key: cord-0956240-l7qdeuzj authors: Palomba, Emanuele; Carrabba, Maria; Zuglian, Gianluca; Alagna, Laura; Saltini, Paola; Fortina, Valeria; Hu, Cinzia; Bandera, Alessandra; Fabio, Giovanna; Gori, Andrea; Muscatello, Antonio title: Treatment of SARS-CoV-2 Relapse with Remdesivir and Neutralizing Antibodies Cocktail in a Patient with X-Linked Agammaglobulinemia date: 2021-07-28 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.07.064 sha: 7bfb38255a7d4331ff8ace67f0de4c72830503d5 doc_id: 956240 cord_uid: l7qdeuzj During the Coronavirus Disease 2019 pandemic, patients with humoral immunodeficiency are at higher risk of developing chronic infection and having negative outcome. Little data are available on therapeutic options for this population. We discuss the treatment of SARS-CoV-2 relapse with remdesivir and monoclonal antibodies in an adult patient with X-Linked Agammaglobulinemia. develop severe manifestations of the infection and are at higher risk of recurrences, with recovery of replication-competent virus that has been reported beyond 20 days, and as long as 143 days after a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result 1 . X-linked agammaglobulinemia (XLA) is a primary humoral immunodeficiency causing significant reduction in mature B-cell blood counts, serum immunoglobulin levels, and lack of recall humoral response to antigens. In this case report we describe the clinical course of a 28-year-old patient with a history of XLA that was admitted to our Hospital with fever, asthenia and diarrhea after a recent hospitalization for SARS-CoV-2 pneumonia. His past medical history revealed multiple episodes of upper and lower respiratory tract infections before the delayed diagnosis that caused bronchiectasis. Since the XLA diagnosis, at 6 years old, he was on replacement immunoglobulins therapy with 500mg/Kg/4weeks intravenous immunoglobulin (IVIG). During his previous hospital stay, the patient needed low flow oxygen therapy and received treatment with a 5-day course of remdesivir, dexamethasone 6mg (10-day course), empirical antibiotic therapy with amikacin (10-day course) and cefotaxime (14-day course), further dose of IVIG 20g, and dismissed after testing negative for SARS-CoV-2 RNA by real-time transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swab, 11 days after the first positive test. Two weeks after he was discharged, the patient suffered a relapse of high recurrent fever associated with diarrhea and was admitted in a COVID-19 free ward after testing negative for SARS-CoV-2 RT-PCR on nasopharyngeal swab. He denied shortness of breath and chest tightness, but he was persistently febrile, despite starting empirical antibiotic therapy with ceftriaxone 2g every 24 hours. The antibiotic therapy was stopped on post-admission day 14. His blood test showed elevated C-reactive protein (CRP) values (6.72 mg/dL), elevated serum IL-6 (33.5 ng/L) and ferritin (1425 µg/L), mild hypertransaminasemia (aspartate aminotransferase 259 UI/mL, alanine aminotransferase 139 UI/mL) and mild lymphocytopenia (1060/mmc). On day 6 after admission, he was retested for SARS-CoV-2 RNA RT-PCR on sputum, resulting positive (viral load: 4976000 copies/mL, 313 copies/100000 copies RNAse P), and was transferred to the Infectious Diseases Unit. Two days after, he underwent chest CRP (0.43 mg/dL), IL-6 (10,3 ng/L) and ferritin (98 µg/L) blood levels were further reduced. Microbiologic and clinical response of SARS-CoV-2 infected-patients to remdesivir and other treatments in immunocompromised hosts have been scarcely evaluated, especially in rare primary immunodeficiencies. Regarding patients with XLA, some case reports described treatment with convalescent plasma, alone or in combination with remdesivir and interleukin inhibitors 2-7 . Intriguingly, some XLA patients were able to recover from the disease without the need for intensive care or oxygen ventilation, despite the lack of specific antibodies. Currently available data shows that SARS-CoV-2 infection may be controlled by a combination of CD4+ and CD8+ T cells without neutralizing antibodies. Nevertheless, a coordinated, early response by all the three above mentioned elements of adaptive immunity is likely to be most successful at controlling infection and limiting COVID-19 severity. Of note, a recent publication has highlighted how cellular immunity is stable whereas humoral responses wanes early during convalescence 8 Interim analysis has showed a reduction in viral load, with a greater effect in patients whose immune response had not yet been initiated (serum antibody-negative), or who had a high viral load at baseline. There are still no data on administration of mAbs in patients with humoral immunodeficiency. We presented a case of COVID-19 relapse in a patient with compromised immune system and recent hospitalization, who had benefited from antiviral therapy, achieving clinical recovery and viral clearance. Given his humoral immunodeficiency, the newly detectable viral load and after having excluded other possible concomitant causes, we decided to treat the patient as COVID-19 recurrence, with two aims. Firstly, we decreased the viral load, administering a longer course of antiviral therapy, which had already been reported to be effective on viral clearance in patient with XLA 11 and in severely immunocompromised patients 12, 13 . Secondly, we administered a combination cocktail of mAbs once the viral load had been reduced, to achieve further passive immunization in a patient with impaired immune response and reduce the risk of reinfection. The clinical and virological outcomes were achieved, with stable apyrexia and viral clearance. We acknowledge that the patient received other therapies during his hospitalization, including IVIG. Nonetheless, clinical and laboratory findings, such as resolution of fever and hyperinflammation reduction, along with viral clearance on molecular tests, were linked in a timely manner to remdesivir and mAbs administration, suggesting that our therapeutic choices have shaped the patient's favorable outcome. More importantly, no side effects were reported. The clinical and virological results were sustained: 19 days after mAbs administration and 17 days after the last dose of remdesivir the patient remained asymptomatic and tested negative for SARS-CoV-2 RNA RT-PCR on sputum. Of note, our follow-up period was within the estimated half-life of mAbs (24 days for 1200mg REGN10933 and 21 days for 1200mg REGN10987). The use of passive immunization in treating COVID-19 remains experimental and as such, it should be carefully monitored. As recently reported by Kemp et al. 14 , prolonged therapy with convalescent plasma can trigger evolutionary response by SARS-6 CoV-2, resulting in the selection of viral variants with reduced sensitivity to neutralizing antibodies. Persistence and accelerated viral evolution have also been described in an immunocompromised patient treated with repeated courses of remdesivir followed by antibody cocktail against the SARS-CoV-2 spike protein 15 . We believe our case shows the potential usefulness of combined therapy with antiviral and mAbs in managing persistent SARS-CoV-2 infection in patients with severe humoral immunodeficiency. Further studies are needed to confirm its efficacy and monitor long terms effects on viral variants. The authors declare no conflict of interest. This research received no external funding. Written informed consent was obtained from the patient. 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