by Frederick M. Schaffer, M.D., Paul V. Holland, M.D. and James D. Strader, D.C.
COVID-19 cases have been documented in over 188 countries. Unfortunately, many high risk patients develop significant morbidity which in turn may result in death. Both vaccine and effective antiviral medication development are in the research phase. Historically, the treatment of particularly severe viral diseases with convalescent plasma (CP) has shown promise. Thus, due to the current lack of effective therapy, the administration of CP to patients with serious or immediately life-threatening COVID-19 infections has been approved by the FDA as an investigational therapy (1).
The concept of passive immunization (PI) for the treatment of human viral disorders was conceived and implemented more than a century ago (2-6). PI is the process in which short-term immunization against virulent (e.g., viral) pathogens is achieved by the acquisition of anti-pathogen specific antibodies. Since its inception, PI has been a life-saving therapeutic modality.
Convalescent blood products (CBP) collected from patients who have developed humeral immunity are a source of human anti-pathogen antibodies. The transfusion of convalescent plasma (CP) containing high-titer anti-viral neutralizing antibodies can result in viral neutralization and significantly diminish morbidity and mortality.
Historically, studies promulgated during and after the Spanish influenza pandemic of 1918 to 1920 implied that the use of CBP might be effective (2-6). More recently, this therapeutic approach has been effective in the treatment of measles, Middle East respiratory syndrome coronavirus, and H1N1 and H5N1 avian flu (7-11). Furthermore, the results of a meta-analysis pertaining to the clinical outcome of patients with virally induced severe acute respiratory infections who were administered CP and hyperimmune immunoglobulin were informative (12). The analyses demonstrated a significant reduction in the odds of mortality among treated patients with severe acute respiratory infections in contrast to their untreated counterparts (12).
The utilization of CP, in severe viral illnesses may lead to viremia suppression (13). This latter concept is in part manifested by the results of studies that demonstrated in animal models that the administration of a neutralizing antibody to HIV-1 prevented infection and suppressed viremia (14). A subsequent human in vivo trial demonstrated that therapeutic administration of this antibody to HIV-1 infected individuals also significantly reduced the viral load and viremia (15).
Preliminary studies, albeit with low patient numbers, about the efficacy of CP administration to patients with severe COVID-19, are promising. In one study of 10 patients with severe COVID-19 who were administered CP containing high titer neutralizing antibodies, seven patients developed undetectable viremia, improved pulmonary radiologic findings, and improved symptomatology (16). In another clinical study, the outcome of the administration of CP to 5 patients with COVID-19 and acute respiratory distress syndrome was documented. All 5 patients developed an improved clinical status, decreased viral loads and improved pulmonary status (17).
The Acquisition of Convalescent Plasma:
The recruitment of potential convalescent plasma donors is not a simple task. The prospective donors need to meet blood bank donor criteria and have laboratory evidence of a recent COVID-19 infection (1). Furthermore, the convalescent plasma may need testing to document a high titer viral neutralizing antibody content before use (1). The FDA has recommended utilizing plasma containing neutralizing antibody titers of at least 1:160 or if not available, then a plasma with a titer of at least 1:80. To reduce the risk of any plasma transmissible pathogens, the use of pathogen inactivated plasma is standard practice. The FDA has issued guidelines on May 1, 2020 for the administration of convalescent plasma to patients infected with COVID-19 (1). One administration pathway encompasses the use of an expanded protocol to acquire access to COVID-19 CP. This access may become available for use by acute care facilities in an expanded access protocol under an IND that is already in place. The FDA has also facilitated access to COVID-19 CP in response to a physician’s request for possible administration to patients with serious and/or immediate life-threatening COVID-19 infections. This is facilitated by the physician requesting a single patient emergency IND under 21 CFR 312.310 (see refer. 1 for specifics). Physicians requesting an emergency IND may review the patient eligibility criteria of the National Expanded Access Treatment Protocol External Link Disclaimer which delineates specific diagnostic and disease severity criteria (1).
Laboratory Evidence of a previous COVID-19 Infection:
Prospective CP donors must be screened by a diagnostic test such as that generated from a laboratory RT-qPCR study result from a nasopharyngeal swab collected from the donor at the time of his or her illness. Alternatively, if prior diagnostic testing was not done though COVID-19 was suspected or if the results were equivocal, then after recovery, the confirmatory positive results of a SARS-CoV-2 serologic antibody test is required (1). The utilization of an antibody serologic test with a high sensitivity and high specificity is recommended. Such a candidate test is the BioHit SARS-CoV-2 IgM/IgG antibody test kit. This test is rapid, reliable, simple to perform, can be completed at the point of care facility (with access to a high-complexity CLIA-compliant lab), and results can be available in 15 minutes or less. This is a rapid, point of care, qualitative IgM and IgG antibody test kit. The recommended use of an assay with a high specificity and selectivity is manifest in that the Biohit assay for IgG has a 100% sensitivity and a 99.7 to 100% specificity while the IgM assay has a 100% sensitivity and a 97.6 to 99.1% specificity (18).
If prospective CP donors did not undergo early diagnostic (qRT-PCR) testing, the serologic antibody test remains the most effective assay after recovery from a COVID-19 infection. Specifically, viral detection is no longer possible after clinical recovery (19). Previous studies have demonstrated that RT-qPCR based viral identification significantly decreases after 18 to 25 days of disease onset (20-22). Whereas, antibody seroconversion from IgM to IgG typically occurs between 11 and 14 days after disease onset with IgG detectable for up to 35 days after symptom onset and peaking during or after clinical recovery (19) As a matter of fact, in part due to the long half life of IgG, it is detectable for many months to years after clinical recovery (19).
The utilization of the Biohit SARS-CoV-2 IgM/IgG antibody test kit can play an integral role in the selection of CP donors and thus, its use will assist in diminishing the morbidity and mortality associated with COVID-19 infections.
- FDA: Recommendations for Investigational COVID-19 Convalescent Plasma
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