Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment?

Context Studies of Spanish influenza that evaluated effects of transfusion with influenza-convalescent blood products might offer insights regarding potential treatments for H5N1 influenza. Contribution This review of 8 controlled studies published in English-language medical literature between 1918 to 1925 found that transfusion with influenza-convalescent human blood products may have reduced risk for death in hospitalized patients with Spanish influenza complicated by pneumonia. Transfusions caused some chill reactions. Cautions Studies had many methodologic limitations. Implications Studies from the Spanish influenza era support the idea that convalescent human H5N1 plasma could be an effective, accessible treatment that should be studied in clinical trials. The Editors The world is bracing for a potential H5N1 influenza pandemic. During the Spanish influenza pandemic, an estimated 30% of the world's population became ill and 50 million people died (1). An H5N1 influenza pandemic could be equally or more severe. Unfortunately, effective vaccines will be difficult to produce before a novel human pandemic strain emerges and will take substantial time to manufacture and distribute in quantity. It is sobering that the world's annual production capacity for influenza vaccine is 300 million doses (2)enough for 4.5% of the world's population. These facts have caused some governments to develop response plans to pandemic influenza that involve creating antiviral stockpiles and increasing the capacity to handle surges in the need for medical care. Patients with H5N1 influenza often develop a fatal case of acute respiratory distress syndrome or multiple organ dysfunction syndrome that is similar to the syndromes reported in patients with Spanish influenza who developed pneumonia-like complications (35). To treat patients with H5N1 influenza, the World Health Organization recommends hospitalization with early use of oseltamivir and supportive care (3). Despite these treatments, 30% to 80% of hospitalized patients with H5N1 influenza have died, and an oseltamivir-resistant virus has developed in some patients (3, 4). A case series report of Vietnamese patients with H5N1 influenza suggested that supportive care may be the only option available (4). Even if more effective standard pharmaceutical treatments are produced, it is unlikely that sufficient quantities will be rapidly or widely available because of financial, logistical, and health care delivery limitations. Passively delivered anti-influenza antibodies in convalescent human plasma obtained from H5N1 survivors may offer a novel treatment approach and possible solution to these problems. Passive antibodies have been used to prevent or treat such diseases as rabies, measles, hepatitis B, cytomegalovirus, and respiratory syncytial virus (6), and convalescent human plasma may have efficacy in the treatment of severe acute respiratory syndrome (7, 8). The modern plasmapheresis systems in many hospitals and blood collection centers currently produce large volumes of plasma for treating coagulopathies and other conditions (9, 10). The same infrastructure, personnel, and regulatory framework could produce convalescent plasma for the treatment of H5N1 influenza. To help assess the potential treatment efficacy of convalescent plasma in reducing mortality in current patients with H5N1 influenza, we conducted a review of studies from the Spanish influenza era that used influenza-convalescent human blood products to treat patients with Spanish influenza complicated by pneumonia (influenza pneumonia). Methods Data Sources and Searches We developed and followed a protocol for the literature review and also followed standard reporting guidelines (11). The medical literature during the 1920s was not centrally indexed in an electronic or text database. Two authors first conducted a preliminary survey and study of the original medical literature published about Spanish influenza. This was done to gain an understanding of the scientific concepts, research methods, medical practices, and vocabulary used during that era to aid in the development of our review and search strategy. Subsequently, 1 author conducted a manual review of the indexes of the following medical journals from 1918 to 1925: Journal of the American Medical Association, Boston Medical and Surgical Journal (now New England Journal of Medicine), British Medical Journal, Canadian Medical Association Journal, Lancet, Archives of Internal Medicine, The Military Surgeon (United States), and Naval Medical Bulletin (United States). We searched 3 terms in the journal indexes: influenza, serotherapy, and pneumonia. We then searched subindexes or article titles that were listed under the 3 categories for any of the following terms: influenza, serotherapy, pneumonia, serum, plasma, blood, bronchopneumonia, convalescent, intravenous, and transfusion. Potentially relevant articles were obtained and reviewed. We also reviewed references of relevant articles. Of note, many of the source journals provided an indexed abstract section of articles drawn from other English-language and nonEnglish-language journals. Original articles on our topic were often published as an abstract by other journals, and the articles often cross-referenced each other. For practical reasons, including feasibility and resource constraints, we limited our searches to years in which relevant studies were likely to be published. Study Selection Two authors selected studies published in an English-language medical journal that met inclusion criteria defined a priori (Figure 1). Studies had to have used convalescent whole blood, plasma, or serum obtained from humans who had recovered from Spanish influenza as the treatment product and had to indicate the type, route, and volume of the product that was used. The treatment and control groups had to have included hospitalized patients with a diagnosis of influenza complicated by pneumonia, and investigators had to report mortality rates. The treatment group had to include at least 10 patients. The control group had to receive standard care and could not be assigned to receive, as a group, an alternative experimental therapy, such as an equine-derived antipneumococcus serum. Studies had to be conducted in a hospital setting during the Spanish influenza pandemic of 1918 to 1920. We excluded studies if they were reported only as an editorial, commentary, or abstract or as a translated synopsis of a nonEnglish-language study. Figure 1. Flow diagram of trial identification and selection. *Most of these studies were excluded on the basis of multiple criteria. Our rationale for the detailed inclusion and exclusion criteria was as follows. Hospitalized patients were likely to have had very severe illness and a more reliable diagnosis of influenza pneumonia than were patients whose illness was diagnosed and treated by general practitioners in the home. Although strains of Spanish influenza probably circulated before 1918 and certainly did so after 1920, the accuracy of a diagnosis of Spanish influenza pneumonia was likely to be reasonably good during years when herd immunity was low, the virus was virulent, and large epidemics occurred. Because scientific concepts, research methods, medical practices, and vocabulary have changed markedly since 1920, we restricted our analysis to articles that we could carefully scrutinize and for which we could reasonably reliably determine the primary clinical condition of patients, the treatment that was given, and characteristics of the treatment and control groups. Data Extraction and Quality Assessment Two authors independently extracted data about study characteristics, outcomes, adverse events, and quality. Disagreements were resolved by consensus. The quality of each study was assessed by using a 27-item checklist that was developed to assess the methodologic quality of randomized and nonrandomized studies of health care interventions (12). The quality scores could range from 0 to 27, with higher scores indicating better quality. Data Synthesis and Analysis We used as the principal measure of effect the range of absolute risk differences in death between the treatment and control groups. We conducted a planned subgroup analysis of mortality among patients who received early treatment (after <4 days of illness) compared with those who received late treatment (after 4 days). We also calculated overall crude case-fatality rates and pooled absolute risk differences in death by using the random-effects model of DerSimonian and Laird (13). Heterogeneity was assessed visually by using Galbraith plots (14) and statistically by using the I 2 statistic (15). To exclude the possibility that any one study was excessively influencing the results, we conducted a sensitivity analysis by excluding each study one at a time. We used the method of Egger and colleagues (16) to assess for statistical evidence of possible publication bias. All analyses were performed by using Stata software, version 9.1 (Stata Corp., College Station, Texas). Role of the Funding Source No funding was received for this review. Results Study Selection and Evaluation We searched hundreds of titles in the topic indexes and retrieved 72 manuscripts for screening (Figure 1). Many of these studies focused on the isolation and identification of the influenza bacillus or known bacterial pathogens or used various animal-derived antipneumococcus serums or other preparations for treatment. In 27 reports, influenza-convalescent human blood products were used to treat patients with Spanish influenza, with or without pneumonia complications. Of these, 8 studies described in 10 reports met all of our inclusion criteria (1726). No included study was identified solely from the citation review. We excluded 17 articles that were small case reports, were incomplete or noninterpretable, were written in a non-English language, or involved o