Convalescent Plasma vs Human Immunoglobulin to Treat COVID-19 Pneumonia

I. Background:

In late December 2019, the health authorities of the Popular Republic of China reported
several cases of pneumonia of unknown origin in Wuhan City, Hubei Province, China. On
December 31, 2019, the Chinese Center for Disease Control and Prevention began etiological
and epidemiological research on this disease. Three samples of bronchoalveolar lavage were
taken from patients from the Jinyintan hospital in Wuhan and through various processes they
came to identify a new coronavirus that they initially called on January 7, 2020 as:
2019-nCoV. On January 2020, the World Health Organization (WHO) made the first
recommendations on the epidemiological surveillance of this new coronavirus.

On January 22, 2020, the first session of the Emergencies Committee was convened by WHO in
Geneva, Switzerland and on January 30 a Public Health Emergency of International Importance
(ESPII) was declared.

On February 11, the International Committee on Virus Taxonomy named this new coronavirus as
SARS-CoV-2 and responds to "Severe Acute Respiratory Syndrome Coronavirus 2 "(Severe Acute
Respiratory Syndrome CoronaVirus 2), the WHO proposes that same day to call the disease
caused by SARS-CoV-2 as COVID-19.

The first case reported in Latin America was in Brazil on February 26 and on the 28th of the
same month, Mexico communicates its first confirmed case of the new coronavirus in a
35-year-old patient from a trip to Italy.

Given the alarming levels of spread and severity of COVID-19, on March 11, WHO
Director-General Tedros Adhanom Ghebreyesus declares the SARS-CoV-2.5 outbreak as a pandemic.
A high percentage of patients especially over 50 y with comorbidities require hospitalization
and intensive care. Mortality of patients with invasive mechanical intubation has been
reported up to 61% .

At this time, there are no treatment that has shown clinical efficacy, so the plasma from
convalescent patients and human immunoglobulin (IVIG) have been proposed as alternatives.

Human immunoglobulin:

There are no controlled studies with the use of IVIG for the treatment of COVID-19 infection.
In observational reports it was found in three patients with early forms in patients
hospitalized for pneumonia secondary to COVID-19, treated with IVIG at a dose of 0.3 - 0.5 gr
/ kg. All three patients showed clinical improvement, so this study justified the start of a
clinical trial.

An observational experience with important limitations in its report, describes the
experience with 58 patients with severe pneumonia who found differences in mortality at 28
days when they divided the groups according to the IVIG administration time (48 hours),
emphasizing the importance of early application.

In similar situations historically diverse scenarios have been found where IVIG has been
administered with apparent success. However, there are no clinical trials supporting its use.

Convalescent patient plasma:

The use of plasma from convalescent patients for the treatment of severe infection by COVID19
has been considered as a first-line therapeutic option since the start of the pandemic. The
seroconversion of the patients during the first months of the outbreak was unknown, being an
obstacle to recommend this type of treatment. Very recently, the serological behavior of 285
patients was published; 100% of the patients have detected antibodies 19 days after detection
of the virus.

The experiences reported so far are only case series without simultaneous comparative groups.
Viral clearance has been effective, in all included patients in a small series of 6 patients.
This viral clearance was not accompanied by mortality benefits, the authors suggesting that
it was probably due to the late administration of plasma.

Data supporting the use of convalescent plasma for severe acute respiratory syndrome (SARS)
are limited to case reports and case series. Use in case series for severe infections due to
MERS, Ebola and influenza have reported clinical improvement, although none of the studies
were conducted comparatively.

Risks associated with plasma transfusion include TRALI, transfusion-associated circulatory
overload, and allergic transfusion reactions. Rare complications include transmission of
infectious diseases and alloimmunization of red blood cells.

Clinical trials are underway to evaluate both convalescent plasma and IVIG from SARS-CoV-2
for the treatment of COVID-19.

The FDA has approved a national expanded access program for the use of convalescent plasma
for the treatment of patients with COVID-19. Physicians can refer to the National
Convalescent Plasma Project COVID-19 website for more information. People who have fully
recovered from COVID-19 for at least two weeks and are interested in donating plasma can
contact their local blood donor or plasma collection center or consult the American Red Cross
website.

The national transfusion center in Mexico has published guidelines for the use of serum from
convalescent patients.

II. Definition of the problem:

COVID-19 infection has had a high rate of spread. In patients with comorbidities and over 50
years, the infection has presented the highest rate of respiratory deterioration and the
requirement for invasive mechanical ventilation. Due to the absence of specific treatment,
various alternatives have been explored. In critically ill patients, the administration of
human immunoglobulin and plasma from convalescent patients have emerged as potential rescue
therapies. The proposed treatments have an adequate margin of safety due to routine clinical
use in other settings. Due to this, in conjunction with the urgent need to seek therapeutic
alternatives, controlled studies are required without assuming efficacy.

III. Justification COVID-19 infection has collapsed health systems in almost all the
countries due to the large number of patients requiring respiratory assistance.

There is no standard treatment for the management of this infection and the focus has been on
the already known life support and management of Adult Respiratory Distress Syndrome in
critically ill patients.

The treatments used empirically have an adequate safety profile due to the experience in
other clinical settings.

The use of these empirical alternatives should be based on clinical trials since efficacy and
safety should not be assumed in the group of patients with COVID-19.

The Miguel Hidalgo Centennial Hospital has been designated as a hospitalization center for
COVID-19 patients who do not have Social Security in the state of Aguascalientes.

IV. Hypothesis

In patients with COVID19 infection with severe respiratory failure or requiring invasive
mechanical ventilation, plasma treatment of convalescent patients will be superior to
immunoglobulin, with a shorter hospital stay and a lower rate of complications: deterioration
of the oxygenation index or death.

V. General objectives.

To assess the safety and efficacy of plasma administration of convalescent patients or
immunoglobulin in patients with severe COVID-19 infection with severe respiratory failure or
requiring mechanical ventilation.

Assess viral clearance time using PCR

VI. Methodology

Randomized controlled trial, Included patients will be randomized (2:1) to receive one of two
maneuvers:

Group 1: Plasma donated from convalescent patients will be extracted in strict compliance
with the following criteria:

- History of a clinical event with symptoms attributed to COVID-19 and a positive PCR test
for COVID-19

- Further confirmation of a negative PCR test for COVID-19

- In order to be eligible plasma donors must complete at least 14 days after the last
negative PCR in the absence of any symptom attributable to COVID-19 infection

- IgG antibodies for COVID-19 must be confirmed POSITIVE when a qualitative assay is being
used

- When quantification of IgG antibodies for COVID-19 is available a title > 1: 640 will be
required for inclusion.

- Apheresis will be used as the only method for plasma extraction. Infusion of 400 ml of
Plasma will be infused

Group 2: Human immunoglobulin 0.3 gr / kg (5 doses)

VII. Definition of the variables:

Days of hospitalization: Days from admission as a suspected case of COVID with
hospitalization criteria until discharge.

Hospital discharge criteria: negative PCR for COVID-19, oxygen saturation in ambient air >
90%, absence of fever and dyspnea.

Oxygen supplementation requirement: This is based on the modality and FiO2 necessary to
maintain a saturation of 90% of ambient air without respiratory distress.

Respiratory distress syndrome: Respiratory rate greater than 25 x minute and use of accessory
muscles.

Respiratory failure: Saturation to ambient air below 90% or PO2 below 60 mmHg. Septic Shock:
Requirement of vasoactive amines to maintain mean arterial pressure above 65 mmHg, in a
patient previously with adequate water resuscitation.

SOFA: Organic failure scale that includes: PaO2 / FiO2 ratio, platelet count, bilirubin,
blood pressure, Glasgow scale and kidney function.

APACHE 2: Morbidity scale in intensive care. PaO2 / FiO2 Index: Ratio of oxygen pressure to
inspired fraction of oxygen RT-qPCR SARS-CoV-2: Quantitative measurement by RT-PCR method
usually performed on blood. It will be evaluated as a start for diagnosis and then a test
will be repeated on days 5, 14 and 21 to assess viral clearance.

Inflammatory markers: Laboratory studies used as markers of disease severity, consist of
procalcitonin, C-reactive protein, lactate dehydrogenase, blood cytometry, dimer-D, ferritin.