key: cord-0966973-jvv8j1ij
authors: Mirihagalle, Noupama; Parajuli, Priyanka; Sundareshan, Vidya; Saha, Debadoot; Shah, Arpan; Chua, Francine; Waqar, Sana; Prakash, Vidhya; Tobian, Aaron A.R.; Bloch, Evan M.; Katz, Louis; Goel, Ruchika
title: Sequential Dosing of Convalescent COVID-19 Plasma with Significant Temporal Clinical Improvements in a Persistently SARS-COV-2 positive Patient
date: 2021-06-03
journal: Transfus Apher Sci
DOI: 10.1016/j.transci.2021.103180
sha: 63a9848195434f5a56a850be5af497fc3eb39688
doc_id: 966973
cord_uid: jvv8j1ij

The current global pandemic, SARS-CoV-2 infection, is still extending across the world affecting millions of lives to the date. While new successful vaccines are available with promising outcomes to minimize the spread and to reduce the severity of the disease optimal therapeutic option still remain elusive. COVID-19 convalescent plasma (CCP) is an investigational treatment option which studies suggesting signals of efficacy and favorable outcomes only for patients treated very early in course of the disease. Benefits of the use of CCP later in the disease remain highly debated and therefore are not common practice. We hereby report a case of severe SARS-CoV-2 infection in a young male patient with prolonged COVID-19 positivity who received repeat doses of CCP treatments later in the disease with temporal clinical improvement. This patient’s case highlights the need of further studies evaluating efficacy of repeated dosing of CCP. This also suggests a potential of successful use of CCP later in the disease in selected COVID-19 patients.

The current global pandemic, SARS-CoV-2 infection, is still extending across the world affecting millions of lives to the date. While new successful vaccines are available with promising outcomes to minimize the spread and to reduce the severity of the disease optimal therapeutic option still remain elusive. COVID-19 convalescent plasma (CCP) is an investigational treatment option which studies suggesting signals of efficacy and favorable outcomes only for patients treated very early in course of the disease. Benefits of the use of CCP later in the disease remain highly debated and therefore are not common practice. We hereby report a case of severe SARS-CoV-2 infection in a young male patient with prolonged COVID-19 positivity who received repeat doses of CCP treatments later in the disease with temporal clinical improvement. This patient's case highlights the need of further studies evaluating efficacy of repeated dosing of CCP. This also suggests a potential of successful use of CCP later in the disease in selected COVID-19 patients. 

The current global pandemic, SARS-CoV-2 infection, is still extending across the world affecting millions of lives to the date. While new successful vaccines are available with promising outcomes to minimize the spread and to reduce the severity of the disease optimal therapeutic option still remain elusive. COVID-19 convalescent plasma (CCP) is an investigational treatment option which some trials suggesting signals of efficacy and favorable outcomes for patients very early in course of the disease. Benefit of the use of CCP later in the disease is not yet determined and therefore not in common practice. We hereby report a case of severe SARS-CoV-2 infection in a young male patient with prolonged COVID-19 positivity who received repeat doses of CCP treatments later in the disease with temporal clinical improvement.

A 49-year-old overweight male (BMI=26.6) with hypertension, uncontrolled type-2-diabetes mellitus, chronic obstructive pulmonary disease was admitted with 1-week history of dyspnea, productive cough, and fever. The patient tested positive for SARS-CoV-2 by PCR on day of admission. Upon admission, the patient was febrile, tachycardic, normotensive, and saturating 98-99% on room air. Physical exam revealed clear lungs. Chest X-ray (CXR) at admission revealed ill-defined bilateral ground glass and reticular opacities ( Figure: 1A ). Patient's oxygen requirement increased during the hospitalization, necessitating intubation and mechanical ventilation on day four of the admission ( Figure 1B ). His PaO2/FiO2 ratio was 232 mmHg indicating mild acute respiratory distress syndrome (ARDS). Two days following intubation, due to the patient's worsening clinical condition and radiological presentation ( Figure 1C ), the patient was transfused with one unit (314 ml) of COVID-19 convalescent plasma (CCP). The patient's radiographic improved significantly within 48 hours of the CCP transfusion ( Figure:  1D ). On the day of transfusion, his PaO2/FiO2 ratio was 290 mmHg; this gradually improved to 305 mmHg 5 days after transfusion. With convalescent plasma therapy, the patient showed improvement of inflammatory markers including LDH, CRP and Ferritin (Figure 2 ). The patient was gradually weaned off of mechanical ventilation, and extubated 7 days after first CCP administration.

However, 2 days following extubation, the patient again exhibited respiratory distress and hypoxia with development of new CXR infiltrates, necessitating re-intubation. The patient again met eligibility criteria for CCP and a second unit of CCP was transfused (357 ml). Of note, the patient was still SARS-CoV-2 RNA positive at the time of second transfusion. There was temporal improvement in patient's clinical status and inflammatory markers after the second CCP transfusion. (Figure: 2) . The patient was extubated seven days after the second unit of CCP and discharged home on room air. There were no reported reactions to CCP during both the transfusions.

On retrospective analysis, robust signal-to-cutoff (S:Co) and IgG ratios at (>8), for Abbott and Euroimmun assays respectively, were seen for both the CCP units (preliminary data suggests ratios >4 correlate with a neutralizing antibody titer >1:200) [2] . Of note, patient was not tested for SARS-CoV-2 antibodies prior to either CCP doses.

The patient did not receive remdesivir or dexamethasone during hospitalization. Hydroxychloroquine was ordered on admission but was discontinued after 1 dose due to QTc prolongation. The patient also received azithromycin and vancomycin from days 1-5. He was also treated with IV furosemide which was later changed to IV bumetanide drip. IV cefepime, linezolid, and metronidazole were started on day 16 (during second intubation) as empiric coverage for possible aspiration pneumonia; these were continued until complete recovery was attained.

This unique case highlights the temporally associated clinical and laboratory improvements following sequential dosing of CCP in a persistently SARS-CoV-2 RNA positive patient. While definitive cause and effect cannot be confirmed, this report provides signals of efficacy with repeated dosing of CCP in a younger patient, much later in the course of disease.

Patients diagnosed with ARDS secondary to SARS-CoV-2 may have positive PCR test results for multiple weeks after the onset of symptoms. Therefore, the clinical relevance of patient's 2nd positive PCR result is not clear [1] . Of note, the PCR CT values or viral load titers were not tracked for the patient. This information could possibly have contributed to the second dose CCP decision as well as timing.

Evolving evidence supports efficacy of early transfusion of CCP to prevent severe SARS-CoV-2 infection in patients [3] and further supports the use of high titer CCP for better clinical outcomes [4] . Early CCP dosing has become the practice in treating patients admitted with SARS-CoV-2 infection currently in the hospital settings. However, there is not enough evidence available advocating the use of CCP later in the course of the disease or its benefits in persistently SARS-CoV-2 RNA positive symptomatic patients [5] . Furthermore, the benefits of multiple dosing of CCP during the illness is yet to be determined. Therefore, this case underscores the need to investigate multiple dosing of CCP, in SARS-CoV-2 RNA positive symptomatic patients especially later in the disease [6] .

Our case has not been previously published and is not under consideration in any other peer-reviewed media. All authors have read and approved the manuscript. No relevant conflict of interest, financial or other, exists. Acknowledgment 1. Informed written consent was obtained from the patient for publication of the case report and the images. 2. This report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 3 Declarations of interest: none J o u r n a l P r e -p r o o f Figure 1 : Chest x-rays before and after CCP treatment 1A-Chest X-ray upon admission revealing minimal ill-defined bilateral ground glass and reticular opacities 1B-Chest X-ray prior to intubation revealing extensive bilateral consolidation and ground glass opacities 1C-Chest X-ray, 18 hours post intubation before convalescent plasma revealing extensive bilateral consolidation and ground glass opacities 1D-Chest X-ray, 32 hours after receiving convalescent plasma therapy revealing significant interval improvement in bilateral opacities 1A 1B

J o u r n a l P r e -p r o o f 

Persistent viral RNA positivity during the recovery period of a patient with SARS-CoV-2 infection

Comparative performance of five commercially available serologic assays to detect antibodies to SARS-CoV-2 and identify individuals with high neutralizing titers

Treatment for emerging viruses: Convalescent plasma and COVID-19

Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults

Patients with Prolonged Positivity of SARS-CoV-2 RNA Benefit from Convalescent Plasma Therapy: A Retrospective Study

Effectiveness of convalescent plasma therapy in severe COVID-19 patients