Combination Treatment of Persistent SARS-CoV-2 Infection with Dual Antiviral Therapy and Intravenous Immunoglobulin: A Novel Approach

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Background: Immunocompromised patients, particularly those with humoral immune deficiencies or receiving B-cell-targeted therapies, are at increased risk of persistent SARS-CoV-2 infection, a condition often underrecognized and lacking standardized treatment. Methods: We present a case series of patients with persistent SARS-CoV-2 infection and underlying humoral immunodeficiency, treated at the General University Hospital “Attikon” from February 2023 to September 2024. Persistent infection was defined by prolonged symptoms, compatible imaging findings, and RT-PCR positivity beyond 21 days. All patients received combination antiviral therapy with remdesivir and nirmatrelvir/ritonavir, and intravenous immunoglobulin (IVIG), using a structured diagnostic and therapeutic algorithm. Results: Eleven patients (55% male), median age 56 [IQR 50–66] years, were included. Seven (64%) had hematologic malignancy, 10 (91%) received anti-CD20 therapy, and 6 (55%) had both. Median symptom duration before diagnosis was 63 [58–135] days. Ten (91%) experienced recurrent symptoms; one (9%) had progressive symptoms with severe respiratory failure requiring high-flow nasal cannula. Persistent infection was confirmed via bronchoscopy with bronchoalveolar lavage in 6 patients (55%). Prior to diagnosis, 5 patients (45%) required one hospitalization, 1 (9%) was hospitalized twice, and 2 (18%) had more than two hospitalizations. Following combination therapy, 10 (91%) achieved complete response at 180-day follow-up. Conclusions: The proposed diagnostic and therapeutic algorithm combining remdesivir, nirmatrelvir/ritonavir, and IVIG enhanced diagnostic value and therapeutic outcomes in this high-risk population.

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