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Additional Clinical Issues and Guidance


Progress Made in Using Convalescent Plasma to Treat COVID-19 Patients

Posted August 25, 2020

The U.S. Food and Drug Administration (FDA) announced Sunday that it issued an Emergency Use Authorization (EUA) to permit the emergency use of COVID-19 convalescent plasma to treat hospitalized patients with COVID-19. Interest in the use of convalescent plasma to treat COVID-19 has been high since the early phases of the pandemic, and while some prominent members of the scientific community are enthusiastic about its use, others are more cautious.

Interest in the use of convalescent plasma to treat COVID-19 was rooted in previous promising experiences with using plasma to treat other viral pandemics and epidemics, including the 1918 influenza, the H1N1 influenza in 2009 and severe acute respiratory syndrome and Middle East respiratory syndrome (both coronaviruses) in the last two decades. An excellent short history and proposal for the development and use of convalescent plasma (sera) was published in early March by Casadevall and Pirofski.

The use of sera is based upon the donation of plasma from patients who have recovered from documented COVID-19 illness. Neutralizing antibodies should be present in this plasma, but concentration varies from none-to-low titers to high titers. Previous experience suggests that high-titer sera are more effective than plasma with low titers (lower concentrations) of neutralizing antibodies.

Early experiences in transfusing severely ill patients with COVID-19 in a small series were published in March and April. These studies showed the promising effects of the use of convalescent plasma but were uncontrolled and not blinded.

One of the first randomized trials of the use of convalescent plasma in COVID-19 treatment was published in June and failed to show a significant improvement over standard treatment without the use of convalescent plasma in patients with severe or life-threatening disease. The trial was suspended prior to planned full enrollment, as the incidence of disease in this study from China declined precipitously as the pandemic waned in many parts of the world. Subgroup analysis, however, showed that patients who were severely ill had better outcomes than patients with life-threatening illness, giving some promise and potential guidance to treating patients earlier in the disease course.

Experience with the use of convalescent plasma grew in the U.S. as the pandemic continued. Data from an expanded access program (EAP) developed in conjunction with the FDA, the Mayo Clinic, and the national blood bank community showed the safety of the use of convalescent plasma in the first 5,000 patients in June. The incidence of serious adverse events was less than 1 percent, and few of these complications could be linked directly to the plasma transfusion. Mortality was noted to be low in treated patients, but the study was not designed to be controlled or randomized, so no inference could be made to show a definite beneficial effect of the plasma.

One of the first controlled prospective propensity score matched trials (not a randomized controlled trial) in the use of convalescent plasma was reported earlier this month. Houston Methodist Hospitals reported on 136 patients transfused with convalescent plasma versus 251 non-transfused patients. Mortality declined significantly in patients with severe or life-threatening disease who received high-titer convalescent plasma within 72 hours of hospital admission.

A pre-peer-reviewed article in July reviewed data from 12 worldwide studies (three randomized clinical trials, five matched-control studies and four case series studies) and concluded that patients treated with convalescent plasma experienced reduced mortality rates compared with patients who received standard treatment.

The most recent and largest study of the use of convalescent plasma has been released as a pre-peer-reviewed manuscript. This study extracted data from a large EAP and looked at outcomes for 35,322 transfused patients receiving convalescent plasma April 4 to July 4. Investigators found that patients transfused within three days of diagnosis were significantly more likely to survive at seven days and at 28 days than patients transfused four or more days after diagnosis. In addition, patients transfused with high IgG plasma were more likely to survive than those receiving low IgG plasma—confirming a dose response relationship that would be expected. It should be noted that this study is a retrospective analysis of data collected in a large group analysis, not a randomized controlled trial.

The most recent response to this data was reported in the New York Times August 19—just days before the FDA released its authorization for the emergency use of convalescent plasma for patients with COVID-19. Concern exists that the EAP has grown so rapidly (the Mayo group database now includes more than 66,000 cases involving transfusion of convalescent plasma) that it may become difficult to perform standard randomized controlled trials because patients and physicians may refuse to accept the possibility of receiving placebo rather than convalescent plasma. We will continue to track and share updates as they are available.

Joint Statement Addresses Rescheduling Operations in Areas Experiencing a Resurgence in COVID-19 Cases

Posted August 18, 2020

The American College of Surgeons, American Society of Anesthesiologists, Association of periOperative Registered Nurses and American Hospital Association issued a joint statement August 10 for maintaining essential surgery during the COVID-19 pandemic. The roadmap responds to the resurgence in COVID-19 cases that is occurring in many parts of the U.S., resulting in hospitals that are near or at bed and intensive care unit capacity. The joint statement notes that health care facilities, physicians and nurses must remain prepared to meet the demands for patients hospitalized with COVID-19 and for patients in need of essential surgery services. It reiterates a list of principles and considerations to guide physicians, nurses and local facilities in their care in ORs and all procedural areas during the ongoing pandemic, including the following:

  • Regional cooperation to ensure access to essential surgical services
  • Collaboration among hospitals, medical professional societies and government to ensure adequate supplies of vital equipment and medications
  • Use of available testing to protect staff and patient safety as well as implementation of policies that address requirements and frequency for patient and staff testing in accordance with current Centers for Disease Control and Prevention guidelines
  • Rescheduling of nonemergent essential operations unless the facility has adequate personal protective equipment and surgical supplies
  • Establishment of a prioritization policy committee consisting of surgeons, anesthesia professionals and nursing leadership
  • Adoption of policies across the five phases of surgical care that address care issues specific to COVID-19 and the postponement of operations
  • Application of procedures to reevaluate and reassess policies and procedures frequently, based on COVID-19-related data, resources, testing and other clinical information

Delays in Surgery Do Not Appear to Affect Overall Survival for Early-Stage Breast Cancer Patients

Posted August 11, 2020

study published in the Journal of the American College of Surgeons shows that surgeons who provide care to women with early-stage breast cancer and who have had to delay operations because of the coronavirus disease 2019 (COVID-19) pandemic can rest a little easier. During the COVID-19 pandemic, surgical delays have been common for patients with ductal carcinoma in situ and early-stage estrogen receptor-positive breast cancer, often in favor of neoadjuvant endocrine therapy. To understand the possible ramifications of these delays, the authors examined the association between time to surgery, pathological staging and overall survival.

The researchers conducted this study using the National Cancer Database and analyzed data for 378,839 patients with early-stage breast cancer in 2010−2016. Patients were divided into two groups: one cohort had ductal carcinoma in situ; the other group had small invasive tumors—stage I and limited stage II—that had not spread to nearby lymph nodes and were estrogen receptor-positive. The researchers evaluated whether longer time to surgical treatment up to one year after diagnosis had an association with final pathologic staging of the cancer or with five-year overall survival.

Among patients who underwent primary surgery, the operations were performed within 120 days in more than 98 percent of all groups. Among cT1-2N0 patients selected for NET, surgery was performed within 120 days in 59.6 percent of cT1N0 and 30.9 percent of cT2N0 patients. Delays in operative care were associated with increased odds of pathological upstaging in DCIS patients, but not in patients with invasive cancer, regardless of initial treatment strategy. No difference in overall survival OS was detected in DCIS or NET patients who experienced delays in surgery.

The authors conclude that delays in surgery was associated with a small increase in pathological upstaging in DCIS patients, but did not impact OS. In patients with cT1-2N0 disease, NET use did not affect stage or OS, supporting the safety of delay strategies in ER-positive breast cancer patients during the pandemic.

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