Critical Care Medicine:
Hark back: Passive immunotherapy for influenza and other serious infections
Luke, Thomas C. MD, MTMH; Casadevall, Arturo MD, PhD; Watowich, Stanley J. PhD; Hoffman, Stephen L. MD, DTMH; Beigel, John H. MD; Burgess, Timothy H. MD, MPH
From Henry Jackson Foundation (TCL), Naval Medical Research Center, Silver Spring,MD; Albert Einstein College of Medicine (AC), Bronx, NY; The University of Texas Medical Branch (SJW), Galveston, TX; Protein Potential LLC (SLH), Rockville, MD; National Institute of Allergy and Infectious Diseases (JHB), Bethesda, MD; Naval Medical Research Center (THB), Silver Spring, MD.
The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. Drs. Luke and Beigel are employees of the Federal Government, and Dr. Burgess is a military service member. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person's official duties.
Drs. Luke, Beigel, Casadevall, Watowich, and Burgess have not disclosed any potential conflicts of interest. Dr. Hoffman holds equity interest in his employer, Protein Potential LLC.
For information regarding this article, E-mail: firstname.lastname@example.org
The world is experiencing a pandemic of swine-origin influenza virus H1N1. A vaccine to prevent disease is now available, and millions have or will become ill before they can be vaccinated. The ability to use swine-origin influenza virus vaccines as a public health tool has been described as a “race against time.” Oseltamivir and related drugs are being used in an effort to reduce morbidity and mortality, but their efficacy for treating severe influenza is suboptimal, and possible wide-spread emergence of oseltamivir-resistant mutants is a concern. Another approach for prevention and treatment of serious influenza is infusion of hyperimmune plasma. The United States has thousands of licensed blood product collection centers that produce millions of liters of plasma licensed by the Food and Drug Administration on an annual basis for the treatment of serious conditions. Immunotherapy using infusion of convalescent plasma (or hyperimmune intravenous immunoglobulin) has been reported to be an effective treatment for severe influenza and other virulent pathogens in animal models and humans. Plasma obtained from those that have recovered or were early recipients of vaccine offers a resource for production of an immediately available and potentially effective therapy at the local, state, and national level. Past, current, and future uses of immunotherapy and current advisory body recommendations for this approach are presented.
The world is experiencing a pandemic of swine-origin influenza virus (SOIV) H1N1. The ability to use SOIV H1N1 vaccines as a public health tool has been described as a “race against time” (1). Epidemiologic data suggest that pregnant women, children younger than 4 yrs, and younger adults may be at higher risk for severe disease (2), and segments of the susceptible population will become ill before they can be immunized (2). The final impact of the SOIV H1N1 pandemic cannot be predicted but local, state, national, and global health and political bodies are preparing for a surge of cases that may place severe strains on healthcare and social systems. Some governments responded to the ongoing threat of H5N1 influenza by creating antiviral, antibiotic, and other medical product stockpiles and developed pandemic response plans that may help to alleviate the severity of this pandemic.
Initial testing of the SOIV H1N1 virus found it susceptible to neuraminidase inhibitors (oseltamivir and zanamivir) and resistant to adamantanes (amantadine and rimantadine) (3). Reports of oseltamivir-resistant mutants, although not unexpected, are nonetheless concerning (4–7). During the 2007 to 2008 influenza season, seasonal H1N1 rapidly developed resistance to oseltamivir, increasing from 12.3% to 98.5% of the samples tested (8, 9). Should a similar pattern of rapid resistance to oseltamivir emerge for SOIV H1N1, satisfactory treatment options will be limited and supportive care will be the only option for most.
One potential therapeutic option is passive immunotherapy with plasma from convalescent patients or hyperimmune intravenous immunoglobulin (hIVIG) containing polyclonal antibodies obtained from recovered patients or recipients of effective vaccine. This approach is not without precedent; human-derived and animal-derived convalescent serum, plasma, and hIVIG were the standard of care for treatment of many pathogen-mediated and toxin-mediated diseases before the advent of “modern” pharmaceuticals in the 1950s (10–12). Historical evidence suggests that this approach might have efficacy for treating influenza. During the Spanish influenza pandemic, investigators reported that convalescent blood products were highly effective in the treatment of influenza pneumonia and what is now known as acute respiratory distress syndrome (13–36).
A recent meta-analysis of these historical studies concluded that patients with Spanish influenza pneumonia who received influenza-convalescent human blood products may have experienced a clinically significant reduction in mortality (37). The authors suggested that convalescent plasma or hIVIG in the modern era could be a timely, effective, and widely available treatment during an H5N1 pandemic (or other infectious disease for which no good treatment exists) and that well-designed clinical trials should be conducted. Further support for this hypothesis comes from human studies conducted in the Soviet Union that reported that convalescent serum products and hIVIG were efficacious in the prevention or treatment of influenza and influenza pneumonia (38–42), and from animal studies (43–50) using various types of passive immunotherapies. Successful treatment of a pulmonary H1N1 infection in severe combined immunodeficiency mice with hemagglutinin-specific antibodies with very low virus-neutralizing activity in vitro (51) and in H5N1-infected mice with equine-derived H5N1 F(ab) fragments (52, 53) provides evidence that passive immunotherapy is beneficial in a model of severe disease for immunologically competent and incompetent hosts.
We present an overview of the modern process for producing large volumes of plasma, historical and current uses of passive immunotherapy to treat infectious agents, a description of advisory body recommendations, and efforts to collect convalescent SOIV H1N1 plasma for use in a clinical trial.
Modern Production of Plasma
The production and transport of licensed blood products in the United States are regulated by the Food and Drug Administration (54). Blood products are obtained in blood donor centers and source plasma centers. Blood donor centers typically rely on volunteers or directed donors who give blood products after a defined screening process and informed consent to insure the safety of both donors and the nation's blood supply. Directed donors provide blood products for personal use or a specific person/purpose. Blood donor centers typically produce fresh-frozen plasma (FFP) that is suitable for patient infusion or that can be used to produce intravenous immunoglobulin (IVIG). Source plasma centers produce frozen plasma, typically from paid donors, for the manufacture of IVIG products. Frozen plasma is not licensed for direct infusion into patients.
Plasma is obtained by two primary methods: automated apheresis or fractionation. The maximum volume of FFP or frozen plasma (Table 1) obtained by automated apheresis has been established by the Food and Drug Administration (55). Automated apheresis can be performed in an individual once or twice within a 7-day period; this equates to a potential volume of 625-1250 to 800-1600 mL per week. The volume of FFP derived from fractionation of 500 mL of whole blood is approximately 250 mL (56). The frequency of whole blood donation is once every 8 wks (56 days) (57).
Before the 1950s, the collection, transport, and transfusion of blood products using glass containers and nonstandardized consumables made the process logistically and clinically challenging. The introduction of plastic equipment and bags by Walter and Murphy (58, 59) radically simplified the process. As a result, the United States (and other nations) have developed a sizeable national infrastructure and workforce devoted to the production of blood products. The American Association of Blood Banks accredits approximately 1200 blood banks, transfusion centers, and blood centers (60). The American Red Cross has established 34 blood services regions with multiple blood collection centers in the United States (61). The America's Blood Centers network has >600 member centers in 45 states (62). The Plasma Protein Therapeutics Association reports that 335 source plasma centers were located in the United States in 2007. It is estimated that 14.6 million liters of frozen plasma and FFP are produced annually (63) and that 4 million units of FFP are annually transfused in the United States, with a similar number in Europe (64–65). This infrastructure could produce a clinically significant volume of convalescent plasma obtained from recovered patients or from early vaccine recipients for treating severe influenza, antiviral-resistant influenza, or new or emerging infectious disease.
Historical Use of Convalescent Serum and Hyperimmune Immunoglobulin
Serum therapy was the only modality available for the treatment of infectious diseases until the introduction of sulfonamides. It was launched by the discovery of Behring and Kitasato that administering immune sera could protect a host against bacterial toxins. Use of serum therapy diminished dramatically in the 1940s with the introduction of penicillin and other antibiotics. The abandonment of serum therapy was the result of the toxicity associated with animal-derived serum, the difficulty of making an early specific diagnosis, and the technical limitations of collecting and administering serum in that era. However, serum therapy retained a niche in the treatment of venomous bites and eventually returned in the 1960s in the form of specific immune globulins for a variety of conditions.
In general, animal sera were used to treat diseases if animals could be infected or immunized to yield high-titer sera in large volumes. In contrast, for diseases that affected only humans and when animal immunization was not practical (such as viral diseases), the serum was usually of human origin. To overcome the collection, cold-storage, transportation, and immunoassay limitations of that era, the “lyophile” process was developed and involved drying pooled hyperimmune serum in a vacuum (66). The powder was solubilized in distilled water and several milliliters were administered intramuscularly. Lyophile sera were available for the prophylaxis and/or therapy of conditions such as scarlet fever, measles, mumps, chickenpox, erysipelas, German measles, and acute hemolytic streptococcal infections (66). Although the majority of historical studies were not conducted by current standards, the results are valuable if considered within the limitations of the data.
Use of Human Convalescent Sera Against Bacterial Diseases.
In general, most bacterial diseases such as pneumococcal pneumonia and meningococcal meningitis were treated with immune sera derived from animal sources (11, 12, 67). Animal sera were preferred because large amounts of sera could be recovered from animals and the material could be standardized in laboratory tests. Nevertheless, it was recognized that human sera had bactericidal activity in the form of complement, and several studies attempted to obtain better results through the use of convalescent sera or fresh serum in combination with an animal-derived specific antiserum. Human serum was administered into the subarachnoid space for meningococcal meningitis when commercial sources of serum failed to produce symptomatic improvement (68). Haemophilus influenzae meningitis in children was treated by mixing human serum with commercial antiserum in a 1:2 ratio and administering 20–25 mL directly into the subarachnoid space (69, 70).
Human convalescent serum also was used for the treatment of scarlet fever. Birkhaug (71) reported the use of 15–85 mL of pooled human convalescent sera obtained 3–5 wks after defervescence of 37 patients during the first 7 days of disease. Although this was not a controlled study, the author noted improvement in most patients, particularly when the serum was administered early in the course of disease. Another bacterial disease treated with human antibody preparations was whooping cough. Administration of “hyperimmune antibacterial pertussis human serum” was considered to have significant value for the treatment and prophylaxis of contacts (72). Another preparation, known as “lyophile hyperimmune serum,” was derived from young boys who had a history of pertussis (73). This preparation was used as late as the 1940s and was reported to be effective in children with and without the addition of sulfonamides (73), but double-blind, controlled studies of pertussis treatment with hIVIG decades later revealed no therapeutic benefit (74).
Human Convalescent Sera Against Viral Disease.
Human convalescent sera have been used to treat and prevent measles, mumps, polio, Spanish flu, vaccinia, and varicella, among others. A review of the use of convalescent sera published in 1943 (75) concluded that measles and mump convalescent sera were effective for the prevention of disease when administered to exposed individuals who were at risk for disease. During a measles epidemic in Baltimore in the winter of 1942, convalescent serum was fractionated to generate fractions enriched in antibodies and used with high efficacy to prevent disease (76). The majority of treated individuals were children who received from 2–5 mL of fractionated convalescent serum by intramuscular injections (76). Varicella convalescent serum was considered of questionable value, but controlled clinical trials conducted in the 1970s found that zoster immune plasma from convalescing adults was highly effective in preventing postexposure varicella in immunosuppressed children (77).
The efficacy of poliomyelitis convalescent therapy was uncertain, especially if administered once the disease had manifested; nevertheless, volumes in the range of 100 to 200 mL delivered intravenously were used in treatment. The relative inefficacy of this therapy may have been a result of inadequate amounts of antibody. One study showed that the amount of neutralizing antibodies in poliomyelitis convalescent sera was highly variable and suggested that better results might be obtained using selected sera with high neutralizing titers to polio virus (78).
Published studies from the Spanish flu H1N1 pandemic reported that transfusion of influenza convalescent human blood products (whole blood, plasma, or serum) reduced morbidity and mortality in patients with influenza complicated by pneumonia. Luke et al (37) conducted a meta-analysis of eight studies involving 1703 patients to determine the impact on mortality and other factors. The typical volume of plasma or serum administered was 125–250 mL on one to two occasions (range, 1–7), and the agent was usually obtained from the donor 7–60 days after symptoms had resolved. The overall crude case-fatality rate was 16% (54 of 336) among treated patients and 37% (452 of 1219) among controls (Fig. 1). The range of absolute risk differences in mortality between the treatment and control groups was 8% to 26% (pooled risk difference, 21%; 95% confidence interval, 15% to 27%). The overall crude case-fatality rate was 19% (28 of 148) among patients who received early treatment (after <4 days of pneumonia complications) and 59% (49 of 83) among patients who received late treatment (after >4 days of pneumonia complications) (Fig. 2). The range of absolute risk differences in mortality between the early treatment group and the late treatment group was 26% to 50% (pooled risk difference, 41%; 95% confidence interval, 29% to 54%). The authors concluded that controlled trials are needed to establish the efficacy of this approach for H5N1 and other influenza strains.
Modern Use of Convalescent Plasma, Serum, and IVIG
The use of convalescent human plasma/serum/IVIG to treat viral infectious diseases in modern medicine is limited, and few randomized, clinical trials have been conducted. Reasons for this development include the development of highly effective vaccines that drastically reduced the number of cases of many infectious diseases; the development of chemotherapeutics and other medical interventions that have, or are perceived to have, a wider utility against pathogens; and a research focus to develop monoclonal antibodies to treat specific pathogens. However, convalescent plasma or hIVIG has been attempted when other therapies were unavailable.
Argentine hemorrhagic fever—caused by Junín virus, a member of the arenaviruses—is the only infectious disease in which convalescent plasma is, to our knowledge, the standard of care. Enria et al (79) recently published a review describing the history, preclinical development, clinical trials, and current status of Argentina's National Program for the treatment of Argentine hemorrhagic fever. This program was established after conclusive results of a double-blind, placebo-controlled study demonstrated that patients treated with 500 mL of convalescent plasma intravenously within 8 days of onset of symptoms had a case fatality rate of 1.1% compared to 16.5% for those treated with nonconvalescent plasma. The treatment volume was later standardized by the development of a formula that included the titer of neutralizing antibodies in each unit of convalescent plasma and the patient's body weight as variables (79).
Chinese investigators treated a previously healthy 31-yr-old man with H5N1 influenza–pneumonia using convalescent H5N1 plasma 11 days after symptoms first began (80). The plasma was obtained from an individual who had recovered from H5N1 16 months previously. Three 200-mL transfusions of convalescent plasma (neutralizing antibody titer 1:80) were administered over 24 hrs. After the first transfusion, the patient's viral load was reduced by a factor of approximately 12 (from 1.68 × 105 to 1.42 × 104 copies/mL)during the first 8 hrs and was undetectable within 32 hrs. Concurrently with plasma administration, the patient was also receiving oseltamivir as the standard of care. The patient made a full recovery and was discharged.
Convalescent plasma and hIVIG were used in hospitals in Southeast Asia to treat severe acute respiratory syndrome often as a “rescue” treatment for patients with a deteriorating clinical course despite other treatments (81–85). All reports were retrospective studies, and different passive immunotherapy products were used in conjunction with steroids, ribavirin, interferon-alpha, and other treatments. Reported outcome measures varied and included death, time to discharge, the development of acute respiratory distress syndrome, and the need for ventilation. Although the authors indicated that passive immunotherapy was beneficial in reducing morbidity and mortality rates, a systematic review categorized the studies as inconclusive because of the confounding effects of varying cotreatments (some possibly harmful), comorbidities, and other factors among the studies (86). The authors suggested that controlled trials for this approach are needed to establish the efficacy of this approach for severe acute respiratory syndrome.
Use of convalescent human immunodeficiency virus plasma to treat patients with acquired immunodeficiency syndrome and human immunodeficiency virus was assessed in multiple clinical trials. The treatment course lasted 1–4 yrs with frequent infusions of high-titer plasma at intervals of every 2–4 wks with 250–500 mL of plasma (87–91). No patient had human immunodeficiency virus infection cured, but investigators reported a halt or delay in the progression of disease or in the number of acquired immunodeficiency syndrome-related complex conditions during the study period. The intensity of the treatment regimen, the lack of viral clearance by convalescent plasma, and the development of highly active antiretroviral therapy products severely limited the utility of this approach for treating human immunodeficiency virus.
Convalescent plasma has been used in the treatment of Lassa fever and Ebola virus with mixed results (92, 93). According to Jahrling et al (92, 93), optimal convalescent plasma containing neutralizing antibodies to specific strains of Lassa fever develops several months after recovery, with only a minority of patients having high titers. Therefore, treatment plasma should be obtained from the same geographical region (strain-specific) and pretested for neutralization titer (92). The usefulness of convalescent plasma in the treatment of Ebola virus is questionable after well-controlled primate studies, regardless of anecdotal reports of human effectiveness (93).
A number of other viral diseases have been treated with hIVIG and IVIG with variable results. Red blood cell aplasia caused by parvovirus B19 infection is the only recognized viral infection in which treatment with IVIG may eradicate infection (94, 95). However, there is considerable evidence that passive immunotherapy may beneficially modify the natural history of viral diseases. These are summarized here.
Cytomegalovirus-enriched immune globulin preparations have shown benefit when used in combination with ganciclovir in the treatment of cytomegalovirus pneumonia. This immune globulin preparation is also utilized in the treatment of ganciclovir-resistant cytomegalovirus infections (96).
Respiratory Syncytial Virus.
In adult bone marrow transplantation patients with respiratory syncytial virus pneumonia, combination therapy using aerosolized ribavirin and standard IVIG (500 mg/kg every other day for 12 days) resulted in a 22% mortality rate, compared to a historical mortality rate of 70% (97). In pediatric bone marrow transplantation patients with respiratory syncytial virus pneumonia, those treated with combination aerosolized ribavirin and respiratory syncytial virus antibody-enriched IVIG had a 9.1% mortality rate, compared with the historical rate of 50% to 70% in patients administered ribavirin alone (98).
Certain complications of vaccination with the vaccinia virus (smallpox vaccine) have been treated with vaccinia immune globulin, including generalized vaccinia, eczema vaccinatum, and progressive vaccinia. Although no controlled trials of efficacy have been reported, anecdotal experience suggests that vaccinia immune globulins for these conditions are beneficial and are now considered the standard of care (99).
Persons who recently have been exposed to hepatitis A and who have not been previously vaccinated against the disease are recommended to receive standard IVIG as postexposure prophylaxis. This recommendation is based on data that showed IVIG, when administered within 2 wks after an exposure, is >85% effective in preventing hepatitis A (100, 101). IVIG also can attenuate the clinical expression of hepatitis A infection when administered later in the incubation period (101). Standard IVIG is used because it contains sufficient anti-hepatitis A antibodies (100).
For patients with hepatitis B and cirrhosis undergoing orthotopic liver transplantation, hepatitis B high-titer immunoglobulin G is administered preoperatively and postoperatively to prevent reinfection. This has been shown to be 50% to 85% effective in preventing recurrence of hepatitis B in the transplanted liver (102). This result may be improved with the concurrent use of the antiviral lamivudine (103).
Rabies high-titer immunoglobulin G is the standard recommended therapy after exposure (104).
A hyperimmune serum derived from goats was developed by Russian researchers. It was reportedly tested in human clinical trials for biological safety and reactivity, and it was immediately and successfully administered to four researchers suspected of becoming infected with Ebola virus during their experimental work (105).
Advisory Body Recommendations and SOIV H1N1 Convalescent Plasma Collection Efforts
The Defense Health Board convened a meeting of national and international experts in February 2008 to evaluate the potential of convalescent plasma. The Defense Health Board is a Federal Advisory Committee to the Secretary of Defense that provides independent scientific recommendations on matters relating to operational programs, health policy development, health research programs, and requirements for the treatment and prevention of disease and injury (106). Participants included representatives from the World Health Organization, the Department of Health and Human Services, the Department of Homeland Security, the Centers for Disease Control, the National Institutes of Health, the Food and Drug Administration, the Center for Biologics Evaluation and Research, the Plasma Protein Therapeutics Association, nonprofit blood donor centers, and clinical care experts. The Defense Health Board recommended that convalescent plasma therapy guidelines should be developed as part of the national pandemic influenza plan and as an alternate treatment for novel, natural, or human-made bioagents in future research and practice (107).
In July 2009, the World Health Organization Blood Regulators Network issued “Position Paper on Collection and Use of Convalescent Plasma or Serum as an Element in Pandemic Influenza Planning” (108). The Blood Regulators Network wrote that “convalescent plasma might play a role in the urgent response to pandemic influenza in settings where vaccination and/or effective antiviral chemotherapy is lacking.” The group emphasized the need for well-designed clinical trials and the need to coordinate with the plasma production industry so that large-scale production could be accomplished if warranted.
Clinical researchers and blood product donor specialists at the National Institute of Allergy and Infectious Diseases, the Naval Medical Research Center, and other institutions are collaborating to address these recommendations. A clinical study (Clinical Trial ID NCT00984451) has been developed to collect plasma that has high titers of anti-influenza novel H1N1 antibodies (109). The plasma will be obtained from individuals who have recovered from the SOIV H1N1 virus or who have been vaccinated. This study is in progress.
In the past 30 yrs, the world has experienced three significant pandemics of new viral pathogens—human immunodeficiency virus, severe acute respiratory syndrome, and SOIV influenza—for which effective and timely quantities of vaccines and/or therapeutics did not exist at the start of the pandemic. The threat of H5N1 or other virulent influenza strains that can explode globally has not diminished. The United States also has experienced the initiating salvo of biowarfare in the form of anthrax attacks with the threat of other viral, bacterial, or toxin agents looming. Researchers, regulatory bodies, industry, and governments responded to the threat of H5N1 influenza and other pathogens by creating oseltamivir and antibiotic stockpiles, maximizing current vaccine production processes, formulating response plans, and developing investigational therapeutics and vaccines, efforts that may make a difference during this SOIV pandemic. However, resistant mutants to existing chemotherapeutics can arise naturally with disturbing speed or potentially by directed design.
Convalescent plasma obtained from those who have recovered or were early recipients of vaccine offers an opportunity to produce an immediately available and potentially effective prophylactic or therapy at the local, state, and national levels for new and emerging diseases. The United States already produces millions of liters of plasma on an annual basis, and the existing infrastructure and personnel could be prepared a priori to produce a potentially therapeutic product. Convalescent plasma is not a panacea and will not be effective for all pathogens. However, for some pathogens—such as Argentine hemorrhagic fever, which can be effectively treated with 500 mL of convalescent plasma—it could be a standard-of-care therapy and produced in clinical population-relevant volumes.
A potentially complete model for such a national program exists for anthrax. Human convalescent plasma obtained from individuals receiving anthrax vaccine adsorbed is effective in the prevention and treatment of anthrax in animal models, and hyperimmune serum was successful in the treatment of human cutaneous anthrax (110–112). A national effort to collect and administer convalescent plasma in real time, or to establish repositories of plasma product for future events (in the form of high titer FFP or lyophilized plasma), could result in an economic and available therapeutic adjunct for anthrax prophylaxis or treatment in large populations (112; Casadevall, Hoffman, and Luke, personal communication). This should be achievable given the several hundred thousands of U.S. military and first responders who are being, or have been, vaccinated against anthrax. The concept also has potential application to epidemics of seasonal and pandemic influenza. Potential donors include the millions who become ill before the delivery of vaccine and the millions of healthcare workers and other groups who have a designated priority for vaccination in accordance with the Health and Human Services Pandemic Influenza Plan (113).
1.Cohen J: Public health. A race against time to vaccinate against novel H1N1 virus. Science
3.Centers for Disease Control and Prevention, Influenza Division: Fluview: A weekly influenza surveillance report: 2009–2010 influenza season week 3 ending January 23, 2010. Centers for Disease Control and Prevention, January 29, 2010. Available at http://www.cdc.gov/flu/weekly
. Accessed February 2, 2010
5.Centers for Disease Control and Prevention: Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis—North Carolina, 2009. MMWR Morb Mortal Wkly Rep
6.Centers for Disease Control and Prevention: Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009–2010 season. Centers for Disease Control and Prevention, December 7, 2009. Available at http://www.cdc.gov/h1n1flu/recommendations.htm
. Accessed September 30, 2009
9.Dharan NJ, Gubareva LV, Meyer JJ, et al: Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA
10.World Health Organization, Blood Regulators Network: Position paper on collection and use of convalescent plasma or serum as an element in pandemic influenza planning. World Health Organization, July 9, 2009. Available at www.who.int/bloodproducts/brn/en/
. Accessed September 30, 2009
11.Casadevall A, Scharff MD: Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis
12.Buchwald UK, Pirofski L: Immune therapy for infectious diseases at the dawn of the 21st century: The past, present and future role of antibody therapy, therapeutic vaccination and biological response modifiers. Curr Pharm Des
13.Stoll HF: Value of convalescent blood and serum in treatment of influenza pneumonia. JAMA
14.O'Malley JJ, Hartman FW: Treatment of influenzal pneumonia with plasma of convalescent patients. JAMA
15.Ross CW, Hund EJ: Transfusion on the desperate pneumonias complicating influenza—Preliminary report on the successful use of total immune citrated blood. JAMA
16.Ross CW, Hund EJ: Treatment of pneumonic disturbance complicating influenza. JAMA
17.Kahn MH: Serum treatment of postinfluenzal bronchopneumonia. JAMA
18.Gould EW: Human serum in the treatment of influenza bronchopneumonia. NY Med J
19.McGuire LW, Redden WR: Treatment of influenzal pneumonia by the use of convalescent human serum—Preliminary report. JAMA
20.McGuire LW, Redden WR: Treatment of influenzal pneumonia by the use of convalescent human serum. JAMA
21.Sanborn GP: The use of the serum of convalescents in the treatment of influenza pneumonia: A summary of the results in a series of one hundred and one cases. Boston Med Surg J
22.Maclachlan WW, Fetter WJ: Citrated blood in treatment of the pneumonia following influenza. JAMA
23.Francis FD, Hall MW, Gaines AR: Early use of convalescent serum in influenza. Mil Surg
24.Redden WR: Treatment of influenza-pneumonia by use of convalescent human serum. Boston Med Surg J
25.Jacobaeus: Treatment of influenza pneumonia with serum from convalescents. Svenska Lakartidnin
26.Bass JA, Ervin CE: Use of serum in the treatment of influenza-pneumonia. Naval Med Bull
27.Simici D: Treatment of influenza with injections of blood from convalescents. Paris Med
28.Holst J: Convalescent serum in treatment of influenza. Norsk Magazine for Laegevidenskaben
29.Lesne E, Brodin P, Saint-Girons F: Plasma therapy in influenza. Presse Med
30.Ehrenberg L, Barkman A: Convalescent serum in the prevention and treatment of influenza. Hygiea
31.Bag O: Convalescent serum in the treatment of influenza pneumonia. Norsk Magazine Laegevidenskaben
32.Bogardus FB: Influenza pneumonia treated by blood transfusions. NY Med J
33.Huff-Hewitt WE: Human serum in influenza. Br Med J
34.Miller OO, McConnell WT: Report of influenza treated with serum from recovered cases. Ky Med J
35.Brown WL, Sweet BL: Treatment of influenzal pneumonia by citrated transfusions. JAMA
36.Carlyle PM: Injection of whole blood in influenza. Br Med J
37.Luke TC, Kilbane EM, Jackson JL, et al: Meta-analysis: Convalescent blood products for Spanish influenza pneumonia: A future H5N1 treatment? Ann Intern Med
38.Berezina AI: [Experience in treating influenza with dry anti-influenza serum of Smorodintsev; preliminary report.] Sov Med
39.Stavskaia VV, Ignateva NA: [On the treatment of influenza and influenzal pneumonia.] Klin Med (Mosk)
40.Selivanov AA, Morozenko MA, Kallas EV, et al: [Experimental for achievement of therapeutic sera against respiratory infections from immunized donors]. Vrach Delo
41.Zhukova EA: [Character of the therapeutic action of different schedules of administration of donor anti-influenza gamma-globulin to influenza patients]. Tr Inst Im Pastera
42.Firsov SL, Zhukova EA: [Experience with the clinical use of donor anti-influenza gamma-globulin]. Tr Inst Im Pastera
43.Sweet C, Jakeman KJ, Smith H: Role of milk-derived IgG in passive maternal protection of neonatal ferrets against influenza. J Gen Virol
44.Sweet C, Bird RA, Jakeman K, et al: Production of passive immunity in neonatal ferrets following maternal vaccination with killed influenza A virus vaccines. Immunology
45.McClure JT, DeLuca JL, Lunn DP, et al: Evaluation of IgG concentration and IgG subisotypes in foals with complete or partial failure of passive transfer after administration of intravenous serum or plasma. Equine Vet J
46.Zhang F, Chen J, Fang F, et al: Maternal immunization with both hemagglutinin- and neuraminidase-expressing DNAs provides an enhanced protection against a lethal influenza virus challenge in infant and adult mice. DNA Cell Biol
47.Reuman PD, Ayoub EM, Small PA: Effect of passive maternal antibody on influenza illness in children: A prospective study of influenza A in mother-infant pairs. Pediatr Infect Dis J
48.Englund JA, Mbawuike IN, Hammill H, et al: Maternal immunization with influenza or tetanus toxoid vaccine for passive antibody protection in young infants. J Infect Dis
49.Virelizier JL: Host defenses against influenza virus: the role of anti-hemagglutinin antibody. J Immunol
50.Takiguchi K, Sugawara K, Hongo S, et al: Protective effect of serum antibody on respiratory infection of influenza C virus in rats. Arch Virol
51.Mozdzanowska K, Furchner M, Washko G, et al: A pulmonary influenza virus infection in SCID mice can be cured by treatment with hemagglutinin-specific antibodies that display very low virus-neutralizing activity in vitro. J Virol
52.Lu J, Guo Z, Pan X, et al: Passive immunotherapy for influenza A H5N1 virus infection with equine hyperimmune globulin F(ab′)2 in mice. Respir Res
53.Treanor J: Avian influenza: Exploring all the avenues. Ann Intern Med
54.U.S. Food and Drug Administration (FDA): FDA, Code of Federal Regulations, CFR600 series, CFR210 series, and CFR211 series (and others that apply). Available at http://www.gpoaccess.gov/CFR/
. Accessed September 30, 2009
56.Weinstein SM: Principles and Practice of Intravenous Therapy. Eighth Edition. Philadelphia, PA, Lippincott Williams & Wilkins, 2007, pp 429
58.Walter CW: Development of plastic equipment for blood bank use. Bibl Haematol
59.Walter CW: Invention and development of the blood bag. Vox Sang
64.Hellstern P, Muntean W, Schramm W, et al: Practical guidelines for the clinical use of plasma. Thromb Res
2002; 107(Suppl 1):S53–S57
65.O'Shaughnessy DF, Atterbury C, BoltonMaggs P, et al: Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol
66.McGuinness AC, Stokes J, Mudd S: The clinical uses of human serum preserved by the lyophile process. J Clin Invest
67.Casadevall A, Scharff MD: “Serum Therapy” revisited: Animal models of infection and the development of passive antibody therapy. Antimicrob Agents Chemotherap
68.Bunim BJ, Wies FA: The use of fresh human serum (complement) in meningococcus meningitis. JAMA
69.Fothergill LRD: Hemophilus influenzae
(Pfeiffer bacillus) meningitis and its specific treatment. N Engl J Med
70.Fothergill LD, Wright J: Influenzal meningitis: The relation of age incidence to the bactericidal power of blood against the causal organism. J Immunol
71.Birkhaug KE: Studies in scarlet fever. II. Studies on the use of convalescent scarlet fever serum and Dochez antistreptococcic serum for the treatment of scarlet fever. Bull Johns Hopkins Hosp
72.Lapin JH: Serum in the prophylaxis of contact and the treatment of whooping cough. J Pediatr
73.Scheinblum IE, Bullowa JGM: The treatment of pertussis with lyophile hyperimmune human pertussis serum. J Pediatr
74.Balagtas RC, Nelson KE, Levin S, et al: Treatment of pertussis with pertussis immune globulin. J Pediatr
75.Wolf AM, Levinson SO: Human serum and plasma: their application in medicine. Med Clin North Am
76.Stokes J, Maris EP, Gellis SS: Chemical, clincical, and immunological studies on the products of human plasma fractionation XI. The use of concentrated normal human serum gamma globulin (human immune serum globulin) in the prophylaxis and treatment of measles. J Clin Invest
77.Balfour HH Jr, Groth KE, McCullough J, et al: Prevention or modification of varicella using zoster immune plasma. Am J Dis Child
78.Brodie M: A comparison between convalescent serum and non-convalescent serum in poliomyelitis. J Exp Med
79.Enria DA, Briggile AM, Sanchez Z: Treatment of Argentine hemorrhagic fever antiviral research. Antiviral Res
80.Zhou B, Zhong N, Guan Y: Treatment with convalescent plasma for influenza A (H5N1) infection. N Engl J Med
81.Chen CY, Lee CH, Liu CY, et al: Clinical features and outcomes of severe acute respiratory syndrome and predictive factors for acute respiratory distress syndrome. J Chin Med Assoc
82.Wang JT, Sheng WH, Fang CT, et al: Clinical manifestations, laboratory findings, and treatment outcomes of SARS patients. Emerg Infect Dis
83.Ho JC, Wu AY, Lam B, et al: Pentaglobin in steroid-resistant severe acute respiratory syndrome. Int J Tuberc Lung Dis
84.Soo YO, Cheng Y, Wong R, et al: Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect
85.Cheng Y, Wong R, Soo YO, et al: Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis
86.Stockman LJ, Bellamy R, Garner P: SARS: Systematic review of treatment effects. PLoS Med
87.Blick G, Scott WF, Crook SW, et al: Passive immunotherapy in advanced HIV infection and therapeutic plasmapheresis in asymptomatic HIV-positive individuals: a four-year clinical experience. Biotherapy
88.Vittecoq D, Mattlinger B, Barre-Sinoussi F, et al: Passive immunotherapy in AIDS: a randomized trial of serial human immunodeficiency virus-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. J Infect Dis
89.Vittecoq D, Chevret S, Morand-Joubert L, et al: 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. Proc Natl Acad Sci
90.Levy J, Youvan T, Lee ML: Passive hyperimmune plasma therapy in the treatment of acquired immunodeficiency syndrome: Results of a 12-month multicenter double-blind controlled trial. The Passive Hyperimmune Therapy Study Group. Blood
91.Stiehm ER, Fletcher CV, Mofenson LM, et al: Use of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin in HIV type 1-infected children (Pediatric AIDS clinical trials group protocol 273). J Infect Dis
92.Jahrling PB, Frame JD, Rhoderick JB, et al: Endemic Lassa fever in Liberia. IV. Selection of optimally effective plasma for treatment by passive immunization. Trans R Soc Trop Med Hyg
93.Jahrling PB, Geisbert JB, Swearengen JR, et al: Ebola hemorrhagic fever: evaluation of passive immunotherapy in nonhuman primates. J Infect Dis
2007; 196(Suppl 2):S400–S403
94.Nour B, Green M, Michaels M, et al: Parvovirus B19 infection in pediatric transplant patients. Transplantation
95.Koduri PR, Kumapley R, Valladares J, et al: Chronic pure red cell aplasia caused by parvovirus B19 in AIDS: Use of intravenous immunoglobulin–a report of eight patients. Am J Hematol
96.Reed EC, Bowden RA, Dandliker PS, et al: Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med
97.Whimbey E, Champlin RE, Englund JA, et al: Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant
98.DeVincenzo JP, Hirsch RL, Fuentes RJ, et al: Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation - a compassionate use experience. Bone Marrow Transplant
100.Center for Disease Control and Prevention: Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep
101.Stokes J, Neefe JR: The prevention and attenuation of infectious hepatitis by gamma globulin: Preliminary note. JAMA
102.Samuel D, Muller R, Alexander G, et al: Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med
103.Engler S, Sauer P, Klar E, et al: Prophylaxis of hepatitis B recurrence after liver transplantation with lamivudin and hepatitis B immunoglobulin. Transplant Proc
104.Centers for Disease Control and Prevention: Human rabies prevention—United States, 2008. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep
105.Kudoyarova-Zubavichene NM, Sergeyev NN, Chepurnov AA, et al: Preparation and use of hyperimmune serum for prophylaxis and therapy of Ebola virus infections. J Infect Dis
1999; 179(Suppl 1):S218–S223
108.World Health Organization, Blood Regulators Network: Position paper on collection and use of convalescent plasma or serum as an element in pandemic influenza planning. Available at http://www.who.int/bloodproducts/brn/en/
. Accessed September 30, 2009
110.Hewetson JF, Little SF, Ivins BE, et al: An in vivo passive protection assay for the evaluation of immunity in AVA-vaccinated individuals. Vaccine
111.Lucchesi PF, Gildersleeve N: The treatment of anthrax. JAMA
112.Casadevall A: Passive antibody administration (immediate immunity) as a specific defense against biological weapons. Emerg Infect Dis
Aug 2002; 8:833–841
This article has been cited 1 time(s).
VaccineNew Wisdom to Defy an Old Enemy: Summary from a scientific symposium at the 4th Influenza Vaccines for the World (IVW) 2012 Congress, 11 October, Valencia, SpainVaccine
influenza; passive; immunotherapy; convalescent; plasma; serum; immunoglobulin; antibody
© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
Highlight selected keywords in the article text.