COVID-19: Clinical Utility of Cycle Threshold Values

COVID-19: Clinical Utility of Cycle Threshold Values. Jefferson T, Heneghan C.

Published on August 12, 2020

Reference Rao SN, Manissero D, Steele VR, et al. A Narrative Systematic Review of the Clinical Utility of Cycle Threshold Values in the Context of COVID-19. Infectious Diseases and Therapy. 2020. 2020
Study type
Country Global
Setting Multiple
Funding Details Industry
Transmission mode Mixed, Viral load

Bottom Line

Lower Cycle threshold values may be associated with worse course of illness and outcomes and threshold values may be useful in predicting the clinical course and prognosis of patients.

Evidence Summary

Of the 18 studies included (mainly from South East Asia) one reported a significant correlation between Cycle threshold (Ct) values and mortality and one study reported a significant correlation between Ct values and progression to severe disease.

Of the fourteen studies assessing a correlation between Ct value or viral loads and disease severity, eight (57%) reported a significant association. 

Four studies reported a significant association between viral load and biochemical and haematological markers, including increased lactate dehydrogenase (n = 4), decreased lymphocytes (n = 3) and increased high-sensitivity troponin I (n = 2). Lower Ct values were associated with higher viral culture positivity (2 studies).

Mortality: (1 study, 308 hospitalised adult patients in China), average Ct values across multiple time points during the course of disease were lower in patients who died compared with those who had recovered or who were still hospitalised (recovered: median 37.43 [interquartile range (IQR) 34.94–38.67]; still hospitalised: median 36.97 [IQR 34.33–38.70]; deceased: median 34.79 [IQR 24.46–37.65];

Disease Progression: SARS-CoV-2 Ct values at hospital admission negatively correlated withthe probability of progression to severe disease in 62 patients who presented with mild-moderate disease (1 study). Lower Ct values were from specimens from patients who became severely ill during hospitalisation than in those who did not (24 vs. 29) 

Disease Severity
Seven out of 11  studies (n= PCR-positive patients 10 to 308) reported lower Ct values from respiratory samples were associated with more severe disease. 

Three studies (n= PCR-positive patients ranging from 23 to 114) reported on the correlation between higher viral load (Ct values) and disease severity. Fifteen  reported on the correlation between Ct value or viral load determined (Ct value and disease severity), 11 were performed in hospitalised patients, eight (73%) reported an association between Ct value and disease severity, three included non hospitalised patients studies and reported that patients with severe disease had higher viral loads compared with those with mild disease.

Biochemical markers: All five studies (n= PCR-positive patients ranging from 12 to 308) showed a correlation with at least one marker. 

Lower Ct values were significantly associated with: higher lactate dehydrogenase (LDH) levels (n = 4); lower lymphocyte counts and/or percentages (n = 3), lower T-cell counts (n = 3), lower serum albumin levels (n = 2). increased levels of creatinine kinase myocardial band (n = 2); increased levels of high-sensitivity troponin 1 (n = 2). Two studies showed that lower Ct values were associated with higher neutrophil counts and/or percentages, but one study showed a negative correlation. One study (12 patients) showed that C-reactive protein levels negatively correlated with Ct value whereas another (25 patients) showed no significant association. Associations were also reported between Ct values and angiotensin, IL-2R, basophil and eosinophil counts as well as levels of myoglobin, N-terminal pro-brain natriuretic peptide, inorganic phosphorus and calcium [11

Infectivity: In one study of 155 patients (Bullard 2020), lower Ct values were associated with higher probability of a positive viral culture. Multivariate logistic regression analyses using time from symptom onset to test, age and gender as independent variables showed a significant effect of Ct value on the culture positivity of samples suggesting that for every one unit increase in Ct, the odds of positive culture decreased by 32%. Infectivity (defined as growth in cell culture) was significantly reduced when RT-PCR Ct values were over 24.

What did they do?

The study  is a narrative review of 18 studies on correlations between SARS-COV-2 Ct values and patient- or healthcare-related outcomes to determine the clinical usefulness of Ct values.

Study reliability

The review is a single database narrative review with no methodological quality assessment and no attempt to assess publication or other biases. Its results would need updating and developing.The review was funded by Qiagen and all authors are employees. The text was ghost written.

Clearly defined setting Demographic characteristics described Follow-up length was sufficient Transmission outcomes assessed Main biases are taken into consideration
Unclear No Unclear Yes No

What else should I consider?

This is an industry funded narrative review.

About the authors

Carl Heneghan

Carl is Professor of EBM & Director of CEBM at the University of Oxford. He is also a GP and tweets @carlheneghan. He has an active interest in discovering the truth behind health research findings

Tom Jefferson

Tom Jefferson, epidemiologist.