Introduction
Seasonal and pandemic influenza cause substantial disease and a high economic burden [
1]. The main treatment for influenza is neuraminidase inhibitor administration [
2]. Despite this therapy, pandemic influenza remains a major cause of morbidity and mortality globally [
1,
3,
4]. Therefore, there is a need for effective therapy against influenza. Convalescent plasma therapy is a promising option that has been used experimentally for the last 100 years, since the Spanish flu of 1917–1918, and is currently being tested as a potential treatment for the novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [
5‐
7].
Preclinical animal studies have demonstrated the therapeutic efficacy of hyperimmune immunoglobulin and IgG antibody from convalescent plasma [
8,
9]. It has been suggested that the administration of high-titer anti-influenza immune plasma derived from convalescent or immunized individuals may be clinically beneficial for the treatment of seasonal and pandemic influenza [
10‐
12]. Additionally, treatment with convalescent plasma was reported to reduce hospital stays and mortality in patients with SARS-CoV infection [
10] and in patients with severe influenza A (H1N1) [
13]. Some systematic reviews of studies using convalescent plasma concluded that there is evidence of clinical benefits in such patients [
10,
14,
15].
Until recently, the collective evidence based on previous studies has been of relatively poor quality because very few randomized trials had been conducted. However, two randomized, controlled, and multicenter trials were reported in 2019, and in both trials, convalescent plasma or hyperimmune intravenous immunoglobulin (H-IVIG) prepared from pooled plasma, obtained from convalescent patients, and conferred no significant benefit over placebo in patients with influenza infection [
16,
17]. This is not concordant with previous studies [
13,
18]. To investigate this discrepancy, the current study conducted a systematic review and meta-analysis evaluating the clinical efficacy of either convalescent plasma or H-IVIG for the treatment of severe influenza.
Materials and methods
Inclusion and exclusion criteria
We conducted this study in compliance with the PRISMA guidelines [
19]. Prospective randomized controlled trials (RCTs) involving patients with influenza who were treated with convalescent plasma and/or H-IVIG were considered for inclusion in the analysis. The reports considered for inclusion were limited to those published in English. Crossover trials, before-after studies, conference presentations, abstract publications, case reports or case series, studies with no comparator, and editorials were excluded from consideration.
Search strategy
Two authors (ZH and JZ) performed the literature search during February 2020. To increase the sensitivity of the search, the search term “influenza” was used in conjunction with AND “convalescent plasma” OR “convalescent serum” OR “hyperimmune immunoglobulin” OR “immune plasma” OR “H-IVIG” as keywords or Medical Subject Heading (MeSH) search terms. The records of four electronic databases (PubMed, EMBASE, Scopus, and Web of Science), dating from their inception to February 10, 2020, were searched.
Definitions
The study population of interest included severe patients of any age or sex who were hospitalized with laboratory-confirmed influenza infection (as defined in the original trials). Severe influenza was defined of having either hypoxia (room air oxygen saturation of < 93%) or symptoms of respiratory distress or using the authors’ definitions, including a National Early Warning (NEW) score of > 2 points or a CURB-65 (severity score for community-acquired pneumonia) score of > 3 points. The interventions of interest were convalescent plasma, serum, or H-IVIG derived from convalescent or immunized individuals. Comparator treatments included placebo and low-titer plasma.
Outcomes
The primary outcome of interest in the current analysis was the influenza case-fatality rate. The secondary outcomes analyzed included antibody levels, cytokine levels, viral loads, incidences of serious adverse events, and numbers of days spent on mechanical ventilation, in the intensive care unit (ICU), and in the hospital.
Two authors (ZX and JZ) independently reviewed the articles retrieved via the above-described search protocol and extracted the relevant data from them. Discrepancies were resolved via discussion.
Quality assessment
The quality of each trial included in the analysis was assessed based on a thorough review of the details provided in the “Materials and Methods” section and any relevant supplementary materials. Trial quality was also assessed using the Cochrane collaboration tool for assessing the risk of bias [
20], including assessment of random sequence generation, allocation concealment, blinding (of interventions and outcome measurement or assessment), incomplete outcome data, selective reporting bias, and other potential sources of bias (e.g., industry funding). For each criterion, the risk of bias was rated as low, high, or unclear in cases where there were insufficient details. Two authors (ZX and JZ) independently assessed the study quality, and disagreements were resolved via discussion.
Assessment of heterogeneity
The
I2 statistic was used to evaluate the influence of heterogeneity on the pooled results, and an
I2 value of > 50% was deemed to indicate substantial heterogeneity [
20]. Fixed-effects models were used to pool data when the level of heterogeneity was insignificant, and random effects models were used to pool data when significant heterogeneity was identified.
Statistical analysis
Categorical data were pooled, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We did not construct funnel plots, as fewer than 10 trials were identified for each comparison. Statistical analyses were conducted using Review Manager software (version 5.3; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark), and two-sided p values of < 0.05 were considered statistically significant.
Discussion
The current analyses suggest that convalescent plasma may not have clinically relevant effects on mortality in patients with influenza. Reductions in the number of days in the ICU, overall hospital stay lengths, and the number of days on mechanical ventilation following treatment with convalescent plasma were also not significant. Of interest, there was evidence of a possible benefit from this therapy by way of increased HAI titers and reduced influenza B viral loads and cytokine levels after convalescent plasma treatment. No serious adverse events were reported.
The use of immune plasma has been recommended as a primary therapy in patients with severe respiratory infectious diseases including influenza, severe acute respiratory syndrome, and Middle East respiratory syndrome [
10,
14,
22]. However, until recently, relevant data pertaining to these recommendations were weak and limited to case reports and case series lacking controls. Compared with the previous meta-analyses [
10,
14,
15], our meta-analysis differs in the inclusion criteria utilized, in the number of trials included, and in the summary estimates of treatment effect, which were strengthened by an extensive search, duplicate citation screening, and data abstraction. We focused on high-quality RCTs and estimated not only fatality rates but also both the biological effects (i.e., HAI titers, viral loads, cytokines) and clinical benefits (i.e., length of ICU/hospital stays, number of days on mechanical ventilation, and adverse events). The evidence for a reduction in mortality associated with convalescent plasma was strongest for influenza A (H1N1) [
18], but this should be interpreted with an appropriate degree of caution because of the limited sample size (
n = 17) and the early use of treatment (onset within 5 days) in that study. Additionally, in an analysis of pooled data derived from four trials (
n = 567) in which deaths were reported, there was no significant association between the use of convalescent plasma and mortality in patients with severe influenza.
With regard to secondary outcomes, including the number of days in the ICU, overall number of days in the hospital, and the number of days on mechanical ventilation, three RCTs reported relevant data, and the reductions in an H-IVIG/immune plasma group compared with a control group were not significant in any of them [
16,
18,
22]. Despite robust increases in the HAI titers against influenza A and B [
17,
21], reductions in the influenza B viral loads [
17], and reductions in the cytokine levels in patients with H1N1 [
18], no clinical benefit of receiving H-IVIG/immune plasma infusion was evident in influenza patients.
Our meta-analysis has some limitations. First, despite an extensive literature search, we identified only four trials with a primary outcome that could be pooled. Second, the severity of influenza may have been different between the evaluated RCTs. Third, we did not registering in PROSPERO, but we conducted this study in compliance with the PRISMA guidelines [
19]. Finally, we were not able to pool all data reported for outcomes such as viral loads, cytokine levels, and ICU and hospital stay lengths, due to variability in the measuring and reporting of these outcomes.
Presently, many questions remain about the use of convalescent plasma for treating influenza. For example, it is still unknown how much of severe disease is due to virus replication versus inflammation. The composition of plasma is complex, and transfusion reactions can occur after the administration of blood products [
23,
24]. Furthermore, titers of the relevant antibodies contained in convalescent serum preparations differ. The standardized extraction and purification of specific antibodies can be difficult and time-consuming. Lastly, viral shedding and the induced immune responses may be different between influenza A and B. Thus, more definitive animal and pilot studies should be conducted to identify the optimal timing, dosage, and indications for the use of H-IVIG/immune plasma in patients infected with different virus subtypes.
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