Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) is an unexplored therapy amidst the rapidly evolving spectrum of medical therapies for COVID-19 and is expected to counter the three most life-threatening consequences of COVID-19 including lung injury by the virus, cytokine storm and sepsis. A single center, phase I/II, randomized controlled, single-blinded trial was conducted at Dow University of Health Sciences, Karachi, Pakistan. Participants were COVID-19 infected individuals, classified as either severely or critically ill with Acute Respiratory Distress Syndrome (ARDS). Participants were randomized through parallel-group design with sequential assignment in a 4:1 allocation to either intervention group with four C-IVIG dosage arms (0.15, 0.20, 0.25, 0.30 g/kg), or control group receiving standard of care only (n = 10). Primary outcomes were 28-day mortality, patient's clinical status on ordinal scale and Horowitz index (HI), and were analysed in all randomized participants that completed the follow-up period (intention-to-treat population). The trial was registered at clinicaltrials.gov (NCT04521309). Fifty participants were enrolled in the study from June 19, 2020 to February 3, 2021 with a mean age of 56.54±13.2 years of which 22 patients (44%) had severe and 28 patients (56%) had critical COVID-19. Mortality occurred in ten of 40 participants (25%) in intervention group compared to six of ten (60%) in control group, with relative risk reduction in intervention arm I (RR, 0.333; 95% CI, 0.087–1.272), arm II (RR, 0.5; 95% CI, 0.171–1.463), arm III (RR, 0.167; 95% CI, 0.024–1.145), and arm IV (RR, 0.667; 95% CI, 0.268–1.660). In intervention group, median HI significantly improved to 359 mmHg [interquartile range (IQR) 127–400, P = 0.009)] by outcome day, while the clinical status of intervention group also improved as compared to control group, with around 15 patients (37.5%) being discharged by 7th day with complete recovery. Additionally, resolution of chest X-rays and restoration of biomarkers to normal levels were also seen in intervention groups. No drug-related adverse events were reported during the study. Administration of C-IVIG in severe and critical COVID-19 patients was safe, increased the chance of survival and reduced the risk of disease progression. Higher Education Commission (HEC), Pakistan (Ref no. 20-RRG-134/RGM/R&D/HEC/2020).

Objectives: The aim of this trial is to investigate the safety and clinical efficacy of passive immunization therapy through Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG: 5% liquid formulation), on severe and critically ill patients with COVID-19. Trial design: This is a phase I/II single centre, randomised controlled, single-blinded, superiority trial, through parallel-group design with sequential assignment. Participants will be randomised either to receive both C-IVIG and standard care or only standard care (4:1). Participants: The study is mono-centric with the participants including COVID19 infected individuals (positive SARS-CoV-2 PCR on nasopharyngeal and/or oropharyngeal swabs) admitted in institute affiliated with Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan. Consenting patients above 18 years that are classified by the treating physician as severely ill i.e. showing symptoms of COVID-19 pneumonia; dyspnea, respiratory rate ≥30/min, blood oxygen saturation ≤93%, PaO₂/FiO₂ 50% on CXR; or critically ill i.e. respiratory failure, septic shock, and multiple organ dysfunction or failure. Patients with reported IgA deficiency, autoimmune disorder, thromboembolic disorder, and allergic reaction to immunoglobulin treatment were excluded from study. Similarly, pregnant females, patients requiring two or more inotropic agents to maintain blood pressure and patients with acute or chronic kidney injury/failure, were also excluded from the study. Intervention and comparator: The study consists of four interventions and one comparator arm. All participants receive standard hospital care which includes airway support, anti-viral medication, antibiotics, fluid resuscitation, hemodynamic support, steroids, painkillers, and anti-pyretics. Randomised test patients will receive single dose of C-IVIG in following four dosage groups: Group 1: 0.15g/Kg with standard hospital care Group 2: 0.2g/Kg with standard hospital care Group 3: 0.25g/Kg with standard hospital care Group 4: 0.3g/Kg with standard hospital care Group 5 (comparator) will receive standard hospital care only Main outcomes: The primary outcomes are assessment and follow-up of participants to observe 28-day mortality and, • the level and duration of assisted ventilation during hospital stay, • number of days to step down (shifting from ICU to isolation ward), • number of days to hospital discharge, • adverse events (Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)) during hospital stay, • change in C-Reactive Protein (CRP) levels, • change in neutrophil lymphocyte ratio to monitor inflammation. Randomisation: Consenting participants who fulfill the criteria are allocated to either intervention or comparator arm with a ratio of 4:1, using sequentially numbered opaque sealed envelope simple randomization method. The participant allocated for intervention will be sequentially assigned dosage group 1-4 in ascending order. Participants will not be recruited in the next dosage group before a set number of participants in one group (10) are achieved. Blinding (masking): Single blinded study, with participants blinded to allocation. Numbers to be randomised (sample size): Total 50 patients are randomised. The intervention arms consist of 40 participants divided in four groups of 10 participants while the comparator group consists of 10 patients. Trial Status: Current version of the protocol is “Version 2” dated 29^th September, 2020. Participants are being recruited. Recruitment started on June, 2020 and is estimated to primarily end on January, 2021. Trial registration: This trial was registered at ClinicalTrials.gov, NCT04521309 on 20 August 2020 and is retrospectively registered. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).

We compared the clinical characteristics and outcome of vaccinated hospitalized COVID-19 patients with unvaccinated hospitalized COVID-19 patients. A retrospective cohort study was conducted at the Sindh Infectious Diseases Hospital and Research Center, Karachi, Pakistan. A total of 1407 hospitalized COVID-19 positive patients were included from April 2021 to March 2022, of which 812 (57.71%) were males. Of the 1407, 378 (26.87%) patients were vaccinated while 1029 (73.13%) were unvaccinated. Of the vaccinated patients, 160 (42.32%) were partially vaccinated while 218 (57.68%) were fully vaccinated (vaccine breakthrough infection). Fewer unvaccinated COVID-19 patients survived compared to vaccinated patients (62.5% vs. 70%, RR 0.89, 95% CI: 0.82–0.96, p-value = 0.004). Despite there being more vaccinated patients above 60 years of age (60.05% vs. 47.13%), their risk of mortality was lower by 43% (OR = 0.578; CI = 0.4201 to 0.7980, p = 0.0009). On survival analysis, vaccinated patients had better 30-day survival compared to unvaccinated patients (p = 0.028). Moreover, comparing waves 3–5, unvaccinated patients of wave 4, which was driven by the delta variant, had the worst survival (51.8%, p ≤ 0.001) while vaccinated patients of wave 3 (driven by the alpha variant) had the best survival (71.6%).