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Cycle Thresholds Among Solid Organ Transplant Recipients Testing Positive for SARS-CoV-2

Theodore, Deborah A. MD1; Greendyke, William G. MD1; Miko, Benjamin MD1; Whittier, Susan PhD2; Green, Daniel A. MD2; Shoucri, Sherif MD1; Verna, Elizabeth C. MD3; Zucker, Jason MD1,4; Sobieszczyk, Magdalena E. MD1; Aaron, Justin G. MD1; Scully, Brian E. MD1; Saiman, Lisa MD4,5; Pereira, Marcus MD1; Furuya, E. Yoko MD, MS1,5

Author Information
doi: 10.1097/TP.0000000000003695
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Abstract

INTRODUCTION

SARS-CoV-2, the virus that causes COVID-19, continues to pose significant infection prevention and control challenges. Currently, reverse transcription polymerase chain reaction (PCR) testing is used for COVID-19 diagnosis and decision making for infection prevention and control. Although PCR testing is highly sensitive, the presence of viral RNA does not equate with infectivity, and PCR testing does not distinguish viable virus from nonviable virus.1,2 As of August 10, 2020, the Centers for Disease Control and Prevention (CDC) recommend a symptom-based strategy using 20 d and symptom improvement to discontinue transmission-based precautions for immunocompromised individuals.3 However, the CDC acknowledged in October 2020 that data in immunocompromised populations are limited and allowed for consideration of a test-based strategy in consultation with infectious diseases experts.4 Hence, questions about the duration of infectivity for immunocompromised individuals remain, especially given the well-described phenomenon of prolonged detection of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by PCR assays.5-7

Recent data show that PCR cycle thresholds (Ct) targeting the envelope (E) gene correlate with SARS-CoV-2 infectivity. In respiratory samples obtained from mostly immunocompetent individuals, higher Ct values, that is, E-gene Ct value >24, were significantly correlated with loss of infectivity, defined as lack of SARS-CoV-2 growth in cell culture.8 Another published report found no positive viral cultures when the E-gene Ct was ≥34, although the immune status of patients in this cohort was not reported.9 Few reports exist regarding Ct data among immunocompromised individuals with COVID-19. In 1 small cohort, among 5 solid organ transplant (SOT) recipients with serial PCR testing, Ct values <35.0 were detected ≥27 d after symptom onset in 2 patients.10 In 1 case report, an immunocompromised individual had persistent detection of SARS-CoV-2 with low Ct values >140 d after the first positive test.11 And a recent series of 20 patients with hematopoietic stem cell transplantation found prolonged viral shedding.12 Here, we review initial and follow-up SARS-CoV-2 PCR testing and associated Ct values among SOT recipients to help address the knowledge gap for safely discontinuing transmission-based precautions for this population.

MATERIALS AND METHODS

We conducted a retrospective study of patients with kidney, liver, lung, or heart transplant with positive SARS-CoV-2 PCR result from nasopharyngeal specimens admitted between March 13, 2020, and May 15, 2020. Beginning on April 4, 2020, all patients were tested for SARS-CoV-2 upon hospital admission per institutional policy. Repeat testing during this period was performed at the discretion of the clinical team; during the study period, a test-based strategy for discontinuation of transmission-based precautions was used for inpatients. Review of the electronic medical record was performed after June 15, 2020 to allow ≥30 d of follow-up for each patient. SARS-CoV-2 PCR tests performed on the Cobas 6800 (Roche Molecular Diagnostics, Pleasanton, CA) platform were included, and E-gene Ct values were obtained, when available. Ct <40 are generally considered positive by manufacturers of the Cobas 6800. Selected clinical characteristics were recorded for patients with E-gene Ct <34 at ≥20 d (“day 20”) after symptom onset (or after the first positive SARS-CoV-2 PCR test for asymptomatic patients). E-gene cutoff of 34 was chosen to reflect the highest published Ct value linked to cultured virus.9 The institutional review board of Columbia University Irving Medical Center approved this study with a waiver of informed consent.

RESULTS

Sixty SOT recipients with a total of 178 SARS-CoV-2 PCR tests were identified. Forty-seven patients had a test collected on or after day 20 (n = 104 tests); 23 patients had a positive test collected on or after day 20 (n = 35 tests). Among those 23 patients, 17 (n = 24 tests) had a test with an available E-gene Ct value. Of these, 10 patients (n = 14 tests) had E-gene Ct <34. Ct values of the E-gene over time are presented in Figure 1. A flow chart of patients is presented in Figure 2.

F1
FIGURE 1.:
Ct for the E-gene over time. Day 0 is the d of symptom onset (or the first positive test if the patient was asymptomatic). Negative SARS-CoV-2 PCR tests are shown at the bottom of the figure on the line “Not detected.” Ct, cycle threshold; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
F2
FIGURE 2.:
Flowchart of patients. Ct, cycle threshold; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

The 10 patients with Ct <34 on or after day 20 are described in Table 1. Mean age was 58.7 y. Transplanted organs included the kidney (n = 6), liver (n = 1), lung (n = 1), and heart (n = 2). Regarding severity of illness, 4 of the 10 patients never required supplemental oxygen during their illness, 2 patients required oxygen by nasal cannula (NC), and 4 patients were intubated or required oxygen by nonrebreather mask or high-flow NC. Regarding persistence of symptoms at or beyond day 20, 3 of the 10 patients had persistent, unimproved symptoms (fever, dyspnea, or hypoxia), 6 of the 10 patients had symptom improvement or resolution and no oxygen requirement, and 1 of the 10 patients was first symptomatic at or beyond day 20 and then had resolution of symptoms while still testing positive. Notably, a 69-y-old heart transplant recipient had a Ct value of 15 at day 46 while dyspneic and on NC and later had a Ct value of 15 at day 62 while asymptomatic and on room air.

TABLE 1. - Characteristics of patients with E-gene cycle threshold <34 at d 20 or later
Patient number Age Organ d Cycle threshold Disposition at time of testing Maximum oxygen delivery Oxygen delivery at time of test Symptoms at time of test
4 36 Kidney 38 31.7 Discharged None None Cough (improved)
52 27.9 Discharged Cough (improved)
14 57 Liver 35 23 Discharged Nasal cannula None None
52 33.5 Readmitted None None
21 65 Kidney 29 32 Discharged None None None
27 71 Kidney 56 32.5 Admitted Mechanical ventilation None None
28 74 Lung 46 32.1 Admitted High-flow nasal cannula Nonrebreather mask Dyspnea
32 69 Heart 38 21.2 Admitted Nonrebreather mask Nasal cannula Dyspnea
46 14.8 Admitted Nasal cannula Dyspnea
62 15.1 Admitted None None
33 69 Kidney 43 33.0 Admitted Nasal cannula None Fever
47 40 Kidney 39 26.2 Admitted Mechanical ventilation Mechanical ventilation Fever
54 52 Kidney 30 32.2 Discharged None None Dyspnea (improved)
61 54 Heart 28 33.5 Discharged None None Weakness (improved)

DISCUSSION

The COVID-19 pandemic has significantly affected the care of SOT recipients, with fewer transplant surgeries, increases in waitlist deaths, and high mortality among patients admitted to the hospital.13-15 Limiting healthcare-associated transmission of SARS-CoV-2, in particular among immunocompromised patients, continues to be a high priority. Nevertheless, there are limited data guiding the duration of transmission-based precautions for this population, in particular those based on PCR results. In this brief study, 10 of 47 (21%) of SOT recipients undergoing SARS-CoV-2 PCR testing at least 20 d after symptom onset or first positive test had a positive result with an E-gene Ct <34, a value associated with potential viral viability. More importantly, the majority of these patients were asymptomatic or symptomatically improved by that time and would have thus been discontinued from transmission-based precautions as recommended by current CDC guidelines. It is unclear if culturing viable virus late in the clinical course of COVID-19 correlates with infectivity because current data suggest that transmission occurs in the early symptomatic and presymptomatic stages.16 However, SOT recipients may be at increased risk of poor outcomes from SARS-CoV-2,11,17,18 so minimizing the potential for transmission is critical.

Our study has several limitations. We did not use viral culture to confirm that tests with a Ct <34 contained a viable virus. Our analysis only included SOT recipients, so results may not be generalizable to other immunocompromised individuals, including bone marrow transplant recipients or patients receiving chemotherapy.

Given shortages of testing supplies and personal protective equipment and the discomfort to patients from repeated nasopharyngeal testing, avoiding PCR-based strategies for discontinuation of transmission-based precautions may be preferable. More data, including prospective studies with set intervals for repeat testing, are needed to clarify the utility of using PCR results with Ct to help determine infectivity and the optimal duration of transmission-based precautions for immunocompromised individuals.

ACKNOWLEDGMENTS

The authors would like to acknowledge the data in the COVID-CARE database based at NYP/CUIMC, Division of Infectious Diseases.

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