key: cord-352985-5ccrkfsa
authors: Putter, Jeffrey S.; Seghatchian, Jerard
title: An Update on COVID-19 Infection Control Measures, Plasma-Based Therapeutics, Corticosteroid Pharmacotherapy and Vaccine Research
date: 2020-09-04
journal: Transfus Apher Sci
DOI: 10.1016/j.transci.2020.102934
sha: 
doc_id: 352985
cord_uid: 5ccrkfsa

This communication provides a compilation on aspects of COVID-19 infection control measures, describes the potential role of therapeutic plasma exchange to reduce fatality rates, addresses precautions concerning dexamethasone pharmacotherapy and updates the current status on the availability of vaccines. As part of passive immunotherapy, it focuses on various blood derivatives. These include coronavirus neutralising antibodies extracted from different sources to be administered as a pure hyper concentrate intramuscularly or for upgrading and standardising the specific potency of high affinity antibodies. These processes are intended to compose standardised pooled bioproducts of corona convalescent plasma/cryosupernatant that are pathogen inactivated for additional safety by well-established UV technologies. For the best practice of optimising plasma exchange, hyper concentrate NAb should be added to the cryosupernatant, which contains some of the active principles of corona convalescent plasma. The cryosupernatant apart from the high molecular weight viscous part of cold insoluble proteins that are removed, is equivalent to CCP, but makes it safer for general application. Such a bioproduct is often used routinely for substitution therapy of thrombotic thrombocytopenic purpura. Alternative resources of large-scale specific coronavirus antibodies warrant further exploration such as cadaveric donations. The early uses of therapeutic plasma exchange and low molecular weight heparin, for any clinical trial in development is warranted, in order to interdict the intense inflammatory/kinin driven cascade. Because coronavirus positive patients are highly prone to thrombosis, thromboprophylaxis is necessary, even some time after recovery guided by the laboratory data.

exchange, hyper concentrate NAb should be added to the cryosupernatant, which contains some of the active principles of corona convalescent plasma.

The cryosupernatant apart from the high molecular weight viscous part of cold insoluble proteins that are removed, is equivalent to CCP, but makes it safer for general application. Such a bioproduct is often used routinely for substitution therapy of thrombotic thrombocytopenic purpura. Alternative We are well cognizant of a nefarious strain of the Coronavirus SARS CoV2 that has been eclipsing the globe causing unprecedented health and economic chaos to the current generation. In a spirit of oneness to combat this marauding infection, we are challenged to develop and harness an arsenal of well-validated tools for the purposes of precision diagnoses, monitoring and treatment. Vigilance in these key areas is critical to protect our national health and economies against a formidable adversary. Currently, a collaboration of all international scientific and medical entities is summoned in an effort to develop effective preventative strategies to slow down the spread of this virus. Equally important are optimising therapeutics to reduce the morbidity and mortality associated with this infection run amok. Certain wellknown interests have sought to downplay the seriousness of the coronavirus problem in order to advance their own political agendas. One notable unsubstantiated allegation is that up to 99% of patient cases are harmless when in reality, the serious illness rate has fluctuated up to 14%. Multiplicities of dangerous complications attendant to the virus, which cannot be ignored, include sepsis, refractory acute respiratory distress syndrome and multi-organ dysfunction and the severe vascular insults of thromboembolism and stroke.

The propagation of the disease is of particular concern to a vulnerable patient population over the age of 65 years and among the ICU patients, wherein mortality rates may exceed 33% for the elderly. Contemporaneously, there are some significant gaps in leadership, often sending misinformation to the public that threatens the capacity to safely reopen. One poignant example is non-compliance in wearing face masks.

There is very fine line between encouraging liberty for all juxtaposed to being responsible members of the society; working in concert to follow the medical guidelines and conscientiously foster public health safety.

Given that the coronavirus has dangerous capacity to cause consequential morbidity and mortality in spite of contemporary therapeutic modalities, we need to aggressively pursue new treatment strategies within our armamentarium, one being therapeutic plasma exchange. As the virus can cause excess inflammatory mediators such as cytokines and chemokines to circulate, in theory it would be advantageous to exchange patients with fresh frozen plasma or convalescent plasma containing a fixed dose of coronavirus neutralising antibody, NAb, if available from a donor.

The perpetuation of the coronavirus onslaught interestingly appears to be non-seasonal in nature and quite pernicious, an apparent continuous wave of infection worldwide. Of special concern to public health officials is the potential devastating impact of other viruses such as influenza in the fall superimposed on the coronavirus plague. This is especially an issue for those that are susceptible, not having received an influenza vaccination. The incidence of coronavirus disease activity in the population appears to fluctuate from partially controlled at lock down to exponential growth of virus dissemination upon opening. The latter problem is thought to be consequent to a lapse in executing effective infection control practices by some noncompliers, with consistency, in the public.

Historically, "passive immunotherapy" has a positive track record as in the treatment of the Ebola virus; these are smaller observational studies but they encourage therapeutic use for coronavirus too [3, 4] . In consideration of the very low risk of complications of plasma exchange therapy, it is a very attractive first treatment option for coronavirus. This is practicable if the usage is standardised, such as the use of (1.) "a minipool of pathogen reduced CCP with an elevated dose of neutralising antibodies from at least two CCP donations" or as a second viable preparation alternative, (2.) namely a homogenous standardised cryosupernatant with a fixed potency of neutralising antibody, as previously proposed by one of us [2] .

In order to apply the use of passive immunotherapy consistently, coronaplasma bioproducts for transfusion exchange should be standardised with respect to the level, potency and avidity of antibodies such as would be advantageous in the processing of minipool convalescent plasma [2] .

Moreover, the antibody levels of CCP can be boosted by hyperimmune COVID antibodies obtainable by using a promising on line affinity column separation methodology or otherwise, as described earlier [2] ; and such a pure hyperimmune coronavirus antibody can be delivered by intramuscular injections with fixed potency and could be prioritised to healthcare workers initially. Alternatively, the above purer hyperimmune products can be used for upgrading the antibody content of the potential pool of CCP or its cryosupernatant, that will be essential as the carrier of such bioproduct in therapeutic plasma exchange (TPE). Incorporating these hyperimmune products in plasma exchange is believed to have potential therapeutic value.

To this end, it is currently indeterminate precisely which components of exchange plasmas might be integral to modulate the hyperinflammatory and hypercoagulable states triggered by the virus.

Exploring further, some large-scale alternative practicable sources of coronavirus neutralising antibodies are warranted for implementation. One possibility is consented cadaveric donations, either from the serum or a pulmonary lavage solution, but clearly in advance of decomposition. Such an approach, if proven to be viable, could alleviate the time and cost-pressure and the need for higher throughput that make developing therapeutic neutralising antibodies at the right dose a real challenge to overcome, given the limited availability of corona convalescent plasma.

Regarding the importance of continual quality and safety improvement strategies related to harvesting corona NAb, all bioproducts for reinfusion need to have pathogen reduction whether used as hyperimmune immunoglobulins or using targeted affinity column processing methods. In fact, this is a current requirement for all human derived bioproducts for which safety practices are already in place. Affinity column processing is a favoured option, to mainly enrich the useful circulatory corona autoantibodies. In concert with the manufacturers, sterilized bioproducts in ampule format could be produced immediately to satisfy demand. It is important to highlight that circulating coronavirus antigen has been identified by RNA assays in some adults who recovered from the infection. As a result of the possibility of a transmissible virus, the implementation of pathogen reduction methodology therefore must become an integral part of all reinfusion programs as highlighted before [1, 2] .

We propose early targeted therapeutic plasma exchange in combination with inflammatory T-cells, monocytes, neutrophils and macrophages. There is thought to be a predisposition to cytokine and/or chemokine release in selected patients triggering a dangerous hyperimmune reaction and associated severe cytopathic effects such as a rapidly progressive pulmonary edema and acute hypercoagulability [11] .

One observation is that patients having the poorest medical outcomes after contracting the infection have a tendency to a higher viral load, an RNAemia as assessed by PCR but not always a consistent finding. Paradoxically, those that develop the highest titers of high affinity antibodies against the virion appear to have the poorest outcomes compared to patients with less severe disease. There is ongoing research into this inter-individual variability in response to coronavirus infection; to determine why these factors appear to be associated with an increased risk of developing a hyperimmune response and heightened allo/autoimmunity in some patients [2, 5] and impairing special T-cell and macrophage function essential for host defenses and recovery from the virus and/or nosocomial infection [7] .

By comparison, it is instructive to reflect historically about the role of corticosteroids and the 2009 influensa A H1N1v outbreak. When studied in that pandemic, very early treatment by corticosteroids of ARDS occurred in a selected cohort of patients, the French registry that specifically excluded confounding comorbidities other than obesity. Statistical analyses showed no medical benefit and yielded poorer outcomes, excess deaths in association with the steroids [8] . This leads us to view extremely cautiously the current recommendation for dexamethasone to treat oxygen dependent COVID-19 patients. Moreover, an endorsement of the use of dexamethasone absent precise guidelines to initiate treatment is of concern. Ostensibly, patient's that would recover absent steroids may receive it anyway and now the ones we propose to protect are exposed to indeterminate risk. Nevertheless, the fact is that vaccines take time to be fully implemented on a large scale globally. Even if any of the trials indicate that such a vaccine is potentially working, a key question is whether there is a durable protective response to promote herd immunity and for how long. It is for this reason that it is more than likely a requirement to implement several different types of effective candidate vaccines and our newer proposal of passive immunity through safer pooled CCP with an upgraded Nab protocol in parallel.

The COVID-19 pandemic has created unique challenges all over the world for infection control. In retrospect, given the easy respiratory transmission of the virus, we should have: (1.) marshalled earlier efforts by the manufacturers to ramp-up production of N95 masks to effectively filter out the virus; and (2.) promoted national educational campaigns on how to properly wear masks. As the virus shall likely linger with us for some years to come, it would clearly be productive to institute these two simple control measures going forward; Current vaccine trials appear promising in the hope to abort the COVID-19 pandemic but are not a panacea. The vaccine is likely to be ineffective for some and non-administered by many for various personal reasons. As a result, we need to encompass a range of therapeutic tools such as TPE, plasma derivatives and well-selected pharmacotherapies to supplant vaccines in order to treat the worst complications of this respiratory viral disease.

A continuous wave of infection is already in place in some parts of Europe and the USA. In the absence of a reliable vaccine, preparation of hyperimmune coronavirus NAb must be pursued consistently and with standardisation from all sources.

Treatment for emerging viruses: Convalescent plasma and COVID-19

Convalescent Plasma, an Apheresis research Project by targeting and motivating the Fully Recovered COVID-19 patients: A rousing message of clinical benefits to both donors/ recipients alike

Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion as an empirical treatment during outbreaks

Ebola virus convalescent blood products: Where we are now and where we may need to go

COVID-19, induced activation of haemostais, and immune reactions: can an auto-immune reaction contribute to the delayed severe complications observed in some patients

Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-1916. RECOVERY trial

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Dexamethasone for COVID-19? Not so fast

Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome

Safety and immunogenicity of the ChAd)x1nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase1/2, single-blind, randomized controlled trial. www.thelancet

Estimating the extent of asymptomatic COVID-19 and its potential for community transmission: systematic review and meta-analysis

Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19)


