FDA approved Houston Methodist to conduct transfused plasma therapy for the treatment of COVID-19

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Houston Methodist received FDA approval Saturday to become the first academic medical center in the nation to transfuse donated plasma from a recovered COVID-19 patient into a critically ill patient.

This treatment was fast-tracked to the bedside over the weekend as the death toll in the COVID-19 pandemic soared to more than 2,000 people across the United States, with more than 100,000 Americans sick from the virus.

Houston Methodist physician scientists began recruiting blood plasma donors on Friday from among the approximately 250 patients who have tested positive for the COVID-19 virus at Houston Methodist hospitals.

Willing donors were immediately identified, who each give a quart of blood plasma in a procedure much like donating whole blood.

Plasma from someone who has recovered from COVID-19 contains antibodies made by the immune system and used to kill the virus.

Transfusing this antibody-rich plasma into a COVID-19 patient – a patient still fighting the virus – may transfer the power of the antibodies into a healing, possibly life-saving therapy.

The first recovered COVID-19 patient to donate plasma was an individual from the Houston metropolitan area who has been in good health for more than two weeks. The plasma was transfused into a COVID-19 patient on Saturday evening at Houston Methodist Hospital.

Known as convalescent serum therapy, the concept dates back more than a century, when similar treatments were used during the Spanish flu pandemic of 1918, a diphtheria outbreak in the 1920s, a flesh-eating bacteria epidemic in the 1930s, and during other outbreaks of infectious diseases.

While literature abounds on the theory that immunity can be transferred from a healthy individual to a sick individual using convalescent plasma, results have varied. A description of the treatment of five patients in China was published this week in the Journal of the American Medical Association, suggesting that the treatment was beneficial.

“Here at Houston Methodist, we have the capability, the expertise and the patient base from our health care system, and we feel obligated to try this therapy,” said Houston Methodist President and CEO Marc Boom.

“There is so much to be learned about this disease while it’s occurring,” he said.

“If an infusion of convalescent serum can help save the life of a critically ill patient, then applying the full resources of our blood bank, our expert faculty, and our academic medical center is incredibly worthwhile and important to do.”

Houston Methodist recruitment began as soon as the FDA issued regulatory guidelines for the study earlier last week.

Physician scientists at Houston Methodist already had designed and validated a COVID-19 molecular test two months ago and were prepared to begin collecting data when COVID-19 patients started arriving.

The Houston Methodist IRB and regulatory affairs experts reviewed the treatment protocol rapidly and secured the FDA approval this weekend.

In New York City earlier this week, Gov. Andrew Cuomo announced that patient recruitment for plasma donations would begin in a matter of days and initially would focus on the heavily hit New York City suburb of New Rochelle, NY.

Eric Salazar, M.D., Ph.D., principal investigator and a physician scientist in the Department of Pathology and Genomic Medicine at the Houston Methodist Hospital and Research Institute, said a review of COVID-19 patients’ charts indicates that nearly two-thirds of the patients may meet the criteria to donate plasma. Patients with critical underlying conditions and advanced age will not be eligible to donate.

The first recovered COVID-19 patient to donate plasma was an individual from the Houston metropolitan area who has been in good health for more than two weeks.

Under FDA guidelines, Houston Methodist’s convalescent serum therapy treatment is classified as an emergency investigational new drug protocol (eIND) that requires FDA approval for each patient infused with donated convalescent serum.

Houston Methodist physician scientists will seek additional FDA approval for follow-up studies, possibly a multicenter national trial on the effectiveness of convalescent serum therapy against the COVID-19 virus.

The process for donating plasma is similar to donating blood and takes about an hour. Plasma donors are hooked up to a small device that removes plasma while simultaneously returning red blood cells to their bodies.

Unlike regular blood donation in which donors have to wait for red blood cells to replenish between donations, plasma can be donated more frequently, as often as twice a week.

“Convalescent serum therapy could be a vital treatment route, because unfortunately there is relatively little to offer many patients except supportive care, and the ongoing clinical trials are going to take a while. We don’t have that much time,” Salazar said.


The use of convalescent plasma is not new; it was used for severe acute respiratory syndrome (SARS), pandemic 2009 influenza A (H1N1), avian influenza A (H5N1), several hemorrhagic fevers such as Ebola, and other viral infections.

For instance, in 2005, Cheng et al reported outcomes of patients who received convalescent plasma in Hong Kong during the 2003 SARS outbreak.2

Although this investigation was not a randomized trial, of 1775 patients, the 80 who received convalescent plasma had a lower mortality rate (12.5%) compared with the overall SARS-related mortality for admitted patients (n = 299 [17%]).

The antibody titers and plasma transfusion volumes varied and did not appear to correlate with clinical response; however, patients receiving transfusion within 14 days of symptom onset (n = 33) had better outcomes.

No adverse events were reported among patients receiving convalescent plasma.

Despite the potential utility of passive antibody treatments, there have been few concerted efforts to use them as initial therapies against emerging and pandemic infectious threats.

The absence of large trials certainly contributes to the hesitancy to employ this treatment. Also, the most effective formulations (convalescent plasma or hyperimmune globulin, H-Ig) are unknown.

Convalescent plasma has the advantage that while its antibodies limit viral replication, other plasma components can also exert beneficial effects such as replenishing coagulation factors when given to patients with hemorrhagic fevers such as Ebola.35 

On the other hand, individual convalescent plasma units demonstrate donor-dependent variability in antibody specificities and titers. H-Ig preparations, in contrast, contain standardized antibody doses, although fractionation removes IgM, which may be necessary against some viruses.

Nonetheless, the construction of a strategic stockpile of frozen, pathogen-reduced plasma, collected from Ebola-convalescent patients with well-characterized viral neutralization activities, is one example of how to proceed despite existing unknowns.6

Deploying passive antibody therapies against the rapidly increasing number of COVID-19 cases provides an unprecedented opportunity to perform clinical studies of the efficacy of this treatment against a viral agent.

If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic.4 

Shen et al used apheresis products produced in the hospital.1

How could this be scaled to meet increased demands?

One approach would be to combine the use of convalescent plasma and H-Ig in a complementary way to treat infected patients in the current COVID-19 pandemic, and subsequent infectious waves, perhaps with the following steps and considerations.

First, blood centers could start collecting plasma from convalescent donors, preferably at the leading edge of the infectious wave; health care workers could encourage COVID-19–infected patients to donate after hospital discharge.

Plasma would be tested, frozen, and distributed to hospitals; paired samples would be retained for concurrent investigations.

Second, within days of collection, clinicians could transfuse convalescent plasma to infected patients.

This approach would be expected to be most effective in patients before they develop a humoral response to COVID-19; serology tests that detect COVID-19 neutralizing antibodies would be beneficial in identifying the best treatment candidates.

Monitoring patient responses by clinical, laboratory, and imaging results could be compared against antibody titers, specificities, and neutralizing activities in paired plasma samples to develop better algorithms for identifying patient and donor factors that predict clinical efficacy.

Third, funding to expand plasma collection capabilities, as well as for academic, industry, and government research initiatives, could mobilize these efforts.

However, despite potentially rapid availability, the deployment of convalescent plasma will have limited reach because transfusions are typically performed in hospital settings and may require large infusion volumes.

In addition, plasma transfusions are also associated with adverse events ranging from mild fever and allergic reactions to life-threatening bronchospasm, transfusion-related acute lung injury, and circulatory overload in patients with cardiorespiratory disorders, which must be carefully tracked.3 

There is also a small, but nonzero, risk of infectious disease transmission.

Fourth, dynamic modeling of COVID-19 infections and factors that are associated with clinical efficacy could be used to inform the distribution of convalescent plasma (and donors) between blood centers and the source plasma industry so the latter can manufacture concentrated COVID-19 H-Ig.

Fifth, within several months, it could be possible for clinicians to begin using small volume H-Ig preparations in ambulatory settings and drive-through clinics, as well as in hospitals.

Concentrated H-Ig preparations are an injectable, time-tested treatment for viral (eg, hepatitis A and B) and bacterial (eg, tetanus, diphtheria) diseases.

In principle, each dose delivers antibody preparations with accurately determined specificities, affinities, and titers against COVID-19 and is logistically simpler than plasma to distribute worldwide.

As with convalescent plasma, it will be critical to identify factors that predict responses to COVID-19 H-Ig, and also to track adverse events.

While H-Ig (like plasma) can be stored for years,7 a similar pathway may need to be reactivated next season, especially as passive antibody efficacy wanes due to accumulated viral mutations.

During each iteration, the investigations performed in parallel to clinical use will drive improvements, for example by guiding the relative amounts of convalescent plasma vs H-Ig that are prepared, or by identifying patients most likely to benefit from these treatments.

Both academic4 and industry groups are beginning to investigate the efficacy of passive antibody therapies for COVID-19 infection. If substantial, robust evidence from rigorously conducted clinical trials clearly establishes effectiveness, and if tests could identify patients who could benefit from passive immunity, the US and other countries could consider a national campaign to provide such treatment.

Although a logistical challenge, this may be one approach to protect high-risk populations and could synergize with parallel efforts to develop vaccines and antiviral drugs.

However, just as executive direction was critical for rapid implementation of COVID-19 tests, so it will be important to accelerate this effort.

Specifically, guidance would be needed to direct blood centers and plasma fractionators to begin prioritizing collections from COVID-19-convalescent donors; expedite the availability of these products for therapeutic use; create a data collection, analysis, and regulatory infrastructure to identify factors that predict therapeutic efficacy and to inform the relative levels of convalescent plasma vs H-Ig production; and remove regulatory barriers that, for example, currently limit the use of pathogen reduction technology for convalescent plasma collections or that require several-month inventory holds on H-Ig


Source:
Houston Methodist

References

1.Shen  C, Wang  Z, Zhao  F,  et al.  Treatment of 5 critically ill patients with COVID-19 with convalescent plasma.  JAMA… Published online March 27, 2020 doi:10.1001/jama.2020.4783

2.Cheng  Y, Wong  R, Soo  YO,  et al.  Use of convalescent plasma therapy in SARS patients in Hong Kong.  Eur J Clin Microbiol Infect Dis. 2005;24(1):44-46. doi:10.1007/s10096-004-1271-9

3.Leider  JP, Brunker  PA, Ness  PM.  Convalescent transfusion for pandemic influenza: preparing blood banks for a new plasma product?  Transfusion. 2010;50(6):1384-1398. doi:10.1111/j.1537-2995.2010.02590.x

4.Casadevall  A, Pirofski  LA.  The convalescent sera option for containing COVID-19.  J Clin Invest. 2020;138003. doi:10.1172/JCI138003

5.Kraft  CS, Hewlett  AL, Koepsell  S,  et al; Nebraska Biocontainment Unit and the Emory Serious Communicable Diseases Unit.  The Use of TKM-100802 and Convalescent Plasma in 2 Patients With Ebola Virus Disease in the United States.  Clin Infect Dis. 2015;61(4):496-502. doi:10.1093/cid/civ334

6.Dean  CL, Hooper  JW, Dye  JM,  et al.  Characterization of Ebola convalescent plasma donor immune response and psoralen treated plasma in the United States.  Transfusion. 2020. doi:10.1111/trf.15739

7.Tabor  E.  The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1.  Transfusion. 1999;39(11-12):1160-1168. doi:10.1046/j.1537-2995.1999.39111160.x

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