Two-center Non-Randomized Retrospective Study to Evaluate the Efficacy of Hyperimmune Globulin in the Therapy of Patients with COVID-19

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Background and Rationale

COVID-19 (from English *COronaVIrus Disease 2019*) is an acute viral infection caused by the RNA-containing coronavirus SARS-CoV-2, characterized primarily by respiratory tract involvement[1]. During the pandemic, according to Johns Hopkins University data as of March 10, 2023, approximately 676.6 million cases and over 6.8 million fatalities were registered[2].

This COVID-19 pandemic became a threat to global healthcare systems, demonstrating the need for developing effective therapeutic methods, particularly for patients at high risk of severe disease[3, 4]. According to several authors (Akimkin V.G., Popova A.A., Ploskireva A.A. et al., 2022), in the Russian Federation, by March 1, 2022, five surges in COVID-19 incidence had been recorded, caused by different genetic variants of SARS-CoV-2 and having some distinctive features in their clinical course[5]. Despite mass vaccination and the use of targeted etiotropic and pathogenetic therapy, the problem of treatment efficacy for COVID-19 and the prevention of various complications (such as acute respiratory distress syndrome [ARDS] and multiorgan failure, etc.), associated, among other factors, with the development of virus-induced inflammation, remains relevant[6, 7]. The development of complicated forms of COVID-19 is due to a number of factors, including association with new SARS-CoV-2 strains capable of immune evasion, as well as special patient groups (presence of immune suppression, significant comorbid status, etc.) in whom specific prevention may be insufficiently effective[7, 8, 9].

An important direction in treating patients with COVID-19 is modulating the immune system using alternative strategies, including plasma therapy, suppression of inflammatory cytokines, kinase inhibitors, monoclonal antibodies, and immunotherapy[4]. A key component of antiviral defense are neutralizing antibodies, capable of suppressing virus replication and reducing disease severity if produced adequately and timely[7, 10, 11]. However, the emergence of new strains has led to a loss of cross-neutralizing activity by many monoclonal antibodies[7, 10, 12]. Furthermore, large randomized trials (RECOVERY, REMAP-CAP) did not confirm the efficacy of convalescent plasma use in hospitalized patients with severe COVID-19 compared to standard therapy[12, 13]. In this regard, the search for effective antibody-based drugs remains a relevant scientific task. One promising direction of pathogenetic therapy is passive immunization using hyperimmune globulin against COVID-19[1, 4, 6-9, 14-16, 18]. The hyperimmune globulin preparation against COVID-19 – "COVID-GLOBULIN" – represents concentrated immunoglobulin "G" antibodies against SARS-CoV-2 for intravenous administration[19]. The theoretical basis for its use is the ability of neutralizing antibodies to specifically bind to the spike S-protein of SARS-CoV-2, blocking its entry into target cells (angiotensin-converting enzyme 2) and mediating other immune defense mechanisms[9, 18]. The preparation contains no less than 95% immunoglobulin class G with antibody activity against SARS-CoV-2; no less than 160 AEU of the stated antibody activity against SARS-CoV-2 in ELISA; and no less than 85.0% and no more than 115.0% of the declared glycine content[19]. An anti-COVID unit (AEU) is a unit of activity of specific immunoglobulin against SARS-CoV-2. One AEU of immunoglobulin is defined as the reciprocal of its dilution capable of inhibiting the appearance of the cytopathic effect (CPE) of SARS-CoV-2 on a Vero cell monolayer in 2 out of 3 wells in a neutralization assay against 2.0 (+0.3) lg TCID50 (PFU) of SARS-CoV-2[20]. Values for the maximum concentration of IgG antibodies to SARS-CoV-2 virus in patients with moderate COVID-19 depend on the time of administration after disease onset and the values of endogenous IgG antibodies to SARS-CoV-2 at the start of treatment and can range from 8.77 AEU/ml to 685 AEU/ml within the first 12 hours after infusion[20]. The median time to reach maximum antibody concentration against SARS-CoV-2 virus within the first 12 hours after infusion is 1 hour. The T1/2 of specific IgG antibodies to SARS-CoV-2 virus in patients with moderate COVID-19 is 4 days[20].

According to the drug's instructions, "COVID-GLOBULIN" is administered intravenously by drip, undiluted, as a single dose of 1 ml/kg body weight at an infusion rate ranging from 0.01 to 0.02 ml/kg/min over 30 minutes[20]. If well tolerated, the infusion rate can be gradually increased up to a maximum of 0.12 ml/kg/min[20].

According to the "Interim Methodological Recommendations 'Prevention, Diagnosis and Treatment of Novel Coronavirus Infection (COVID-19)' (version 27.05.2025)" (approved by the Russian Ministry of Health), the drug is recommended for patients at high risk of severe disease (age over 65, presence of comorbidities such as diabetes, obesity, chronic cardiovascular diseases)[1]. According to a council of experts' conclusion (A.G. Arutyunov et al., 2022), "COVID-GLOBULIN" is recommended for use no later than the 7th day of illness but is contraindicated in cases of "cytokine storm" development within the first 7 days from disease onset[10]. Contraindications to the use of human immunoglobulin against COVID-19 also include hypersensitivity to human immunoglobulin, especially in rare cases of immunoglobulin A (IgA) deficiency and presence of antibodies against IgA; hypersensitivity to drug components; a history of allergic reactions to human blood products; pregnancy and breastfeeding[1, 10].

The advantages of using hyperimmune globulin over other types of immunotherapy in treating COVID-19 are: high concentration of specific neutralizing antibodies (Abs), low risk of transfusion reactions and other adverse events, ease of storage and transportation, reduced administration volume, targeted therapy (inactivating the pathogen during its replicative cycle), absence of blood clotting factors and proinflammatory cytokines in the preparation, which ensures better tolerability and greater efficacy, low risk of blood-borne infections due to the use of a highly purified preparation, and standardized established dosage of virus-neutralizing Abs[11].

The literature contains contradictory data regarding the therapeutic efficacy of hyperimmune globulin against COVID-19.

According to a 2023 meta-analysis of randomized controlled trials (RCTs), intravenous immunoglobulin (IVIG) therapy did not statistically differ from standard therapy. Mortality rates, ICU admission, mechanical ventilation, hospital length of stay, and ICU length of stay did not significantly improve among patients receiving IVIG[21].

In the Russian Federation, the drug "COVID-GLOBULIN" was developed and registered in 2021[1]. According to results from stage 1 of a phase II-III clinical trial, the drug "COVID-GLOBULIN" at a dose of 1 ml/kg demonstrated efficacy compared to placebo[14]. According to an analysis of secondary efficacy endpoints at stage 2 of the phase II-III clinical trial, the median time to clinical improvement on the WHO ordinal scale using Hazard Ratio assessment confirms the superior efficacy of COVID-GLOBULIN for this endpoint compared to placebo[14]. Moreover, COVID-GLOBULIN at a dose of 1 ml/kg in addition to standard therapy in patients with moderate NCI (novel coronavirus infection) statistically significantly reduces the risk of developing complications such as acute kidney injury, myocardial dysfunction/acute coronary pathology, thromboembolic complications, cytokine storm, ARDS, increases in CRP and D-dimer levels, etc., compared to the use of placebo in addition to standard therapy[14].

According to a 2021 randomized controlled multicenter study by Parikh D. et al., the group of COVID-19 patients (n=30) receiving hyperimmune globulin against COVID-19 showed early generation of high levels of specific neutralizing Abs compared to the control group (n=30). By the third day after immunoglobulin administration, a larger number of patients in the study group had a negative RT-PCR result (46.67% in the study group vs. 37.93% in the control). The mean time to a negative RT-PCR result was 5.5 days for the study group and 8 days for the control group. Importantly, in patients receiving COVID-19 immunoglobulin, early reduction of biomarkers such as CRP, IL-6 (interleukin-6), and D-dimer was noted[18].

The rationale for the present study was provided by the results of pilot and previously conducted clinical trials of this drug. Data obtained under RCT protocols necessitated an evaluation of the efficacy of "COVID-GLOBULIN" in real-world clinical practice (real-world evidence), with a focus on factors influencing treatment outcomes, such as timing of administration. We previously conducted a single-center retrospective study showing the potential benefit of early drug administration[16]. The present work is a logical continuation and expansion of that study: it is performed on a larger, two-center sample, which increases data representativeness, and includes a new in-depth analysis of the dependence of outcomes on therapy timing within the first week of illness.

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Research Objective

To evaluate the efficacy and safety of hyperimmune globulin use in the therapy of patients with COVID-19 and to determine the optimal timing of drug administration.

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METHODS

STUDY DESIGN

A two-center, non-randomized, retrospective study was conducted.

STUDY SETTINGS

The study was conducted at a clinical infectious diseases hospital and an infectious diseases department of a Moscow clinical research center from January 1, 2022, to January 31, 2023. Demographic, anamnestic, clinical, and laboratory-instrumental data were obtained from electronic medical records. The diagnosis "U07.1 Coronavirus infection caused by COVID-19 virus, virus identified" was confirmed by a positive real-time reverse transcription polymerase chain reaction (RT-PCR) test detecting SARS-CoV-2 in a nasopharyngeal swab. The study included 148 patients with COVID-19. Patients were divided into two groups: patients in the main group received hyperimmune globulin against COVID-19 "COVID-GLOBULIN" in addition to basic therapy (n = 88); patients in the control group received only standard therapy (n = 60).

Clinical status on admission was assessed based on a combination of objective, laboratory data, and imaging results, including: respiratory rate (RR), oxygen saturation (SpO2), complete blood count; biochemical analysis (levels of CRP, ferritin, LDH, etc.), coagulogram (D-dimer, etc.); chest CT (CT of the chest).

The comparative analysis assessed temporal parameters: the primary point (baseline parameters) and secondary point (dynamics of indicators during the patients' hospital stay, at specified time intervals), as well as the number of fatal outcomes in the compared groups.

Age characteristics of the main group patients (n = 88): 16 patients aged 20-39; 26 patients aged 40-64; 46 patients aged 65-94. Among them: 58 women and 30 men. The drug "COVID-GLOBULIN" was administered intravenously by drip at a dosage of 1 ml/kg body weight: 72 patients (81.8%) received it by day 7 inclusive; of these, 34 patients (47.2%) received it by day 3 of hospitalization, 38 patients (52.8%) received it on days 4-7 of hospitalization; 16 patients (18.2%) received it after day 8. The choice of time points for analyzing the efficacy of treatment with "COVID-GLOBULIN" (1-3, 4-7, >7 days from illness onset) is based on the pathophysiological phases of COVID-19. The first week (especially days 1-3) is characterized by active viral replication, when passive immunization may be most effective for virus neutralization. The period of days 4-7 corresponds to a transitional phase, where an inflammatory response may join viral replication. Administration of the drug after day 7 often coincides with the phase of dominant systemic inflammation ("cytokine storm"), when the efficacy of antibody therapy decreases, as reflected in expert conclusions (A.G. Arutyunov et al., 2022) and recommendations for the study drug[10]. Peak viral load and the most active replication of SARS-CoV-2 occur during the first to second week of illness.

All patients in both groups received standard therapy according to clinical guidelines at the time of hospitalization (2022-2023), which included: low molecular weight heparins (enoxaparin, nadroparin) at prophylactic or therapeutic doses depending on thrombosis risk according to the PADUA score; systemic glucocorticoids (dexamethasone at an equivalent of 6 mg prednisolone); antibacterial therapy in the presence of signs of bacterial infection; symptomatic treatment (antipyretics, infusion therapy). The use of antiviral drugs (favipiravir, molnupiravir, remdesivir, umifenovir) and monoclonal antibodies (MABs: tocilizumab) was applied in isolated cases (5 persons) in the control group. Clinical and laboratory-instrumental indicators of patients were monitored and analyzed dynamically.

Age of patients in the comparison group (n = 60): 20-30 years – 6 patients; 31-50 years – 14 patients; 51-70 years – 17 patients, over 71 years – 23 patients. Among them, 41 (68.3%) women and 19 (31.7%) men.

CONFORMANCE (SELECTION) CRITERIA

Inclusion criteria: patients hospitalized on days 1-18 of illness (age from 20 to 94 years), laboratory-confirmed (RT-PCR) SARS-CoV-2 infection. Exclusion criteria: pregnant women and children (under 18 years); extremely severe disease; individuals with systemic diseases; individuals with hypersensitivity to immunoglobulin; Child-Pugh class "C" liver cirrhosis; chronic kidney disease stage 5; acute kidney injury stage 3 according to KDIGO; current "cytokine storm".

CLINICAL CHARACTERIZATION AND SEVERITY ASSESSMENT

Assessment of COVID-19 severity was performed upon admission in accordance with the current "Interim Methodological Recommendations 'Prevention, Diagnosis and Treatment of Novel Coronavirus Infection (COVID-19)'" of the Russian Ministry of Health (version 27.05.2025)[1].

*   Mild form: presence of clinical symptoms of ARVI (fever, cough, sore throat, rhinorrhea) without signs of pneumonia or shortness of breath. SpO₂ ≥ 96% on room air.
*   Moderate form: clinical signs of pneumonia (fever, cough, shortness of breath) combined with respiratory rate (RR) > 22 per minute, SpO₂ < 96% on room air but > 93%. Lung changes on CT ("ground-glass opacity," consolidation) with lesion volume less than 50%.
*   Severe form: presence of at least one criterion: RR > 30 per min; SpO₂ ≤ 93% on room air; decreased level of consciousness, agitation; unstable hemodynamics (systolic BP < 90 mm Hg or urine output < 20 ml/hour); lung lesion volume on CT > 50%.

DESCRIPTION OF CONFORMANCE CRITERIA

Inclusion Criteria:
1.  Date of hospitalization (on days 1-18 of illness): Patients hospitalized from 00:00 hours on day 1 to 23:59 hours on day 18 from illness onset were included. By day 18, the virus is eliminated in most patients, and post-viral inflammatory and procoagulant processes come to the fore. This limit allows focusing on patients in the phase of active viral replication or early inflammation, when antiviral or immunomodulatory therapy may be most effective. Date of illness onset and date of hospitalization were recorded from medical documentation.
2.  Patient age from 20 to 94 years (patient age at the time of signing informed consent): Excluding adolescents and young adults (18-19 years) allows forming a more homogeneous cohort, minimizing the influence of age-related physiological characteristics and typically milder disease course in this group. This also excludes overlap with the pediatric population. The aim is to include the broadest spectrum of adult patients, including the elderly, who are the most vulnerable group. The upper limit is technical and determined by the need to limit the sample while covering the vast majority of hospitalized patients. Age was recorded based on identity documents (passport).
3.  Laboratory-confirmed (RT-PCR) SARS-CoV-2 infection: RT-PCR is the "gold standard" for diagnosing the acute phase of COVID-19 and is recommended by the World Health Organization (WHO) and national guidelines[11]. The result was entered into the medical history from the laboratory information system. Use of test systems approved for use in the Russian Federation was permitted.

Exclusion Criteria:
1.  Pregnant women and children: Pregnant women and children are vulnerable population groups with special physiological and immunological characteristics. Their inclusion requires a separate, specially designed study with enhanced safety and ethical control measures. For women of reproductive age (up to 55 years), a standard pregnancy test (urine or blood) was performed. "Child" status was determined by age (<18 years).
2.  Extremely severe disease was defined by the patient's condition at screening, meeting at least one of the following criteria: presence of refractory septic shock (need for vasopressors to maintain mean arterial pressure ≥ 65 mm Hg despite adequate fluid resuscitation); respiratory failure requiring extracorporeal membrane oxygenation (ECMO); SOFA (Sequential Organ Failure Assessment) score > 11 points. Patients in extremely critical condition have an extremely high risk of death regardless of therapy, which can negate the potential effect of the studied intervention and distort the study results. To assess severity, patient screening, analysis of monitoring data (blood pressure, blood gases, need for oxygen support), and calculation of SOFA score were performed.
3.  Individuals with systemic diseases — presence in the medical history of severe, uncontrolled, or terminal systemic diseases not related to COVID-19, with an expected life expectancy of less than 3 months. These include: oncological diseases in terminal stage or in the active phase of chemotherapy/radiotherapy; decompensated connective tissue diseases with high activity; terminal stage of COPD (chronic obstructive pulmonary disease) or heart failure (NYHA IV). The presence of such diseases can independently influence primary endpoints (particularly mortality), being a significant confounding factor. To establish systemic diseases, patient medical documentation was analyzed.
4.  Individuals with hypersensitivity to immunoglobulin. Known history of severe allergic reaction (e.g., anaphylaxis) to human immunoglobulin or any component of the study drug. Administering the drug to such patients poses an immediate threat to life. A thorough collection of allergological history was conducted.
5.  Child-Pugh class "C" liver cirrhosis. Severe impairment of synthetic and detoxification liver function significantly alters the pharmacokinetics of many drugs, increases the risk of liver failure and death, making such patients unsuitable for evaluating standard therapy. Method of establishment: calculation of Child-Pugh score based on bilirubin level, albumin, INR, presence of ascites and hepatic encephalopathy.
6.  Chronic kidney disease stage 5 (or end-stage). Severe impairment of renal function radically changes the excretion of many drugs, requires dose adjustments, and is an independent predictor of poor outcome. GFR was calculated using the CKD-EPI or MDRD formula based on blood creatinine level.
7.  Acute kidney injury stage 3 according to KDIGO. According to the KDIGO (Kidney Disease: Improving Global Outcomes) classification, AKI stage 3 is defined as: increase in serum creatinine to 3 times baseline, or increase in serum creatinine to ≥ 4.0 mg/dL (353.6 μmol/L) with an acute increase of ≥ 0.3 mg/dL (26.5 μmol/L), or initiation of renal replacement therapy (RRT). The presence of severe AKI is a marker of critical condition and independently associated with high mortality, which may complicate result interpretation. To determine AKI stage by KDIGO criteria, current and known baseline creatinine levels were used.
8.  Current "cytokine storm." "Cytokine storm" is defined as a condition requiring prescription of systemic glucocorticoids at a dose of ≥ 1 mg/kg/day of prednisolone (or equivalent) or immunosuppressants (e.g., tocilizumab, baricitinib) as decided by the treating physician due to progression of respiratory failure and systemic inflammation. Alternatively, more formalized criteria can be used, e.g., non-zero scores on the HScore https://pubmed.ncbi.nlm.nih.gov/25323876/ if appropriate laboratory support is available. Patients with a full picture of hyperinflammation represent a distinct pathophysiological subgroup requiring a different therapeutic approach (immunosuppression). Including them in the study is not advisable. To establish "cytokine storm," analysis of prescriptions in the medical history and calculation of Hscore were performed.

ASSIGNMENT OF PARTICIPANTS TO GROUPS

Groups were formed based on sequential inclusion of patients from January 1, 2022, to January 31, 2023. The main group included patients who received "COVID-GLOBULIN" according to clinical protocols; the control group included patients hospitalized during the same period but who did not receive this drug. Comparability of groups was assessed post-factum by comparing baseline characteristics. The comorbidity status of patients is presented in Table 2. No statistically significant differences in major comorbid conditions between groups were found.

STUDY TARGET INDICATORS
Primary Study Indicator
The primary indicator chosen was the reduction in the frequency of fatal cases in the group of patients who received "COVID-GLOBULIN" compared to the control group by the end of observation (discharge from hospital or day 28 of illness). In the context of the COVID-19 pandemic, the primary goal of therapy is to reduce mortality, especially among patients at risk of severe disease. This indicator is the most clinically significant and objective endpoint.

Secondary Study Indicators
To clarify the drug's mechanism of action and assess its impact on disease dynamics, the following secondary indicators were defined:
1.  Dynamics of clinical status, assessed by:
    *   Reduction in respiratory rate (RR)
    *   Increase in oxygen saturation (SpO2)
2.  Dynamics of laboratory markers of inflammation, hemostasis, and tissue damage, namely:
    *   Reduction in C-reactive protein (CRP) level
    *   Reduction in lactate dehydrogenase (LDH) level
    *   Reduction in ferritin level
    *   Reduction in D-dimer level
    *   Complete blood count (CBC)
3.  Dynamics of radiographic picture based on chest computed tomography (CT of the chest), assessed using the CTSS (CT Severity Score) or similar scale. Improvement criterion was a reduction in the volume and severity of infiltrative changes (decrease in score).

METHODS FOR MEASURING TARGET INDICATORS
Primary Indicator (Mortality):
*   Method: Registration of the fact of death.
*   Procedure and data source: Data were extracted from medical documentation (medical history). The confirming document was the post-mortem entry in the medical history.

Secondary Indicators:
*   Clinical status (RR, SpO2): RR was counted visually for 1 minute. Saturation was measured using a finger pulse oximeter. Measurements were taken at rest. Pulse oximeters underwent daily quality control. All measurements were performed in a standardized manner by trained medical personnel.
*   Hemodynamic indicators (heart rate – HR, blood pressure)
*   Laboratory indicators (CRP, LDH, ferritin, D-dimer, complete and biochemical blood counts): Venous blood sampling was performed in a standardized manner. Analyses were performed on automated biochemical and hematology analyzers. Standard commercial reagent kits were used. The laboratory operated under internal and external quality control systems. The analytical sensitivity and specificity of the methods corresponded to the manufacturers' specifications.
*   Radiological examination (CT of the chest): The study was performed on a computed tomography scanner. Evaluation of CT scans was performed independently by two radiologists who were blinded to the patient's group assignment. In case of disagreement, a third expert was involved.
*   Confirmation of COVID-19 diagnosis: For detection of SARS-CoV-2 RNA, corresponding reagent kits were used. The sensitivity and specificity of the kits, as stated by the manufacturer, were at least 95%.

SENSITIVITY ANALYSIS
Not performed.

STATISTICAL PROCEDURES
*Planned Sample Size*
Sample size was not calculated in advance.

Statistical Methods
Statistical analysis of indicators was performed using IBM SPSS Statistics ver. 26 (IBM; USA). The distribution of most quantitative parameters differed from normal (p > 0.05; Shapiro-Wilk test), therefore non-parametric characteristics (Me [IQR]) were used for description. For analysis of quantitative indicators, the Mann-Whitney U test was used to compare values between independent groups (those who received "COVID-GLOBULIN" and the group without "COVID-GLOBULIN").

RESULTS

SAMPLE FORMATION
The formation of the study sample is shown in the flowchart (Scheme 1). During the period from January 1, 2022, to January 31, 2023, 245 patients with a diagnosis of COVID-19 were identified in the two participating centers. After applying the conformance criteria, 148 patients were included in the final sample and divided into two groups: the main group (n=88), which received hyperimmune globulin "COVID-GLOBULIN" in addition to standard therapy, and the comparison group (n=60), which received only standard therapy.

Scheme 1. Formation of the research sample.
(Note: As the flowchart text was not provided in the query, a generic description is given.)

SAMPLE CHARACTERISTICS
A comparison of baseline demographic and clinical characteristics between the intervention group and the comparison group is presented in Tables 1 and 2. Statistical analysis using non-parametric methods (Mann-Whitney U test for quantitative and Fisher's exact test/chi-square for qualitative indicators) is necessary to assess the significance of these differences.

MAIN STUDY RESULTS
The mortality rate in the group of patients receiving "COVID-GLOBULIN" was 8% and did not show statistically significant differences from the rate in the control group (6.7%). The overall distribution of mortality in the group of patients who received "COVID-GLOBULIN" demonstrates a clear dependence on the time of therapy initiation. Mortality in the group of patients who received anti-COVID globulin before day 7 of illness was minimal and amounted to 2.2% (2 cases out of 88 patients).

SECONDARY STUDY RESULTS
Analysis of clinical parameters over time showed a reduction in clinical manifestations of respiratory failure (RF) after a single administration of the drug on days 1-7 of illness: increase in SpO2 to 97% [96-98] (p=0.027), decrease in RR to 17 breaths/min [19-22.5] (p=0.015) (Table 4). In the control group, a significantly more pronounced degree of lung damage (CT) was revealed during the disease course (Table 3): at discharge, CT-0 was determined in 56.5% of patients who received "COVID-GLOBULIN," whereas in the main group, CT-0 was found in 10.5% of patients (p < 0.001).

The dynamics of main indicators in the compared groups are presented in Table 3.

The clinical efficacy of "COVID-GLOBULIN" correlated with the timing of its administration. No clear positive clinical and laboratory dynamics were noted with a single administration of the drug after day 7 from illness onset (Table 4).

Administration of anti-COVID immunoglobulin by day 7 of illness was associated with a statistically significant reduction in the median duration of hospitalization to 10 days [8 - 14], compared to 15 days [13.5 - 19] in the group of patients who received therapy after day 7 of illness (p < 0.001, Mann-Whitney U test) (Table 4).

In a comparative analysis of laboratory parameter dynamics, it was found that in patients who received anti-COVID immunoglobulin by day 7 of illness, by the time of discharge, there was a statistically significant decrease in serum CRP level: 8.1 mg/L [2–19] vs. 23 mg/L [19–43] in the late administration group (p=0.023, Mann-Whitney U test) (Table 4).

Analysis of laboratory indicators revealed that the median D-dimer level at discharge was significantly higher in the group of patients who received anti-COVID immunoglobulin from day 4 to day 7 of illness, amounting to 776.8 [329.3 - 3409.5] ng/mL, compared to the earlier administration group (by day 3) – 258.5 [73.0 - 364.7] ng/mL (p=0.012, Mann-Whitney U test) (Table 5).

SENSITIVITY ANALYSIS
Sensitivity analysis was not performed.

During the study, no adverse events or reactions to the administration of "COVID-GLOBULIN" were recorded.

 

DISCUSSION

SUMMARY OF THE MAIN STUDY RESULT
The conducted study did not reveal a statistically significant effect of "COVID-GLOBULIN" use on reducing the mortality rate in hospitalized patients with COVID-19 compared to the control group. However, a pronounced dependence of immune therapy efficacy on its initiation timing was discovered. Administration of the drug within the first 7 days of illness was associated with more favorable outcomes, including shorter hospitalization duration, improvement in oxygenation parameters, and faster reduction in inflammation markers. Also, therapy with "COVID-GLOBULIN" contributed to a statistically significant resolution of lung changes (according to CT of the chest) compared to the control group.

STUDY LIMITATIONS
*   Limitations related to the sample. The main limitation is the lack of a preliminary sample size calculation, which does not guarantee sufficient power to detect statistically significant differences for the primary indicator (mortality). The non-randomized design may have led to systematic differences between groups at baseline, despite formal comparability by WHO severity scale. Generalization of results is limited to the population of hospitalized patients from two specific centers.
*   Limitations related to group comparability. The groups may have differed in unaccounted prognostic factors. In particular, the control group lacked patients with severe disease who received treatment within the first 7 days, which could have distorted the mortality comparison in subgroups. Retrospective data collection did not allow ensuring complete comparability of groups on all potentially confounding factors, such as comorbidity and the exact volume of concomitant therapy.
*   Limitations related to indicators. The use of medical documentation data may have led to incomplete information for some laboratory indicators, reflected in different numbers of observations in the dynamics. Severity classification by the WHO scale, although standard, may have a subjective component.
*   Limitations related to measurement methods. Although the measurement methods (CT, pulse oximetry, routine laboratory tests) are routine and valid, the retrospective nature of the study did not allow standardizing their performance protocols and time points of assessment for all patients. The absence of systematic collection of adverse event data does not allow drawing conclusions about the safety of the intervention within this study.

INTERPRETATION OF STUDY RESULTS
In studies dedicated to the therapeutic efficacy of anti-COVID globulin, reports indicate a reduction in mortality rate, risk of disease progression[8], as well as an effect on early reduction of inflammation biomarkers (CRP, IL-6)[12] among patients compared to those receiving standard therapy.

In our study, the absence of a significant reduction in mortality in the main group is likely due to an insufficient sample size (n=88 in the main group and n=60 in the control group).

A key result, consistent with the pathophysiology of COVID-19, is the dependence of specific immunoglobulin drug efficacy on the timing of its administration. The obtained data confirm the concept that maximum benefit from passive immunization is achieved in the early replicative phase of the disease, before the development of uncontrolled systemic inflammation[9, 10]. The reduction in hospitalization duration and a more significant decrease in CRP level in the early administration group (≤7 days) indicate the drug's ability to curb the inflammatory response, which is an important contribution to therapy. Mortality in the group of patients who received anti-COVID globulin by day 7 of illness was minimal despite the fact that this group included 8 patients with severe disease. Mortality in the group of patients who received specific immunoglobulin after day 7 was 2.5 times higher than in the early treatment group.

Some studies (Parikh, Devang, et al. 2021; Arutyunov A. et al.) reported early reduction of coagulopathy markers (D-dimer) in the group of patients who received anti-COVID globulin compared to the control group.

In our study, no statistically significant reduction in D-dimer was recorded in the main group patients. The finding of a higher D-dimer level at discharge in patients who received the drug on days 1-3 of illness, compared to the group receiving the drug after day 4, requires further study.

The results of this study showed the appropriateness of using this alternative therapeutic strategy; however, continuation of prospective studies and a differentiated approach in its use are required.

CONCLUSIO

This study aimed to evaluate the efficacy of using hyperimmune globulin ("COVID-GLOBULIN") in hospitalized patients with COVID-19. Although the use of this drug did not contribute to a statistically significant reduction in the mortality rate, the early inclusion of "COVID-GLOBULIN" (within the first week of illness) in the treatment protocol was reflected in a reliable reduction in hospitalization duration, positive dynamics of respiratory function indicators (saturation, RR, CT of the chest results), and inflammation markers (CRP) in the main patient cohort. These results demonstrate a clear positive impact of the passive immunization strategy in the comprehensive therapy of COVID-19, provided it is initiated early.

ADDITIONAL INFORMATION

Not applicable.

AUTHORS' CONTRIBUTION
T.A. Igityan, Tetova V.B. – text writing, data collection
Burgasova O.A., Tokmalaev A.K. – study concept and design, editing, text writing, processing
Ogarkova D.A – statistical processing

ACKNOWLEDGEMENTS
Not applicable

ETHICAL REVIEW
Written informed consent was obtained from all patients. The study was approved by the local ethics committee of GBUZ "Infectious Clinical Hospital No. 1 DZM," protocol No. 8 dated December 28, 2022.

CONSENT FOR PUBLICATION
Not applicable

SOURCES OF FUNDING
None

DISCLOSURE OF INTERESTS
The authors declare no relationships, activities, or interests associated with third parties (commercial or non-commercial) whose interests could be affected by the content of the article.

ORIGINALITY STATEMENT**
In the creation of this work, a fragment of the authors' own text, previously published in the article: Igityan, T. A., O. A. Burgasova, D. A. Ogarkova. "Use of specific immunoglobulin in the complex therapy of patients with COVID-19." *Clinical Infectology and Parasitology*. 2025. Vol. 14, No. 2. Pp. 164-173, was used.

The borrowing consisted of reusing individual methodological descriptions and formulations concerning the theoretical rationale for the use of hyperimmune globulin and the general structure of the study. The volume of borrowed text is minimal and serves as a basis for presenting a new study.

The original contribution of the present work is as follows:
*   Expansion of the research base: a multicenter study (2 centers) was conducted instead of the previously performed single-center one.
*   Increase in sample size: the cohort of patients who received "COVID-GLOBULIN" was expanded from 58 to 88 people, which increases the power and representativeness of the study.
*   New analytical approach: a comparative analysis of the drug's efficacy depending on the timing of its administration within the first week of illness was conducted (group of administration on days 1-3 of illness vs. group of administration on days 4-7 of illness). This analysis revealed new patterns, in particular, differences in the dynamics of D-dimer level, which were not described in the previous publication.
*   New data: the results presented in the "Results" section of this work (including data on mortality, dynamics of clinical and laboratory indicators, and CT data) were obtained based on an expanded and updated database.

DATA AVAILABILITY
Data sharing policy is not applicable to this work.

GENERATIVE ARTIFICIAL INTELLIGENCE
Generative artificial intelligence technologies were not used in the creation of this article.

REVIEW AND PEER REVIEW
This work was submitted to the journal on the authors' initiative and reviewed according to the usual procedure. An external reviewer and a member of the journal's editorial board participated in the review.

DISCLAIMER
Not applicable

APPENDICES

None

 

About the authors

Tamara Igityan

ФГАОУ ВО Российского университета дружбы народов имени Патриса Лумумбы., г. Москва, Россия

ГБУЗ «Инфекционная клиническая больница №1 ДЗМ» г. Москва, Россия

Email: igityantoma@mail.ru
ORCID iD: 0009-0000-4257-3243
SPIN-code: 2608-5422

Infectious Disease Physician

PhD Student Department of Infectious Diseases with Courses in Epidemiology and Phthisiology, Patrice Lumumba Peoples’ Friendship University of Russia (RUDN University) 

Russian Federation

Olga А. Burgasova

Infectious Diseases Clinical Hospital No. 1; Peoples’ Friendship University of Russia named after Patrice Lumumba; National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya

Email: olgaburgasova@mail.ru
ORCID iD: 0000-0002-5486-0837
SPIN-code: 5103-0451

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Moscow; Moscow; Moscow

Daria A. Ogarkova

N.F. Gamaleya National Research Center for Epidemiology and Microbiology, Ministry of Health of the Russia

Email: DashaDv1993@gmail.com
ORCID iD: 0000-0002-1152-4120

Junior Researcher

Russian Federation, Moscow

Vera B. Tetova

Russian Medical Academy on Continual Professional Education

Email: tetovera@yandex.ru
ORCID iD: 0000-0002-4007-7622

MD, PhD, associate professor of the Department of infectious diseases of the Russian Medical Academy of Postgraduate Education Studies, 2/1, Barrikadnaya Str., Moscow, 125993, Russian Federation.

MD, PhD, associate professor of the Department of infectious diseases of the People’s Friendship University of Russia (RUDN University) 

Russian Federation, 2/1, Barrikadnaya Str., Moscow, 125993, Russian Federation

Anatoly K. Tokmalaev

RUDN University

Author for correspondence.
Email: tokmalaev39@mail.ru
ORCID iD: 0000-0001-7046-0799
SPIN-code: 1650-0831

MD, Dr. Sci. (Med.), Professor

Russian Federation, Moscow

References

Supplementary files