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Convalescent Blood Products - Serology

September 9, 2020

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History of Medicine
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O positive blood type: the patient's red cells are agglutinated by Anti-D (anti-Rh factor) antisera, but not by anti-A and anti-B antisera. The patient's plasma agglutinates type A and B red cells. Photo credit: by SpicyMilkBoy - Own work, CC BY-SA 4.0, https://commons.wikimedia.org

From the 1880s to the antibiotic era, convalescent blood products (CBP) were used to prevent and treat many bacterial and viral infections in humans and in animal models. In 1890, the first rational approach exploited by the physiologists von Behring and Kitasato to treat diphtheria was blood serum; initially, it was produced from immunized animals but soon whole blood or serum from recovered donors with a specific humoral immunity were identified as a possible source of specific antibodies of human origin. There are several examples of the use of CBP for the prophylaxis or treatment of bacterial infectious diseases such as scarlet fever in the 1920-40s and pertussis until the 1970s.

Emil Behring (1854-1917) had pioneered the technique, using guinea pigs to produce serum. Based on his observation that people who survived infection with the diphtheria bacterium never became infected again, he discovered that the body continually produces an antitoxin, which prevents survivors of infections from being infected again with the same agent. It was necessary for Behring to immunize larger animals in order to produce enough serum to protect humans, because the amount of antiserum produced by guinea pigs was too little to be practical. Horses proved to be the best serum producer, as the serum of other large animals is not concentrated enough, and horses were not believed to carry any diseases that could be transferred to humans.

Due to the First World War, a large number of horses were needed for military purposes. It was difficult for Behring to find enough German horses for his serum facility. He chose to obtain horses from Eastern European countries, mostly Hungary and Poland. Because of Behring's limited financial resources, most horses he selected had been intended for slaughter; however, the usefulness of the animal to others had no influence on the production of serum. Serum horses were calm, well-mannered, and in good health. Age, breed, height, and color were irrelevant.

Horses were transported from Poland or Hungary to the Behring facilities in Marburg, in the west-central part of Germany. Most of the horses were transported by rail and treated like any other freight load. Once the horses arrived in Marburg, they had three to four weeks to recover in a quarantine facility, where data on them was recorded. They had to be in perfect medical condition for the immunization, and the quarantine facility ensured that they were free of microbes which could infect the other horses. In the Behring facilities, the horses were viewed as life savers; therefore, they were well treated. A few of the individual horses used for serum production were named, and celebrated for their service to medicine, both human and non-human.

At the end of the 19th century, every second child in Germany was infected with diphtheria, the most frequent cause of death in children up to 15 years. In 1891 Emil Behring saved the life of a young girl with diphtheria by injecting antiserum for the first time in history. Serum horses proved to be saviors of diphtheria-infected people. Subsequently, treatment of tetanus, rabies, and snake venom developed, and proactive protective vaccination against diphtheria and other microbial diseases began.

In 1901, Behring won the first Nobel Prize in Medicine for his work in the study of diphtheria.

Studies conducted during the Spanish influenza pandemic of 1918 to 1920 suggested that the use of CBP might be effective and for the first time CP was identified as a potential therapy for a number of viral infections. In the following decades, possible therapeutic efficacy was claimed for the management of measles, Argentine hemorrhagic fever, influenza, chickenpox, infections by cytomegalovirus, parvovirus B19 and, more recently, Middle East respiratory syndrome coronavirus (MERS-CoV), H1N1 and H5N1 avian flu, and severe acute respiratory infections (SARI) viruses. Furthermore, animal models of influenza pneumonia have shown the benefit of CS (protection against H1 and H3 challenge), equine hyperimmune F(ab') globulin (protection against H5N1 challenge), and monoclonal antibodies (against H1, H3, and H5N1 challenge). Interestingly, hospitalized patients with Lassa fever were also reported to have an apparently better outcome after CP administration. Furthermore, a meta-analysis on Spanish influenza-CBP (involving 8 suitable studies for a total of 1,703 patients) showed a significantly reduced mortality risk in the treated patients and suggested that CBP could be evaluated in the treatment of H5N1-related diseases.

A 2015 systematic review and exploratory post-hoc meta-analysis by Mair-Jenkins et al. on the effectiveness of CP and hyperimmune Ig for the treatment of SARI of viral etiology reported a statistically significant reduction (75%) in the odds of mortality among SARI-affected patients who were treated in comparison to those who received a placebo or no therapy. Analyses showed “consistent evidence for a reduction in mortality“, especially with early CP administration. However, as studies were “commonly of low or very low quality, lacked control groups, and at moderate or high risk of bias“, the authors claimed that “this therapy should be studied within the context of a well-designed clinical trial or other formal evaluation“, including the treatment of MERS-CoV infection.

As far as concerns CBP in the treatment of hemorrhagic fevers, in 1976 CP was used for a young woman infected with EBOV (Ebola as we know it now) in the Democratic Republic of Congo. The woman was treated, without benefits, with plasma from a person who had survived an infection with the closely related Marburg virus. During the same outbreak, 201 units of CP containing anti-EBOV antibodies (titre of at least 1:64) were obtained and frozen. Two units were transfused to an infected laboratory worker and the subject's recovery suggested the possible therapeutic effect of CP for EBOV patients.

CP was also used to treat patients with Argentine hemorrhagic fever caused by the Junin virus. In a double-blind trial carried out in 1979, patients treated with CP had a lower mortality rate compared to subjects treated with “normal plasma“. An analysis of 23 consecutive annual epidemics of Argentine hemorrhagic fever in a group of 4,433 patients, observed from 1959 to 1983, showed a significant difference in overall mortality between patients managed with conventional treatment or CP (42.85% vs 3.29%). Immunotherapy was also attempted through the passive transfer of immunity with CP from patients who had recovered from Crimean Congo hemorrhagic fever, but the efficacy of this treatment for this disease is still not clear.

Since the first EBOV outbreak in Congo, passive immunization in infected animals (e.g. monkeys) has been obtained with the administration of IgG preparations from horses hyper-vaccinated with EBOV thus suggesting a potential use in humans. In a 1995 outbreak in Kikwit, Zaire, eight patients received 150-400 mL of CWB and seven survived, for a mortality rate of 12.5% in comparison to 80% in untreated patients. However, give the small number of treated patients and the lack of control subjects, the authors recognized the high risk of their work not being representative and involving confounding issues. In 2007, Oswald and colleagues reported a failure of passive transfer to protect macaques against challenge with EBOV. These negative findings contrasted with the above mentioned claimed results in the treatment of EBOV infection and highlighted the need for better comprehension not only of the characteristics and titre of antibodies able to affect the course of diseases but also of the role of the recipients' immune response. In 2012, Dye and colleagues reported that passively transferred species-matched polyclonal IgG were able to provide total protection in Filovirus-challenged non-human primates as well as the maintenance of sufficiently high levels of IgG after multiple administrations until the host's adaptive immune responses could be recruited to clear the viral infection. In the same year, Olinger et al. and Qiu et al. reported that neutralizing anti-EBOV glycoprotein monoclonal antibodies protected monkeys before and after lethal virus challenge.

Sources: ncbi.nih.gov; Wikipedia

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