Overview

This is a multicenter, randomized controlled trial aiming to investigate the efficacy of intravenous immunoglobulin (IVIG) replacement therapy under the hypothesis that immunoglobulin replacement would have therapeutic effects on persistent COVID-19 in patients with B-cell impairment.

Eligibility

Inclusion Criteria:

1. Voluntary written consent to participate in the trial
2. Age≥ 19 years
3. Diagnosed as COVID-19: the definitive diagnosis of COVID-19 will be made at a healthcare facility based on COVID-19 tests approved in Korea, such as reverse transcription polymerase chain reaction (RT-PCR), Xpert, film array, and rapid antigen test (RAT).
4. The diagnosis of persistent COVID-19 will be made following the criteria below:
5. No improvement or worsening of symptoms/signs of active inflammation, such as fever, pneumonia, and dyspnea requiring oxygen, even after 2 weeks of the initial symptom onset or diagnosis of COVID-19 (persisting symptoms/signs at or after the third week of illness).
6. The day count for the disease course is based on the symptom onset or diagnosis date, whichever is earlier, with Day 1 being the date of symptom onset or diagnosis. The third week refers to the period including and following Day 15. For the purpose of day count calculation, self-test results using RAT are accepted.
7. Both symptoms and signs indicative of active inflammation must be present. This status corresponds to the Modified WHO clinical progression scale of ≥ 4.
   • Symptoms include at least one of the following.
     1. Fever of 37.8°C or higher lasting for >48 h (determined based on self-measurement and statements from the patient or caregiver, with fevers persisting from Day 13 to Day 15 also accepted)
     2. Persistent cough despite taking appropriate expectorants and cough suppressants
     3. Dyspnea upon walking on a flat surface (modified Medical Research Council grade >2) ② At least one of the following signs of active inflammation must be present.
     4. Pulmonary infiltration suggestive of COVID-19 observed in chest radiograph or computed tomography scan findings. Findings may vary, from ground-glass opacities to patchy consolidation, and are determined by the clinician or radiologist.
     5. Decreased oxygen saturation (PaO2/FiO2 ≤300 mmHg, SpO2 ≤92%, or PaO2 ≤63%)
     6. Cases of patients with B-cell impairment:

        (1) Patients with B-cell lineage hematologic malignancies, such as B-cell lymphoma or
        multiple myeloma, who are presumed to have impaired B-cell function owing to B-cell
        targeting chemotherapy (i.e., those receiving rituximab, CAR-T, Bispecific T-cell engager
        therapies), or second-line or higher treatments, such as autologous stem cell
        transplantation (AutoPBSCT) (2) Patients suffering from diseases known to result in B-cell
        depletion, such as Good's syndrome associated with thymoma (3) Cases of patients with a
        congenital primary immunodeficiency who have reduced antibody formation and have not
        undergone IVIG replacement in the past 3 months.
        Among these, those who received B-cell targeting chemotherapy within the past 3 months are
        eligible for enrollment based on clinical criteria, but other patients must confirm the
        reduction of peripheral B cells to <1% via flow cytometry to be eligible for enrollment.
        Exclusion Criteria:
          1. Difficulty controlling the underlying disease or life expectancy of <3 months even
             after COVID-19 is successfully treated.
          2. T-cell impairment.
        (1)T-cell suppressive drugs (e.g., cyclosporine, tacrolimus) cannot be suspended owing to
        organ transplantation or autoimmune disorder.
        (2) Patients with human immunodeficiency virus (HIV) infection with a CD4 T-cell count <500
        cells/μL or persistent detection of HIV viral RNA in the blood.
        3. IVIG or COVID-19 convalescent plasma therapy within 3 months of screening 4. History of
        serious reaction or hypersensitivity to blood, blood products, blood-derived products,
        IVIG, and IgG 5. Immunoglobulin A (IgA) deficiency or IgA antibodies present 6.
        Uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure >
        100 mmHg) 7. Hemolytic anemia, hemorrhagic anemia 8. Impaired cardiac function [New York
        Heart Association Functional Class Ⅲ or IV] 9. High risk for thrombosis/embolism clinically
        owing to a history of cerebrovascular and cardiovascular disorders, thrombosis, or embolism
        10. Cases of pregnant or breastfeeding women 11. Current participation in another clinical
        trial related to COVID-19 drugs 12. Cases of participants that are inappropriate to
        participate in the trial based on the investigator's discretion