Efficacy of convalescent plasma for the treatment of severe influenza
Crit Care. 2020;24(1):469
BACKGROUND Convalescent plasma administration may be of clinical benefit in patients with severe influenza, but reports on the efficacy of this therapy vary. METHODS We conducted a systematic review and meta-analysis assessing randomized controlled trials (RCTs) involving the administration of convalescent plasma to treat severe influenza. Healthcare databases were searched in February 2020. All records were screened against eligibility criteria, and the risks of bias were assessed. The primary outcome was the fatality rate. RESULTS A total of 2861 studies were retrieved and screened. Five eligible RCTs were identified. Pooled analyses yielded no evidence that using convalescent plasma to treat severe influenza resulted in significant reductions in mortality (odds ratio, 1.06; 95% CI, 0.51-2·23; P = 0.87; I(2) = 35%), number of days in the intensive care unit, or number of days on mechanical ventilation. This treatment may have the possible benefits of increasing hemagglutination inhibition titers and reducing influenza B viral loads and cytokine levels. No serious adverse events were reported. The included studies were generally of high quality with a low risk of bias. CONCLUSIONS The administration of convalescent plasma appears safe but may not reduce the mortality, number of days in the intensive care unit, or number of days on mechanical ventilation in patients with severe influenza.
Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial
Patients hospitalized with severe influenza (5 studies, n= 598).
Convalescent plasma or hyperimmune intravenous immunoglobulin (H-IVIG).
Various comparators (normal intravenous immunoglobulin, standard care, low-titre anti-influenza, placebo).
Pooled analyses yielded no evidence that using convalescent plasma to treat severe influenza resulted in significant reductions in mortality, number of days in the intensive care unit, or number of days on mechanical ventilation.
The Lancet. Respiratory medicine. 2019
BACKGROUND Infection with influenza virus causes substantial morbidity and mortality globally, although antiviral treatments are available. Previous studies have suggested that anti-influenza immune plasma could be beneficial as treatment, but they were not designed as randomised, blinded, placebo-controlled trials. Therefore, we aimed to prospectively evaluate the clinical efficacy of high-titre immune plasma compared with standard low-titre plasma to improve outcomes in patients with severe influenza A infection. METHODS We did this randomised, double-blind, phase 3 trial at 41 US medical centres to assess the efficacy of high-titre anti-influenza plasma (haemagglutination inhibition antibody titre ≥1:80) compared with low-titre plasma (≤1:10). Children and adults with PCR-confirmed influenza A infection, a National Early Warning score of 3 or greater, and onset of illness within 6 days before randomisation were eligible. Patients were randomly assigned (2:1) using an interactive web response system to receive either two units (or paediatric equivalent) of high-titre plasma (high-titre group) or low-titre plasma (low-titre group), and were followed up for 28 days from randomisation. High-titre and low-titre plasma had the same appearance. Randomisation was stratified by severity (in intensive care unit, not in intensive care but requiring supplemental oxygen, or not in intensive care and not requiring supplemental oxygen) and age (<18 years and ≥18 years). All participants, site staff, and the study team were masked to treatment allocation until after the final database lock. The primary endpoint was clinical status assessed by a six-point ordinal scale on day 7 (death, in intensive care, hospitalised but requiring supplemental oxygen, hospitalised not requiring supplemental oxygen, discharged but unable to resume normal activities, and discharged with full resumption of normal activities) analysed in a proportional odds model (an odds ratio [OR] >1 indicates improvement in clinical status across all categories for the high-titre vs the low-titre group). The primary analysis was done in the intention-to-treat population, excluding two participants who did not receive plasma. This trial is registered with ClinicalTrials.gov, NCT02572817. FINDINGS Participants were recruited between Jan 26, 2016, and April 19, 2018. Of 200 participants enrolled (177 adults and 23 children), 140 met the criteria for randomisation and were assigned to the high-titre group (n=92) or to the control low-titre group (n=48). One participant from each group did not receive plasma. At baseline, 60 (43%) of 138 participants were in intensive care and 55 (71%) of 78 participants who were not in intensive care required oxygen. 93% of planned plasma infusions were completed. The study was terminated in July, 2018, when independent efficacy analysis showed low conditional power to detect an effect of high-titre plasma even if full accrual (150 participants) was achieved. The proportional OR for improved clinical status on day 7 was 1.22 (95% CI 0.65-2.29, p=0.54). 47 (34%) of 138 participants experienced 88 serious adverse events: 32 (35%) with 60 events in the high-titre group and 15 (32%) with 28 events in the low-titre group. The most common serious adverse events were acute respiratory distress syndrome (ARDS; four [4%] vs two [4%]), allergic transfusion reactions (two [2%] vs two [4%]), and respiratory distress (three [3%] vs none). 65 (47%) participants experienced 183 adverse events: 42 (46%) with 126 events in the high-titre group and 23 (49%) with 57 events in the low-titre group. The most common adverse events were anaemia (four [3%] vs two [4%]) and ARDS (four [3%] vs three [5%]). Ten patients died during the study (six [7%] in the high-titre group vs four [9%] in the low-titre group, p=0.73). The most common cause of death was worsening of acute respiratory distress syndrome (two [2%] vs two [4%] patients). INTERPRETATION High-titre anti-influenza plasma conferred no significant benefit over non-immune plasma. Although our study did not have the precision to rule out a small, clinically relevant effect, the benefit is insufficient to justify the use of immune plasma for treating patients with severe influenza A. FUNDING National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, MD, USA).
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis
Journal of Infectious Diseases. 2015;211((1):):80-90.
BACKGROUND Administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (SARIs) of viral etiology. We conducted a systematic review and exploratory meta-analysis to assess the overall evidence. METHODS Healthcare databases and sources of grey literature were searched in July 2013. All records were screened against the protocol eligibility criteria, using a 3-stage process. Data extraction and risk of bias assessments were undertaken. RESULTS We identified 32 studies of SARS coronavirus infection and severe influenza. Narrative analyses revealed consistent evidence for a reduction in mortality, especially when convalescent plasma is administered early after symptom onset. Exploratory post hoc meta-analysis showed a statistically significant reduction in the pooled odds of mortality following treatment, compared with placebo or no therapy (odds ratio, 0.25; 95% confidence interval, .14-.45; I(2) = 0%). Studies were commonly of low or very low quality, lacked control groups, and at moderate or high risk of bias. Sources of clinical and methodological heterogeneity were identified. CONCLUSIONS Convalescent plasma may reduce mortality and appears safe. This therapy should be studied within the context of a well-designed clinical trial or other formal evaluation, including for treatment of Middle East respiratory syndrome coronavirus CoV infection. The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
Is fresh frozen plasma effective for thrombocytopenia in adults with dengue fever? A prospective randomised double blind controlled study
The Ceylon Medical Journal. 2008;53((2):):36-40.
RATIONALE Thrombocytopenia is a common problem which causes concern and complications in dengue fever. If proven effective, intravenous fresh frozen plasma is a simple and widely available therapeutic option to manage thrombocytopenia. OBJECTIVE To test the efficacy of fresh frozen plasma (FFP) on thrombocytopenia in patients with dengue fever. DESIGN 109 serologically confirmed dengue patients with platelet counts <40 000/mm3 were randomised into two groups. Group A (treatment) comprised 53 patients and group B (control) 56 patients. Group A received an intravenous infusion of 3 units (600 ml) of FFP over 90 minutes. Group B received an intravenous infusion of an equal volume of isotonic saline over the same period. The primary outcome measure was the difference between pre- and post-interventional platelet counts at 12, 24 and 48 hours. RESULTS Following Intervention, the mean platelet count was significantly higher in Group Athan in Group B at 12 hours (p=0. 04; t-test). The mean platelet counts continued to be higher in Group A than in Group B at 24 and 48 hours post-intervention, but the differences were not statistically significant. CONCLUSIONS In dengue patients with thrombocytopenia, infusion of 600 ml FFP may contribute to a significant increase in platelet count in the first 12 hours, but not thereafter.
Passive immunotherapy in AIDS: a double-blind randomized study based on transfusions of plasma rich in anti-human immunodeficiency virus 1 antibodies vs. transfusions of seronegative plasma
Proceedings of the National Academy of Sciences of the United States of America. 1995;92((4):):1195-9.
A randomized double-blind controlled trial was conducted to determine the efficacy of passive immunotherapy in the treatment of symptomatic human immunodeficiency virus (HIV) infection. This trial included 86 symptomatic patients randomized to receive plasma rich in anti-HIV-1 antibody or standard seronegative plasma. Each patient in both groups received a 300-ml infusion every 14 days over a 1-year period, and every 28 days thereafter, in addition to zidovudine and other conventional prophylactic treatments. Plasma donors were selected among symptomless seropositive individuals with a CD4 lymphocyte count > or = 400 x 10(6) cells per liter, a negative p24 antigen assay, and a high concentration of anti-p24 antibody. The plasmas were heat-inactivated before infusion. During the study period (day 28-day 365) scheduled by the protocol, clinical benefit from passive immunotherapy was observed in delaying the appearance of the first AIDS-defining event (P < 0.009) and reducing the cumulative incidence of such events, which was estimated 3-fold higher in the control group compared to the treatment group. Seven deaths occurred in the treatment group vs. 11 in the control group (P = 0.27). A total of 47 patients died or exhibited new AIDS-defining events, 18 in the treatment group and 29 in the control group (P = 0.009). No clinical benefit was observed after the 1-year period with infusions performed every 4 weeks. These results indicate a favorable effect of passive immunotherapy on the evolution of advanced AIDS.
Treatment of severe infectious purpura in children with human plasma from donors immunized with Escherichia coli J5: a prospective double-blind study. J5 study Group
Journal of Infectious Diseases. 1992;165((4):):695-701.
To evaluate the efficacy of anti-J5 serum in the treatment of severe infectious purpura, 73 children were randomized to receive either anti-J5 (40) or control (33) plasma. Age, blood pressure, and biologic risk factors were similar in both groups. At admission, however, tumor necrosis factor serum concentrations were 974 +/- 173 pg/ml compared with 473 +/- 85 pg/ml (P = .023) and interleukin-6 serum concentrations were 129 +/- 45 compared with 19 +/- 5 ng/ml (P = .005) in the control and treated groups, respectively. The duration of shock and the occurrence of complications were similar in both groups. The mortality rate was 36% in the control group and 25% in the treated group (P = .317; odds ratio, 0.76; 95% confidence interval, 0.46-1.26). This trend disappeared after correction for unbalances in risk factors at randomization using a logistic regression model. These results suggest that anti-j5 plasma did not affect the course or mortality of severe infectious purpura in children.
Efficacy of immune plasma in treatment of Argentine haemorrhagic fever and association between treatment and a late neurological syndrome
In a double-blind trial patients with Argentine haemorrhagic fever treated with immune plasma within 8 days of the onset of the disease had a much lower mortality than those given normal plasma. Some patients treated with immune plasma developed late neurological complications.