Convalescent plasma

Convalescent plasma is the blood plasma collected from a survivor of an infectious disease. This plasma contains antibodies specific to a pathogen and can be used therapeutically by providing passive immunity when transfusing it to a newly infected patient with the same condition. Convalescent plasma can be transfused as it has been collected or become the source material for hyperimmune serum or anti-pathogen monoclonal antibodies; the latter consists exclusively of IgG, while convalescent plasma also includes IgA and IgM. Collection is typically achieved by apheresis, but in low-to-middle income countries, the treatment can be administered as convalescent whole blood.

Specific antibodies to a pathogen are thought to be the primary driver of clinical benefit from convalescent plasma. In the case of viral pathogens, the subset of antibodies that retain most of the activity is the one that drives viral neutralization, i.e. neutralizing antibodies, which can be quantified in a viral neutralization assay. This belief is based on dose-response clinical studies demonstrating that clinical benefit is directly related to the content of neutralizing antibodies, and mechanistic studies that have established the antiviral activity of antibodies in convalescent plasma. In addition to higher antibody concentrations being more effective, the timing of therapy is essential. Preparations are typically most effective when given prophylactically or early in the disease course (i.e. until pathogen replication persists or until the infected host's endogenous immune response develops).

In addition to antibodies, convalescent plasma includes a mix of many different proteins and nonprotein factors that can occur in healthy individuals as well as develop in parallel with convalescence. These compounds may affect infection, coagulation, and inflammation independently of the effect of anti-pathogen antibodies. Because convalescent plasma therapy is generally safe, and the effects of neutralizing antibodies dominate the therapeutic response, the current understanding of these potential additional effects is limited and constitutes an area of ongoing research.

In 1890, Emil von Behring and Shibasaburo Kitasato used convalescent serum obtained from large mammals to treat infectious diseases and found that it was particularly effective at preventing and treating diphtheria. Convalescent serum and plasma differ in that the former has all the coagulation components intact, but both are comparable regarding their antibody content. Hence, the older literature is focused on serum while today most preparations use plasma. Following the discovery by von Behring and Kitasato, antibody therapy garnered support worldwide as a treatment for infections. Von Behring was awarded the first Nobel Prize in Physiology or Medicine in 1901 for his discoveries.

Before the development of antimicrobial treatment in the 1930s, antibody therapy in the form of serum therapy were the primary means of treating many bacterial and viral infections. This treatment appears to have reduced the mortality of meningococcal meningitis, pneumonia, and erysipelas. Additionally, antibody therapy seems to have been used successfully to prevent infection after exposure to measles, mumps, and chickenpox.

The 1918 Spanish influenza pandemic was caused by an H1N1 influenza virus of avian origin, and around 500 million people, or one-third of the world's population, became infected with this virus. The Spanish influenza pandemic was the first pandemic in which convalescent plasma was used as a therapy. A 2006 meta-analysis of eight studies from the Spanish influenza pandemic, including 1,703 patients, found that infected patients who received convalescent plasma had a 21% lower absolute mortality risk than patients not treated with convalescent plasma (16% vs. 37%). Consistent with the general treatment principles of antiviral therapy, the most significant clinical and mortality benefits were noted among patients receiving convalescent serum in the early stages of the disease course.

After the introduction of antibiotics, the use of convalescent serum or plasma as a therapy for infectious diseases has been restricted mainly to replacement therapy for patients with immunoglobulin deficiencies or in the context of viral epidemics or pandemics for which no widely available antiviral could be repurposed. Modern use has also included several randomized controlled trials providing conclusive evidence of efficacy. Selected viral epidemics or pandemics in which convalescent plasma has been used are reviewed below.

First identified in 1958, Argentine hemorrhagic fever is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina. Convalescent plasma has been used during Argentine hemorrhagic fever epidemics; a double-blind, randomized clinical trial conducted from 1974 to 1978 demonstrated that patients treated with convalescent plasma within eight days of disease onset had a 15.4% lower absolute mortality rate than patients who received control plasma without neutralizing antibodies to Argentine hemorrhagic fever virus (1.1% vs. 16.5%). Comparable results were described in subsequent outbreaks of Argentine hemorrhagic fever.