Use of Convalescent Plasma Collected From Donors Recovered From COVID-19 Virus Disease for Transfusion, as an Empirical and Preemptive Treatment During Viral Pandemic Outbreak
Phase: PHASE2
Conditions: COVID
Sponsor: Northside Hospital, Inc.

1 
 
 
 
 
 
 
 
 
 
 
 
Use of Convalescent Plasma Collected From Donors Recovered From COVID-19 Virus 
Disease for Transfusion, as an Empirical and Preemptive Treatment during Viral 
Pandemic Outbreak 
 
Principal Investigator:  
H. Kent Holland, MD 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol version: 
 
12/7/2020 
 
 
 
 

2 
 
Protocol Summary 
 
Study Title:  Use of Convalescent Plasma Transfusion, Collected From Donors Recovered 
From COVID-19 Virus Disease, as an Empirical and Preemptive Treatment during Pandemic 
Outbreak 
Phase II 
Expected Numbers of Patients:   
Group 3: High risk patients  
n=159 
Group 4: Health Care Providers 
n=152  
 
Study Objectives:   
 
1. 
To transfuse COVID-19 infected patients with convalescent plasma and to 
observe whether this will result in a significant improvement in clinical outcome in 
comparison to historical experience.  Patients eligible include the following study groups: 
 
Group 3:  As preemptive therapy for High Risk Patients who present with mild or non-
severe COVID-19 infection. 
Group 4:  As preemptive therapy for health care providers who have developed 
asymptomatic, mild or non-severe COVID-19 infection. 
 
a. Primary objective is whether infusion of convalescent plasma will reduce the probability 
of progressing to severe or critical disease significantly lower than the reported case rate 
(for Group 3 and 4, respectively).  
 
b. Secondary objectives are to determine if infusion of convalescent plasma will impact 
the patient’s clinical course including days in hospital, days requiring ICU care, days on 
mechanical respirator/BIPAP, days on non-mechanical oxygen support, days with 
pneumonia, fever, and viral clearance.   
 
Overview of Study Design 
As of late 2019, the world population has been threatened by a life-threatening novel severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is abbreviated COVID-19.  This 
virus is a new human pathogen with no known treatment available.  Currently, there are no 
vaccines, monoclonal antibodies (mAb) or drugs available for COVID-19.  While it is hoped 
that new drugs and vaccines will be developed and proven efficacious, these efforts will take 
many months to develop and test in clinical trials. Antimicrobial and immune modulating 
medications that are approved for other indications are being tested in clinical trials with the 
hope of abrogating the disease’s progression to severe cardiopulmonary injury, but to date 
have not been shown to have definitive benefit.  While there is no proven treatment available 
for COVID-19 virus disease, plasma collected from patients in the convalescent phase of 
infection has been used as an empirical treatment during viral pandemics for over one-hundred 
years with well documented benefit in reducing morbidity and mortality.1,2  Most Individuals 
who recover from the viral infection develop humoral immunity with neutralizing antibodies that 
may persist for years.  Collection of convalescent plasma and transfusion into an infected 
patient transfers immediate passive immunity, which was the only means to treat infections 
prior to the development of modern vaccine therapy.  Not all patients benefit from convalescent 
plasma.  Experience would indicate that the earlier in the course of illness convalescent 
plasma or immunoglobulin therapy was administered, the more likely benefit will be observed 

3 
 
with the highest benefit when used as prophylactic therapy. 
 
In the past two decades there have been two epidemics with coronavirus that resulted in high 
mortality, SARS-1 in 2003 and Middle East respiratory syndrome (MERS) in 2012.  The latter 
infections became an epidemic in the Middle East and triggered a secondary outbreak in South 
Korea.  Due to the high mortality and lack of an effective therapy, convalescent plasma was 
utilized.  The largest report involved 80 patients with severe SARS disease in Hong Kong.9  
For patient who received convalescent plasma transfusion prior to day 14 of the infection have 
an improved prognosis and an earlier hospital discharge prior to day 22 (58.3% vs 15.6%, 
P<.001).  The mortality rates in the two groups were 6.3% and 21.9%, respectively.  This 
observation is consistent with the prior historical observations that earlier administration in the 
course of the infection is more likely to be effective.   
 
China has offered convalescent plasma therapy for 245 COVID-19 patients, and 91 cases 
have shown improvement in clinical indicators and symptoms, per press report.3  Treatment 
of five critically ill patients in China with COVID-19 and acute respiratory distress syndrome 
(ARDS) with convalescent plasma was followed by resolution of ARDS in 4 patients within 9 
days following transfusion.4  Of the 5 patients 3 had been discharged and 2 were in stable 
condition at 37 days post-transfusion.  In a third report, 10 patients with severe COVID-19 
infection received one dose of convalescent plasma derived from recently recovered donors.5  
The primary endpoint was safety of plasma infusion and secondary endpoint was efficacy.  
Clinical symptoms improved along with improved oxygenation within 3 days of transfusion.  
The viral load was undetectable after transfusion in the seven of seven patients who had 
detection pretreatment at a median of 3 days (2-6 days).  Cytokine surrogate marker, C-
reactive protein, fell from a median before transfusion of 55.98 mg/L (nl range 0 – 6) to 18.13 
following the treatment.  No serious adverse reactions or safety events were recorded. 
 
Group sequential design is employed for each hypothesis that analysis will be performed after 
enrolling and observing outcomes of one-third of maximum sample size. Our design includes 
two interim analyses and a final analysis for each hypothesis. The Pocock method is used to 
determine sample size and each study is sized to maintain the power of 80% and overall type 
I error 5%. To calculate the sample size, the large-sample Z test for a proportion is utilized for 
each analysis.  The maximum number of enrollment for the four groups are:  Group 1: 81, 
Group 2: 423, Group 3: 228 and Group 4: 219.  Due to the likelihood that we may terminate a 
study for efficacy after an interim analysis, the expected numbers of enrollment for the four 
groups are 56, 296, 152 and 152, respectively. 
 

4 
 
 
Study Population:  Eligible patients will be 18 years or older and must have a  positive test 
result forCOVID-19 infection toand meetthe inclusion criteria described in Section 4.1  
 
Duration of Study:  24 months 
 
Participant Duration:  30 days or in the case of hospitalization, upon discharge; whichever 
is longer. 
 
Schema:  Convalescent Plasma Treatment for COVID-19 Infection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definitions: 
COVID-19 severity categories: 
• Mild – No pneumonia but with typical symptoms such as fever, dry cough, fatigue, nausea, emesis 
or diarrhea. 
• Non-severe – Radiographic changes compatible with viral PNA, but no signs of respiratory 
compromise or hypoxemia. 
• Severe – Respiratory compromise with one of the following: Tachypnea with RR ≥30, O2 Sat ≤93% 
at rest, Pa02/Fi02 index ≤ 300 mmHg 
• Critical – One of the following: requiring mechanical ventilation, requiring pressor support, multi-
organ failure. 
 
Patient Risk Category: 
High risk: 
• Immunocompromised (e.g. neutropenia, h/o hematopoietic stem cell transplant (<3 months post-
autologous transplant, <6 months post-allogeneic transplant), on systemic immunosuppression, 
h/o solid organ transplant, Cancer patient receiving active chemotherapy, insulin dependent 
diabetes mellitus, poorly controlled HIV, moderate or severe asthma history, serious heart 
condition, ESRD on hemodialysis, morbid obesity, moderately severe or greater COPD. 
• Age ≥ 65 years 
 
 
 
 
 
Confirmed COVID-19 
Mild or Non-severe 
Health Care Worker 
Low Risk  
High Risk 
Yes 
No 
Yes  

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Contents 
 
 
1.0 
Study Rationale 
 
 
1.1 
Background and Rationale 
  
1.2 
Clinical Characteristics 
  
1.3      High Risk Clinical Characteristics 
  
1.4  
Convalescent Plasma Information 
  
1.5  
Risks and Benefits of Convalescent Plasma Therapy 
  2.0      Study Objectives 
  
2.1 
Eligible Groups 
  
2.1 
Collection from Eligible Donors 
 
3.0  
Study Design 
 
 
3.1  
Overview of Study 
 
 
3.2 
Number of Patients  
 
 
3.3 
Duration of Study 
 
 
3.4 
Participant Duration 
4.0 
Study Population 
4.1  
Inclusion Criteria  
4.2 
Exclusion Criteria  
5.0 
Treatment Plan and Convalescent Plasma 
 
5.1   
Consented Patients 
 
5.2   
Discontinuation of Study Intervention 
 
5.3   
Participant Discontinuation/Withdrawal  
 
5.4   
Lost to Follow-Up 
6.0 
Statistical and Quantitative Analysis 
 
6.1 
Determination of Sample Size 
 
6.2  
Secondary Endpoints 
 
6.3 
Statistical Analysis 
7.0 
Adverse Event Reporting 
 
7.1  
Definition 
 
7.2 
Procedure for Reporting Serious Adverse Events 
 
8.0 
Administrative Requirements 
 
8.1  
Good Clinical Practice 
 
8.2 
Ethical Considerations 
 
8.3 
Patient Information and Informed Consent 
 
8.4  
Patient Confidentiality 
 
8.5 
Investigator Compliance 
 
8.6 
Investigator and Site Responsibility 
 
8.7 
Closure of Study 
 
8.8 
Record Retention 
 
8.9 
COVID-19 Convalescent Plasma Products 
9.0 
References 
 
 
 

6 
 
1.0 
Study Rationale 
Convalescent plasma has been utilized for over one-hundred years for the empirical treatment 
of viral pandemics and has been reported to reduce duration of symptoms and mortality risk.  
Preliminary evidence indicates that convalescent plasma may possibly be of benefit for some 
patients with COVID-19, leading to clinical improvement.  
1.1 Background and Rationale 
 
1.1.1 Introduction 
 
Since the early twentieth century convalescent plasma has been used during pandemics 
including the 1918 H1N1 Influenza virus pandemic (Spanish Flu),vi poliomyelitisvii, measles,viii,ix 
mumps,x 2009-2010 H1N1 Influenza virus pandemic,xi SARS-1 in 2003xii,xiii and Middle East 
respiratory syndrome (MERS) in 2012.xiv,xv  The most recent example is the West Africa Ebola 
epidemic, which was associated with a high mortality risk with no known drug or vaccine 
therapy.  A small nonrandomized trial demonstrated significantly improved survival for those 
who received convalescent whole blood, and two patients urgently transferred to the United 
States and treated with a combination of convalescent plasma survived.xvi,xvii,xviii  
 
While every viral disease and epidemic are different, immunological responses are similar and 
these historical precedents provide both reassuring and useful data in developing a treatment 
protocol using convalescent plasma for COVID-19 disease. 
 
1.1.2 Rationale for using COVID-19 convalescent plasma 
Experience with the use of convalescent plasma against coronavirus 
diseases 
 
In the past two decades there have been two epidemics with coronavirus that resulted in high 
mortality, SARS-1 in 2003 and Middle East respiratory syndrome (MERS) in 2012.  The latter 
infections became an endemic in the Middle East and triggered a secondary outbreak in South 
Korea.  Due to the high mortality and lack of an effective therapy, convalescent plasma was 
utilized.  The largest report involved 80 patients with severe SARS disease in Hong Kong.9  
For patient who received convalescent plasma transfusion prior to day 14 of the infection have 
an improved prognosis and an earlier hospital discharge prior to day 22 (58.3% vs 15.6%, 
P<.001).  The mortality rates in the two groups were 6.3% and 21.9%, respectively.  This 
observation is consistent with the prior historical observations that earlier administration in the 
course of the infection is more likely to be effective. Convalescent plasma given to three 
patients in Taiwan with severe SARS disease resulted in reduction the serum virus titer and 
each survived.10 
 
China has offered convalescent plasma therapy for 245 COVID-19 patients, and 91 cases 
have shown improvement in clinical indicators and symptoms, per press report.xix  Treatment 
of five critically ill patients in China with COVID-19 and acute respiratory distress syndrome 
(ARDS) with convalescent plasma was followed by resolution of ARDS in 4 patients within 9 
days following transfusion.xx  Of the 5 patients 3 had been discharged and 2 were in stable 
condition at 37 days post-transfusion.  In a third report, 10 patients with severe COVID-19 
infection received one dose of convalescent plasma derived from recently recovered donors.xxi  
The primary endpoint was safety of plasma infusion and secondary endpoint was efficacy.  
Clinical symptoms improved along with improved oxygenation within 3 days of transfusion.  
The viral load was undetectable after transfusion in the seven of seven patients who had 
detection pretreatment at a median of 3 days (2-6 days).  Cytokine surrogate marker, C-
reactive protein, fell from a median before transfusion of 55.98 mg/L (nl range 0 – 6) to 18.13 
following the treatment.  No serious adverse reactions or safety events were recorded. 

7 
 
 
 
 
 
Figure 1. Schematic of the use of convalescent sera for COVID-19. An individual who is 
sick with COVID-19 and recovers has blood drawn and screened for virus-neutralizing 
antibodies. Following identification of those with high titers of neutralizing antibody, serum 
containing these virus-neutralizing antibodies can be administered in a prophylactic manner 
to prevent infection in high-risk cases, such as vulnerable individuals with underlying medical 
conditions, health care providers, and individuals with exposure to confirmed cases of COVID-
19. Additionally, convalescent serum could potentially be used in individuals with clinical 
disease to reduce symptoms and mortality. The efficacy of these approaches is not known, 
but historical experience suggests that convalescent sera may be more effective in preventing 
disease than in the treatment of established disease.2 
 
1.2 Clinical Characteristics of COVID-19 Disease 
 
In the largest published review from Wuhan China, 1099 patients were followed with confirmed 
COVID-19 infection.xxii  A primary composite end-point event occurred in 67 patients (6.1%), 
including 5% who were admitted to the ICU, 2.3% who underwent invasive mechanical 
ventilation, and 1.4% who died.  The majority of patients (58%) received intravenous antibiotic 
therapy and oxygen was administered in 41.3% of patients.  CT radiograph was performed on 
975 patients and it showed ground-glass opacities in 56.4%, local patchy shadowing in 41.9% 
and bilateral patchy shadowing in 51.8% and interstitial abnormalities in 14.7%.  Chest 
radiographs were performed in 274 patients and abnormalities were documented in 59.1% 
(20.1%, 28.1%, 36.5% and 4.4%; respectively).  In severe cases, radiographic abnormalities 
were seen on CT study in 94.6% of patients.  For hospitalized patients, fever was present in 
88.1% of non-severe and 91.9% of severe patients. 
 
A total of 173 patients were classified as having severe disease per the guidelines of the 
American Thoracic Society guidelines.xxiii  For those 926 that presented with non-severe 
disease, 35.7% required oxygen, 2.4% required ICU admission and none required mechanical 
ventilation.  For those with severe disease, 71.1% required oxygen therapy, 19.1% were 
admitted to the ICU and 38.7% required mechanical ventilation.  The median length of hospital 
stay for the non-severe was 11 days (10-13) and for the severe 13 days (11.5-17).  Death 
occurred in 0.1% of the patients with non-severe disease and 8.1% of patients with severe 
disease. For patients presenting with severe disease 71.1% required oxygen therapy, 15.6% 
developed acute respiratory distress syndrome, admission to the ICU was 19.1%, 38.7 percent 
required mechanical ventilation (14.5% invasive and 32.4% noninvasive) and median hospital 
duration was 13 days. 
   
Correlate laboratory studies included C-reactive protein that was elevated above 10 mg/L in 
81.5% of those with severe disease and in 56.4% with non-severe disease.  Procalcitonin 

8 
 
greater than 0.5 ng/mL was seen in only 3.7% of those with non-severe disease and 13.7% 
with severe disease presentation. 
 
In a larger report from Chinese Center for Disease Control and Prevention of 72,314 cases 
14% presented with severe disease that was defined as dyspnea, respiratory frequency > 30, 
blood oxygen saturation < 93%, partial pressure of arterial oxygen to fraction of inspired 
oxygen ratio < 300, and/or lung infiltrates >50% within 24-48 hours.xxiv  Critical disease 
developed in 5% that resulted in respiratory failure, septic shock and/or multi-organ failure.  In 
this report the case fatality rate (CFR) was 8.0% in patients age 70-79, 14.8% in patients over 
age 80, and 49% in critical cases.  CFR was elevated among those with preexisting comorbid 
conditions:  10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory 
disease, 6.0% for hypertension and 5.6% for cancer.  A total of 1,716 infected were health 
care workers.  Overall, 14.8% of health care workers developed severe or critical disease, and 
5 deaths were observed.xxv 
 
1.3 High Risk Clinical Characteristics of COVID-19 Disease 
 
High risk groups for developing severe COVID-19 infection have been defined by the Center 
of Diseases and Control Prevention (CDC) and include:xxvi 
 
 
 
Persons 65 years and older 
 
Chronic Lung disease  
 
Moderate to Severe Asthma 
 
Serious Heart Conditions 
 
Immunocompromised patients (including undergoing cancer treatment, bone 
marrow or organ transplantation, immune deficiency diseases, poorly controlled 
HIV or AIDS, prolonged use of corticosteroids and other immune weakening 
medications (e.g. cyclosporine, tacrolimus, etc.) 
 
Severe obesity (BMI of 40 or higher) 
 
Diabetes  
 
Chronic Kidney disease and undergoing dialysis 
 
Liver Disease 
 
On 3/26/2020, the FDA release selection criteria for COVID-19 disease to be eligible for donor 
convalescent plasma who met their definition for severe disease or immediately life-threatening 
status.   
 
Severe disease is defined as: 
 
Dyspnea 
 
Respiratory frequency > 30/min 
 
Blood oxygen saturation < 93% 
 
Partial pressure oxygen to fraction of inspired oxygen ratio <300, and/or 
 
Lung infiltrates > 50% within 24 to 48 hours 
 
Life-threatening disease is defined as: 
 
Respiratory failure 
 
Septic shock, and/or 
 
Multiple organ dysfunction or failure 
 
 
1.4 Convalescent Plasma Information 
 
Convalescent Plasma may be collected by either apheresis (often in combination with 
concurrent platelet apheresis collection) or via traditional phlebotomy followed by centrifuge 

9 
 
separation.  For purposes of being able to safely expedite and optimize plasma donation for 
an otherwise healthy donor apheresis is the preferred procedure. 
 
Donors must undergo screening as per guidelines set out by the FDA for collection of COVID-
19 Convalescent Plasma.  
 
We have previously initiated an IRB approved Convalescent Plasma Donor Program and are 
actively recruiting donors.  Donors are being recruited in collaboration with the Georgia 
Department of Public Health, hospital epidemiology program and through public outreach.  
Donors are having sample(s) of their sera stored.  Currently, quantitation of IgG Ab titers 
against COVID-19 is not available.  Once testing is approved and commercially available 
potential donors will have their IgG Ab titers measured.   
 
1.5 
Risks and Benefits of Convalescent Plasma Therapy 
 
It is anticipated that the risks associated with the infusion of convalescent donor plasma will 
be low, and of those events, most are expected to be of low grade (Grade 2 or less) 
severity.xxvii,xxviii,xxix  The most common observed risk is allergic transfusion reaction (ATR) that 
has an estimated frequency of <1% - 3% of all transfusions.xxx,xxxi  Most ATR are mild and 
limited to urticarial rash, pruritis, flushing and/or fever.  These are generally reversible events.  
Rare side effects include anaphylactic allergic reactions characterized by bronchospasm, 
angioedema and/or hypotension; and have an estimated frequency range from 1:591 to 
1:2,184 plasma units transfused.  Antibodies to human IgA that are passively transfused in the 
plasma into IgA deficient patients can cause dramatic anaphylactic reactions mediated by 
complement activation to small amounts of plasma containing IgA proteins.  The prevalence 
ranges from 1:100 to 1:1000 in Caucasian, African American and Middle Eastern 
populations.xxxii   
 
Transfusion associated adverse effects include transfusion related acute lung injury (TRALI). 
and transfusion associated circulatory overload (TACO).xxxiii,xxxiv  The incidence of TRALI is 
rare with an estimated incidence 1:12,000 transfusions since deferring female donors with 
HLA alloantibodies.  TRALI is characterized by acute hypoxemia and noncardiogenic 
pulmonary edema within 6 hours of transfusion.  Majority of patients recover within 72 hours, 
but there is a reported mortality rate of 5%-25%.xxxv,xxxvi  TACO is similar to TRALI in that it is 
also characterized by acute respiratory distress, hypoxia and pulmonary edema; however, the 
edema is due to hydrostatic pressure changes that is associated with acute rise in BNP; and 
is not due to immune reaction and passive permeability edema.xxxvii  The incidence of TACO 
ranges from <1% to 8%.xxxviii,xxxix  Patients generally respond promptly to medication to promote 
diuresis, but the mortality risk has been reported to be 5%-15%.xl  Risk factors include older 
and young patients, preexisting cardiac and/or renal dysfunction.  BNP should be part of the 
investigation to ascertain whether TACO adverse effect has occurred.xli  Because the majority 
of non-severe, severe and critical COVID-19 patients receiving convalescent donor plasma 
will have pulmonary infiltrates and require oxygen support, it will be difficult to ascertain 
whether an acute change in respiratory status is the result of the plasma infusion.  As part of 
the study entry evaluation, BNP lab test is recommended pre-transfusion. If BNP is 
significantly elevated, then it may place the patient at higher risk for developing TACO.  Clinical 
judgement regarding the use of concurrent diuretic therapy, whether to transfuse the plasma 
over a longer interval, or to defer the transfusion will need to be considered by the treating 
physician.   
 
Other rare adverse events include acute hemolytic transfusion reaction and sepsis, the latter 
from bacteria growth in the product.xlii  The latter is unusual in plasma products as they are 
either frozen or refrigerated shortly after collection.  Hypotensive reactions may occur, and a 
specific risk has been associated with patients receiving angiotensin-converting enzyme 
inhibitors.xliii,xliv  A patient with a suspected acute transfusion reaction should have the following 
performed:  stop the transfusion and return bag for a transfusion reaction workup, confirmation 

10 
 
that the correct product was infused.  Risk of infectious disease transmission is extremely low 
due to FDA required extensive donor medical screening and infectious disease testing.  The 
estimated risk for acquiring HIV, HCV and HBV through transfusion is 1:1,467,000, 
1:1,149,000 and 1:280,000 donations, respectively.   
 
Hypothetical concerns regarding the use of convalescent plasma include the phenomenon of 
antibody-dependent enhancement of infection (ADE).  For coronaviruses, several 
mechanisms for ADE have been described and there is the theoretical concern that antibodies 
to one type of coronavirus could enhance infection to another viral strain.xlv  Because 
convalescent plasma will have titers of neutralizing antibody against COVID-19, ADE is not 
anticipated to develop. The anecdotal report of the use of convalescent sera in patients with 
SARS1 and MERS, and evidence from its use in 245 patients with COVID-19 acute infection 
suggest it is safe and has not resulted in ADE.  Another hypothetical concern is that the use 
of convalescent plasma may suppress the hosts humoral immune response, thereby, leaving 
the patient vulnerable to subsequent reinfection.  There is no data to substantiate this concern 
in prior use of convalescent plasma for coronavirus diseases.  There is also the risk that 
convalescent plasma for COVID-19 infection may be ineffective. 
 
The potential benefits of administering convalescent plasma have been outlined in Section 
1.1. The infusion of convalescent plasma will likely provide immediate passive neutralizing 
antibodies against the virus. Historical observations for other viral pandemic infections have 
demonstrated lower risk for morbidity and mortality.  Investigators have shown correlation of 
rapid reversal of inflammatory response to the infection and cytokines following infusion of 
convalescent plasma for the SARS Coronavirus. In the recent report from China, 245 patients 
were given convalescent plasma and it was concluded that approximately 35% showed clinical 
benefit.  It is hoped that the administration of convalescent plasma to the study patients will 
reduce the severity and duration of the infection, and the risk for death. 
2.0 
Study Objectives 
2.1 
To transfuse COVID-19 infected patients with convalescent plasma and to observe  
whether this will result in a significant improvement in clinical outcome in comparison 
to historical experience.  Patients eligible include the following study groups: 
 
Group 3:  As preemptive therapy for high-risk patients who present early with mild or non-severe 
COVID-19 infection. 
 
1.1.2.1 
Primary objective is whether this will reduce the probability of progressing to 
severe or critical disease significantly lower than the reported case rate (for 
Group 3 and 4, respectively). 
 
1.1.2.2 
Secondary objectives are to determine if this will impact the patient’s clinical 
course including days in hospital, days on non-mechanical oxygen support, 
days with pneumonia and/or fever, days requiring ICU care, days on 
mechanical respirator/BIPAP, and death.  Corollary laboratory studies will 
include days to viral clearance. 
 
Group 4:  As preemptive therapy for health care providers who have developed asymptomatic, 
mild or non-severe COVID-19 infection. 
 
1.1.2.3 
Primary objective is whether this will result in a lower risk of developing 
severe COVID-19 disease. 
 
1.1.2.4 
Secondary objectives are to determine if this will impact the patient’s clinical 
course including days in hospital, days requiring ICU care, days on 
mechanical respirator/BIPAP, days on non-mechanical oxygen support, days 
with pneumonia and fever.  Corollary laboratory studies will include days to 

11 
 
viral clearance. 
 
3.0 Study Design 
 
3.1   Overview of Study 
 
COVID-19 infected patients will be screened per selection criteria shown in the Objectives and 
Study Population Sections.  All patients must have confirmed COVID-19 disease and meet 
the inclusion and exclusion criteria established.  Eligible patients for study after completing 
consenting process will be stratified into 4 treatment groups. 
 
3.1.1  Primary and Secondary Endpoints and Efficacy Assessments 
 
The primary endpoint of the study will be: 
1) progression to severe disease for those with high-risk disease that present with     
mild/non-severe disease, and 
2) progression to severe disease for health care workers who present with 
asymptomatic, mild or non-severe disease. 
 
Secondary endpoints will include: 
1) Acute care facility/hospital length of stay 
2) Number of days requiring oxygen support 
3) Number of days in an intensive care unit 
4) Number of days on mechanical ventilation (invasive, noninvasive and ECMO) 
5) Incidence of viral disease associated cardiomyopathy 
6) Incidence of multi-organ dysfunction/failure 
7) Safety of transfusion—Incidence of severe adverse events 
 
3.1.2  Study Entry:  Time from COVID-19 Infection Onset 
 
3.1.2.1  High Risk group:  Entry within 14 days of COVID-19 infection documentation. 
 
Patients in the High-Risk group must present with either mild or non-severe disease for 
to be eligible for study entry; thereby, being identified early in the infection.  These 
patients are to be entered and consented within 14 days of symptomatic COVID-19 
infection documentation.  Mild symptoms could include typical symptoms such as fever, 
dry cough, fatigue, nausea, emesis or diarrhea 
 
3.1.2.2  Health Care Providers group:  Healthcare worker must present with 
asymptomatic and with a positive NP swab; or  mild or non-severe disease for to be 
eligible for study entry; thereby, being identified early in the infection.  Asymptomatic 
patients must be enrolled within 14 days of the positive COVID-19 test.  Mild or non-
severe must be enrolled within 14 days of symptomatic infection documentation. 
 
3.1.3 Additional Considerations for Study Design 
 
 
3.1.3.3  Repeat testing for COVID-19 via nasal pharyngeal swab will be performed 
at 7 days and 14 days following infusion of convalescent plasma in all patients.   
 
3.1.3.4  When available, serology testing for COVID-19 neutralizing antibodies 
will be measured prior to transfusion of convalescent plasma and again between 
21 to 30 days following study entry (if test not available, sera sample(s) will be 
collected and stored).   

12 
 
 
3.1.3.5  Data for secondary objective endpoints will be collected and analyzed, 
including Charlson comorbidity index, KPS, and concurrent immunosuppressive 
therapy. 
 
3.2 Number of Patients 
 
The number of patients expected per each of the 2 groups: 
 
Group 3: High Risk: 
 
n=159 
Group 4: Health Care Providers: n=152 
 
3.3 Duration of Study 
 
Enrollment is expected to last for at least 48 months.  This may be less or longer 
depending upon the pandemic outbreak patterns for recurrent flares infection peaking 
within the community.   The study may be curtailed early if an effective vaccine is 
developed and there has been wide spread immunization.  
 
3.4 Participant Duration 
 
Participation in this study will last 30 days.  For patients in the hospital longer than 30 
days, the date of discharge will be noted regardless of the time.     
4.0 Study Population 
 
4.1 Inclusion Criteria for the selection of COVID-19 Infected Patients for    Convalescent 
Plasma Transfusion 
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
1. Age > 18 years 
2. Documented COVID-19 infection with nasal pharyngeal sampling test by real time 
reverse transcription polymerase chain reaction (rRT-PCR), or nucleic acid 
amplification technology (NAAT) molecular testing.  A partial list of available tests can 
be accessed at https://www.fda.gov/medical-devices/emergency-situations-medical-
devices/emergency-use-authorizations 
3. Have COVID-19 Disease criteria that meets one of the 2 following groups: 
 
 
4.1.1 Group 3:   High Risk Patients with Mild or Non-severe Disease 
1. Mild Disease:  upper respiratory symptoms, cough, gastrointestinal symptoms 
(emesis, diarrhea, abdominal pain) or fever; but no radiograph evidence for viral 
pneumonitis. 
2. Non-severe Disease:  Chest radiographic changes compatible with COVID-19 
disease, but no signs of respiratory compromise or hypoxemia. 
3. High Risk condition must include one of the following:  Immunocompromised (e.g. 
neutropenia, active chemotherapy for cancer or hematological malignancy, less 
than 12 months after undergoing allogeneic hematopoietic stem cell transplant or 
100 days from autologous hematopoietic stem cell transplant, on systemic 
immunosuppressive therapy, history of solid organ transplant and poorly 
controlled HIV disease (e.g. CD4, 250/uL, recurrent opportunistic infections), 
insulin dependent diabetes mellitus, moderate to severe asthma history, severe 
COPD (DLCO < 60), morbid obesity (BMI > 40),age > 65 years, hypertension, 
moderate or severe cardiac disease (eg. Cardiomyopathy, CHF, moderate or 

13 
 
severe valvular stenosis, ischemic heart disease), patients with severe renal 
disease (e.g. on dialysis), or liver disease 
4. Informed consent signed within 14 days of symptoms developing for mild disease.  
For patients in the non-severe cohort, the time to consent must be within 14 days 
of positive chest x-ray or 14 days of first symptom whichever is longer (maximum 
14 days to enrollment). 
 
4.1.2 Group 4:   Health Care Providers with asymptomatic, mild or non-severe 
disease 
1. Health care providers who as part of their activities from time to time are at 
risk to exposure to COVID-19 infection.  This includes administrative staff and 
ancillary support staff associated with hospitals or ambulatory clinic facilities. 
2. Asymptomatic is defined as having diagnosis of COVID-19 without symptoms 
or clinical findings. 
3. Mild or non-severe disease:  Refer above for definitions. 
4. Informed consent signed within 14 days positive COVID-19 test. 
 
     4.2  Exclusion Criteria for Selection of COVID-19 Patients 
 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Known history of IgA Deficiency 
2. History of anaphylactic reaction to blood product transfusion including 
hypersensitivity to immunoglobulin therapy. 
5.0 Treatment Plan and Convalescent Plasma 
 
5.1 Treatment plan for patients consented to receive convalescent COVID-19 donor 
plasma 
5.1.1 Lab and Clinical Studies Pre-Transfusion (may be completed 72 hours before 
consent) (results are not required to be available prior to patient eligibility/administration of 
convalescent plasma but all tests must be completed before infusion) 
1. Confirmation of COVID-19 positive nasal pharyngeal sampling test – documentation 
of NP testing is required.  Repeat testing is not required. 
2. ABO Blood Typing and Cross & Match 
3. CBC with platelets and differential 
4. CMET including liver and renal function 
5. COVID-19 neutralizing antibody titer (if test not available, to collect and store sera 
sample).  Sample should be collected in an EDTA (lavender/purple or pink top tube) 
6. Chest Radiographic study (CXR or CT-chest (preferred) within 72 hours of planned 
transfusion of Convalescent Plasma if clinically indicated. 
7. Charlson Index Comorbidity Score (for all Groups) 
8. Karnofsky Performance Score (for all Groups) 
9. Baseline evaluation (see baseline treatment worksheet)  
10. Recording of concurrent COVID-19 antiviral investigational therapy or other anti-viral 
therapies (e.g. IL-6 inhibitors (Tocilizumab), IL-1 inhibitors, hydroxychloroquine, 
ribavirin, lopinavir (for all Groups) 
11. Recording of concurrent immunosuppressive medications (e.g. tacrolimus, 
cyclosporine, ruxolitinib, sirolimus, prednisone (steroids), Rituximab (within prior 12 
months), chemotherapy treatment in prior 6 months, rheumatology therapy, Crohn’s 
Disease or Ulcerative Colitis therapy) (for all Groups). 
12. Documentation of days of symptoms preceding infusion of convalescent plasma 
(fever, cough, shortness of breath/dyspnea, emesis, diarrhea, abdominal pain, 
pharyngitis) (for all Groups) 
 
    5.1.2  Transfusion of COVID-19 Convalescent Plasma 
1. Following verification of study eligibility and consenting of the subject, the Atlanta 

14 
 
Blood Center (or blood center providing the plasma) and the hospital blood bank will 
be notified to assign and release a Convalescent Donor Plasma Product.  The intent 
is to release the product for transfusion within 24 hours following the consent being 
signed.  On occasion a delay beyond 24 hours may occur if there is a scheduling 
delay for a courier to transport the product to an outlying hospital facility, or there is 
a delay due to waiting for a donor plasma product to complete release criteria as 
established by the FDA. 
2. Directed Donor Convalescent Plasma Product(s) to have a two-person verification 
per institution protocol for identification of patient and product prior to transfusion of 
product(s). 
3. Convalescent Plasma Product to be provided in 200-425 ml transfusion pack.  The 
bag will be transfused (over at least 2 hours).   
4. If patient demonstrates non-severe allergic transfusion reaction or any other mild 
adverse reaction to the plasma infusion, the infusion is to be held until resolution of 
signs and symptoms.  Following evaluation and assessment by medical team that 
may include need for antihistamine, corticosteroid and/or diuretics administration, 
transfusion may be restarted at a slower infusion rate per directive of medical team. 
5. If patient develops anaphylactic reaction or severe acute reaction, then the 
transfusion should be stopped.  Institutional policy for managing severe transfusion 
reactions should be initiated in consultation with medical team.  
 
   5.1.3 Laboratory and Clinical Monitoring Post-COVID-19 Convalescent Plasma Infusion 
 
5.1.3.1 Fever (maximum value) monitoring daily through D30.  For patients who are 
discharged from the hospital, they will be provided the diary and asked to 
complete it from discharge until Day 30. 
 
5.1.3.2 For patients in group 3 and 4, they will be asked to maintain a daily diary log 
for symptoms through day +30  
 
5.1.3.3 Recording of inpatient hospital days, days in ICU, days on mechanical 
ventilator (invasive and noninvasive). 
 
5.1.3.4 Chest radiograph (CT chest or CXR) on days 7 and 14: for patients in groups 
3 and 4, if a baseline chest  xray/radiograph was completed, follow up 
radiographic studies will be required on days 7 and 14.   
 
5.1.3.5 COVID-19 sera neutralizing antibody titer (when test is available) to be 
obtained between days 21-30 following infusion of convalescent plasma.  If test 
is not available sera will be collected and stored. This will be collected in an 
EDTA tube (lavender/purple or pink top)  
 
5.1.3.6 COVID-19 NP swabs will be repeated all subjects on Days 7 & 14.  . 
 
5.2 
Discontinuation of Study Intervention 
The study involves one-time administration of ABO matched COVID-19 convalescent 
plasma.   
 
5.3 
Participant Discontinuation/Withdrawal from the Study 
Study participant is free to withdraw consent from participation in further data collection 
at any time during the study.  If a patient withdraws consent, survival data will still be 
collected. No additional data will be collected.  
 
5.4 
Lost to Follow-Up 
The protocol follows the subjects only for a limited interval.  It is not anticipated that 
study participants will be lost to follow-up. 
 

15 
 
6.0 Statistical and Quantitative Analysis 
 
6.1 Determination of Sample Size and Statistical Analysis 
 
Group sequential design is employed for each hypothesis that analysis will be performed after 
enrolling and observing outcomes of one-third of maximum sample size. Our design includes 
two interim analyses and a final analysis for each hypothesis. The Pocock method is used to 
determine sample size and each study is sized to maintain the power of 80% and overall type 
I error 5%. To calculate the sample size, the large-sample Z test for a proportion is utilized for 
each analysis. 
 
 
Enrollment at 
stage 1 
Enrollment at 
stage 2 
Enrollment 
at stage 3 
Maximum 
enrollment 
Expected 
enrollment 
for projected 
proportion 
Study group 
3 
76 
76 
76 
228 
159 
Study group 
4 
73 
73 
73 
219 
152 
 
 
Group 3 
For high-risk COVID-19 infected patients that present with early mild or non-severe disease 
the estimated percent who will develop severe disease is 27% for those over age 65.  There 
is insufficient data on patients who have coexisting severe immune compromised status; 
however, for patients that presented with diabetes or heart disease/hypertension risk was 16% 
- 30%, respectively.22  Assuming a reported risk of progression of 25%, it is postulated that the 
infusion of convalescent plasma will reduce the probability for progression to severe disease 
by a factor of 0.35 to 16.3% or lower. We will carry out 3-stage of enrollment and 76 patients 
are enrolled in each stage. The interim analysis will be performed after enrolling and observing 
outcomes of 76 patients. Our design leads to the maximum size of 219 patients after 
completing 3-stage of enrollment and the expected size is 159 patients.   
 
Group 4 
Among healthcare workers 14.8% of cases were classified as evolving to severe or critical per 
the Chinese epidemiological review.24,25  It is postulated that the infusion of convalescent 
plasma will reduce the probability for progression from asymptomatic, mild or nonsevere 
disease to that of severe disease will be reduced by a factor of .5 to 7.5% or lower. We will 
carry out 3-stage of enrollment and 73 patients are enrolled in each stage. The interim analysis 
will be performed after enrolling and observing outcomes of 73 patients. Our design leads to 
the maximum size of 219 patients after completing 3-stage of enrollment and the expected 
size is 152 patients.   
 
6.2  Secondary Endpoints 
 
6.2.1   
Secondary endpoints will be analyzed for potential efficacy and statistically compared to 
historical or matched controlled comparison population. For patients with severe disease, the 
expected rate of ICU admission is 19.%, with 38.7% requiring mechanical ventilation (14.5% 
invasive), 94.6% had radiographic abnormalities of the chest, 15.6% developing acute 
respiratory distress syndrome, and median hospital stay of 13 days. A total of 14% of 
patients with COVID-19 disease developed severe disease.                                                                             
 
6.2.2   
Impact of donor sera neutralizing antibody titer will be correlated to clinical outcome. 
 
6.3 Statistical Analysis 

16 
 
 
We will perform intention-to-treat analysis to analyze outcomes of all enrolled patients. The 
primary analysis is to evaluate the CRF or disease progression rate against the null proportion. 
We plan to perform two interim analyses and one final analysis. The first interim analysis will 
be performed after enrolling and observing outcomes of one-third of maximum sample size. 
At an interim analysis, CRF or disease progression rate will be reported, together with a score 
confidence interval for the rate. The critical value used to evaluate the confidence interval is 
2.289 based on the Pocock method. We will compare the upper limit of the confidence interval 
with the assumed null proportion. We will conclude efficacy of the treatment if the upper limit 
is less than the null proportion and terminate enrollment for the relevant study group. If the 
upper limit is greater than the null proportion, we will proceed to the second stage of enrollment 
and then perform the second interim analysis on the cumulative data. The same evaluation 
will be replicated in the second interim analysis, as well as in the final analysis should we 
proceed to this step. 
 
After completing the trial, we will conduct secondary analysis to compare outcomes of this trial 
with published historical experience.22,24 We will use the score test for comparing two 
proportions in each evaluation. We will report both p value and 95% score confidence interval 
for difference between two proportions. 
 
It is acknowledged that COVID-19 viral pandemic outbreak remains dynamic.  Epidemiological 
update reports from the CDC may result in reassessment for case fatality rates as well as case 
rates for disease progression used in our study design that may require adjustments in sample 
size determinations at the interim analysis as independently allowed by the biostatistician. 
 
7.0 
Adverse Event Reporting 
 
7.1 
Definitions 
 
7.1.1 
Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a donor convalescent plasma product; the untoward medical occurrence does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of the (investigational) product, whether or not it is related to the 
medicinal product.  This includes any newly occurring event, or a previous condition that has 
increased in severity or frequency since the administration of study drug. 
 
Only adverse events that are possibly, probably or definitely related to the infusion of 
convalescent plasma should be captured.  
 
7.1.2 
Serious Adverse Event Reporting 
The investigator will comply with all safety reporting regulations as set forth in the Code of 
Federal Regulations.  The investigator being the sponsor of the study has the sole responsibility 
for reporting all serious adverse events to the Northside Hospital Institutional Review Board (the 
IRB of record), and if serious and either likely, possibly, probably, or definitely related to study 
drug to the FDA via Form3500A.  The investigator will communicate the occurrence of serious 
adverse events to the IRB of record within 24 hours of becoming aware of the event.     
 
7.1.3 
Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 
Results in death. 
 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time 
of the event.  It does not refer to an event which hypothetically might have caused death 
if it were more severe). 

17 
 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
 
Is a congenital anomaly/birth defect. 
 
Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent.   Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   
 
Results in a development of drug dependency or drug abuse 
 
Is a serious adverse drug experience 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 
 
7.2 Procedures for Reporting Serious Adverse Events 
Reporting will only be required for serious adverse events judged by the treating physician to 
be potentially related to the administration of COVID-19 convalescent plasma.  This will include 
determination plasma related allergic reaction, urticarial eruption, adverse change in 
cardiopulmonary status and other organ injury.  The NIH grading criteria will be utilized.  
Special consideration will include the development of TACO or TRALI blood transfusion 
associated reaction, and anaphylactic reaction temporally related to the infusion of the donor 
product transfusion.   
 
Serious adverse events judged by the treating physician to be potentially related to the 
administration of COVID-19 convalescent plasma should be reported to the principal 
investigator. 
 
All SAEs should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
 
8.0 
ADMINISTRATIVE REQUIREMENTS 
 
8.1 
Good Clinical Practice 
 
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be thoroughly familiar with the appropriate use of the study drug as described in 
the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should 

18 
 
be established at the beginning of the study, maintained for the duration of the study and retained 
according to the appropriate regulations.  
  
8.2 Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB/IEC will review all appropriate study documentation in order 
to safeguard the rights, safety and well-being of the patients.  The study will be conducted only 
at sites where IRB/IEC approval has been obtained.  The protocol, informed consent form, 
advertisements (if applicable), written information given to the patients (including diary cards), 
safety updates, annual progress reports, and any revisions to these documents will be provided 
to the IRB/IEC by the investigator. 
 
8.3 Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative before study participation using the most 
current IRB approved consent form.  The method of obtaining and documenting the informed 
consent and the contents of the consent must comply with the ICH-GCP and all applicable 
regulatory requirements. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in 
the medical record or research file. 
 
 
8.4 Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the assigned patient number.  The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations. 
 
8.5 Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies).  The IRB/IEC may provide, 
if applicable regulatory authority(ies) permit, expedited review and approval/favorable opinion for 
minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC.   
Any departures from the protocol must be fully documented in the source documents.  
 
 
8.6 Investigator and Site Responsibility for COVID-19 Donor Convalescent Plasma 
Accountability 
Accountability for the administration of convalescent plasma at all study sites is the responsibility 
of the principal investigator.  The investigator will ensure that the convalescent plasma product(s) 
is used only in accordance with this protocol.  Accountability records will include dates, 
quantities, lot numbers, expiration dates (if applicable), and patient numbers.   
 
8.7  Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator there is sufficient 
reasonable cause.   
 
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to patients 
 
Failure to enter patients at an acceptable rate 
 
Insufficient adherence to protocol requirements 
 
Insufficient, incomplete and/or unevaluable data 
 
Determination of efficacy based on interim analysis 
 

19 
 
8.8 Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). 
 
      8.9 COVID-19 Convalescent Plasma Products  
Convalescent Plasma products will be provided by donor blood centers in accordance with FDA 
regulations and guidance.  This will be transported to hospital blood bank for storage and 
subsequent distribution to the study patient, per FDA regulator guidelines for transportation, 
storage and distribution and transfusion of blood products.    
 
     9.0 References  
 
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immunotherapy for influenza and other serious infections. Crit Care Med. 2010 Apr;38(4 
Suppl):e66-73. 
 
2  Cassadevall A, Liise-anne P.  The convalescent sera option for containing COVID-19.  J Clin Invest 2020; 
https://doi.org/10.1172/JCI138003 
 
 
3 China puts 245 COVID-19 patients on convalescent plasma therapy.  News release.  Xinhua.  Feb 28, 2020.   
Accessed March 10, 2020.  http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm 
 
xvii AABB’s CCP Collection Protocol 03 31 2020, COVID-19 Convalescent Plsama Collection: Donor Eligibility, 
Processing, Labeling and Distribution. Accessed March 31, 2020 
http://www.aabb.org/advocacy/regulatorygovernment/Documents/COVID-19-Convalescent-Plasma-Collection.pdf 
 
4 Shen C, et al.  Treatment of 5 critically ill patients with COVID-19 with convalescent Plasma.  JAMA 
doi:10.1001/jama.2020.4783 
 
5 Duan K, et al.  Effectiveness of convalescent plasma therapy in severe COVID-19 patients.  PNAS 
doi:10.1073/pnas.2004168117/-/DCSupplemental. 
 
vi  Luke TC, Kilbane Em, Jackson JL, Hoffman SL.  Meta-analysis:  convalescent blood products for Spanish Influenza 
pneumonia:  a future of H5N1 treatment?  Ann Intern Med 2006; 145(8): 599-609. 
 
vii Park WH.  Therapeutic use of antipoliomyelitis serum in preparalytic cases of poliomyelitis.  JAMA 1932; 99:1050-
1053. 
 
viii Park WH, Freeman RG.  The prophylactic use of measles convalescent serum.  JAMA 1926; 87(8):556-558. 
 
ix Gallagher JR.  Use of convalescent measles serum to control measles in a preparatory school.  Am J Public Health 
Nations Health 1935; 25(5):595-598. 
 
x Rambar AC.  Mumps; use of convalescent serum in the treatment and prophylaxis of orchitis. Am J Dis Child 1946; 
71:1-13. 
  
xi Hung IF, et al.  Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A 
(H1N1) 2009 virus infection.  Clin Infect Dis 2011; 52(4):447-456. 
 
xii Cheng Y, et al.  Use of convalescent plasma therapy in SARS patients in Hong Kong.  Eur J Clin Microbiol Infect Dis 
2005; 24(1):44-46. 
 
xiii Yeh KM, et al.  Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare 
workers in a Taiwan hospital.  J Antimicrob Chemother 2005; 56(5):919-922. 
 
xiv Ko JH, et al.  Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection:  a 
single centre experience.  Antiv Ther (Lond) 2018; 23(7):617-622. 
 
xv Arabi YM, et al.  Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia.  
                                               

20 
 
                                                                                                                                                                          
Emerging Infect Dis 2016; 22(9):1554-1561. 
 
xvi Luke TC, Casadevall A, Watowich SJ, Hoffman SL, Beigel JH, Burgess TH. Hark back: Passive 
immunotherapy for influenza and other serious infections. Crit Care Med. 2010 Apr;38(4 
Suppl):e66-73. 
 
xvii Sahr F, et al.  Evaluation of convalescent whole blood for treating Ebola virus disease in Freetown, Sierra Leone.  J 
Infect 2017; 74(3):302-309. 
 
xviii Kraft CS, et al.  The use of convalescent plasma in 2 patients with Ebola virus disease in the United States.  Clin Inf 
Dis 2015; 61(4):496-502. 
 
xix China puts 245 COVID-19 patients on convalescent plasma therapy.  News release.  Xinhua.  Feb 28, 2020.   
Accessed March 10, 2020.  http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm 
 
xvii AABB’s CCP Collection Protocol 03 31 2020, COVID-19 Convalescent Plsama Collection: Donor Eligibility, 
Processing, Labeling and Distribution. Accessed March 31, 2020 
http://www.aabb.org/advocacy/regulatorygovernment/Documents/COVID-19-Convalescent-Plasma-Collection.pdf 
 
xx Shen C, et al.  Treatment of 5 critically ill patients with COVID-19 with convalescent Plasma.  JAMA 
doi:10.1001/jama.2020.4783 
 
xxi Duan K, et al.  Effectiveness of convalescent plasma therapy in severe COVID-19 patients.  PNAS 
doi:10.1073/pnas.2004168117/-/DCSupplemental. 
 
xxii Guan W, et al.  Clinical characteristics of coronavirus disease 2019 in China.  NEJM 2020; 
10.1056/NEJM012002032. 
 
xxiii Metlay JP, et al.  Diagnosis and treatment of adults with community-acquired pneumonia:  an official clinical 
practice guideline of the American Thoracic Society and Infectious Disease of America.  Am J Respir Crit Care Med 
2019; 200(7):e45-e67. 
 
xxiv Wu A, McGoogan  JM.  Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) 
outbreak in China.  Summary of a report of 72,314 cases from the Chinese center for disease control and prevention.  
JAMA 2020; doi:10.1001/jama.2020.2648 
  
xxv Novel Coronavirus Pneumonia Emergency Response Team.  Viral surveillances: the epidemiological characteristics 
of 2019 novel coronavirus diseases (COVID-19)—China, 2020.  China CDC Weekly.  Accessed February 20, 2020.  
http://weelky.chinacdc.cn/en/article/id/e53946e2-c6c4041e9-9a9b-fea8db1a8f51. 
 
xxvi  https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-
risk.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fspecific-
groups%2Fpeople-at-higher-risk.html 
 
xxvii Circular of Information for the use of Human Blood and Blood Components, AABB Press 2017. 
 
xxviii AABB Technical Manual, 19th Edition AABB Press, Bethesda MD 2018 
 
xxix Pandey S, Vyas GN.  Adverse effects of plasma infusion.  Transfusion 2012; 52(Suppl 1):65S-79S. 
 
xxx Domen RE, Hoeltge.  Allergic transfusion reactions:  an evaluation of 273 consecutive reactions.  Arch Pathol Lab 
Med 2003; 127:316-320. 
 
xxxi Vamvakas E.  Allergic and anaphylactic reactions.  In: Popovsk M, editor.  Transfusion Reactions. 3. Bethesda, MD:  
AABB Press; 2007. p:105-156. 
 
xxxii Hostolffer RW.  Selective IgA deficiency:  Clinical manifestations, pathophysiology and diagnosis.  Up to Date, 
March 2020.   
 
xxxiii Church GD, et al.  Transfusion-related acute lung injury in the paediatric patient:  Two case reports and a review of 
the literature.  Transfus Med 2006; 16:343. 

21 
 
                                                                                                                                                                          
 
xxxiv Skeate RC, Eastlund T.  Distinguishing between transfusion associated related acute lung injury and transfusion 
associated circulatory overload.  Curr Opin Hematol 2007; 14:682. 
 
xxxv Silliman CC, McLaughlinNJ.  Transfusion-related acute lung injury.  Blood Rev 2006; 20:139-159. 
 
xxxvi Sheppard CA, et al.  Transfusion-related acute lung injury.  Hematol Oncol Clin North Am 2007; 21:163-176. 
 
xxxvii Skeate RC, Eastlund T.  Distinguishing between transfusion-related acute lung injury (TRALI) and transfusion 
associated circulatoryoverload.  Curr Opin Hematol 2007; 14:682-687. 
 
xxxviii Gajic O, Groper MA, Hubmayr RD.  Pulmonary edema after transfusion.  How to dirrerentiate transfusion-
associated circulatory overload from transfusion-related acute lung injury.  Crit Care Med 2006; 34:S109-13. 
 
xxxix Li G, et al.  Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical 
intensive care unit patients.  Transfusion 2011; 51:338-43. 
 
xl Popovsky MA.  Transfusion and the llung: circulatory overload and acute llung injury.  Vox San 2004; 87:62-65. 
 
xli Li G, et al.  The accuracy of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic) in the 
differentiation between transfusion-related acute lung injury and transfusion-related circulatory overload in the critically 
ill.  Transfusion 2009; 49:13-20. 
 
xlii Transfusion transmitted injuries surveillance system program report:  Public Health Agency of Canada.  2002-2003. 
 
xliii Mair B, et al.  Hypotensive reactions associated with platelet transfusions and angiotensin-converting enzyme 
inhibitors.  Vox Xang 1998; 74:27. 
 
xliv Metcalf RA, et al.  Clinical pattern in hypotensive transfusion reactions.  Anesth Anaig 2016; 123:268. 
 
xlv Wan Y, et al.  Molecular mechanism for antibody-dependent enhancement of coronavirus entry.  J Virol 2020; 
94(5):e02015-19.