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).
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).
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).
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