CD20 therapy and at high risk for exposure. In the current case, known mutations associated with increased transmissibility or virulence were not detected despite probable ongoing viral replication for several months. However, significant viral mutation and evolution of SARS CoV-2 has been reported in cases of prolonged illness due to immunosuppression, both with and without CCP treatment 4, 22 . Although such evolution may occur during prolonged viral replication in the absence of A c c e p t e d M a n u s c r i p t 14 Figure 1 Persistent COVID-19 in an Immunocompromised Patient Temporarily Responsive to Two Courses of Remdesivir Therapy Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with COVID-19 in persons with multiple sclerosis treated with ocrelizumab -A pharmacovigilance case series Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient The duration of infectiousness of individuals infected with SARS-CoV-2 On the whereabouts of SARS-CoV-2 in the human body: A systematic review Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer Negative SARS-CoV-2 antibody testing following COVID-19 infection in Two MS patients treated with ocrelizumab. Multiple sclerosis and related disorders COVID-19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response Bhise V, Dhib-Jalbut S. Potential Risks and Benefits of Multiple Sclerosis Immune Therapies in the COVID-19 Era: Clinical and Immunological Perspectives Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience Impact of disease-modifying drugs on the severity of COVID-19 infection in multiple sclerosis patients COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis COVID-19 in ocrelizumab-treated people with multiple sclerosis SARS-CoV-2/COVID-19 in multiple sclerosis patients receiving disease-modifying therapy Incidence and Impact of COVID-19 in MS: A Survey From a Barcelona MS Unit First results of the COVID-19 in MS global data sharing initiative suggest anti-cd20 dmts are associated with worse COVID-19 outcomes Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation M a n u s c r i p t 9 antibody therapy, the possibility that prophylactic or therapeutic use of monoclonal antibodies may facilitate such selection in immunocompromised hosts needs to be considered.Additional research is needed to further elucidate the role of the humoral immune system in controlling SARS CoV-2 infection and establish optimal treatment strategies for patients on B cell depleting therapies.A c c e p t e d M a n u s c r i p t 10 Acknowledgements:The authors thank Salika Shakir, PhD for her assistance locating laboratory samples and ensuring completion of appropriate testing at ARUP laboratories. SS was supported by NIH R01 CA08311. All No conflicts of interest reported. The patient's written consent was obtained. The work conforms to standards currently applied in the USA. We have followed the procedures in accordance with the Helsinki Declaration.