PubMed searches identified 162 unique records for screening and one study was identified through manual citation searches. The PRISMA flowchart of included studies is shown in Figure 1. Data from 18 studies were relevant for inclusion and are summarised in Tables 1 and 2.
Twelve studies (63%) were conducted in China or Hong Kong,10-21 three studies were performed in Europe22-24 and three studies were carried out in the USA or Canada.25-27 Nearly all studies reported data for specimens from the respiratory tract, although two studies analysed saliva,21,22 one used stool and serum samples in addition to respiratory samples,19 and one used both throat and anal swabs.18 The real-time PCR targets varied between studies and included ORF1ab (including RdRp), N, E genes and the 5’ untranslated genome region. Six studies analysed SARS-CoV-2 Ct values at multiple time points for each patient,10,11,18-21 and seven studies determined Ct values at hospital admission or diagnosis.12-17,22 Fourteen studies reported on the direct correlation of outcomes with Ct values.10-14,16,17,20,22-27 Three studies reported on the correlation of outcomes with viral load, determined using standard curves of Ct values versus RNA copy number,15,19,21 and one study correlated outcomes with the inverse of Ct values, taken as a proxy for viral load.18
Only one study reported on the correlation between SARS-CoV-2 Ct values and mortality (Table 1). In 308 hospitalised adult patients in China, average Ct values multiple time points during the disease course were lower in patients who died compared with those who had recovered or who were still hospitalised at the end of the study (recovered: median 37.43 [IQR 34.94–38.67]; still hospitalised: median 36.97 [IQR 34.33–38.70]; deceased: median 34.79 [IQR 24.46–37.65]; p < 0.001).11
One study reported that SARS-CoV-2 Ct values at hospital admission negatively correlated with the probability of progression to severe disease in 62 patients who presented with mild–moderate disease (Table 1).17 Lower Ct values were observed in specimens from patients who became severely ill during hospitalisation than those who did not (24 vs. 29; p = 0.008).
Eleven studies (with numbers of PCR-positive patients ranging from 10 to 308) reported on the correlation between Ct value and disease severity,10-14,16,17,20,23,25,26ower Ct values from respiratory samples were associated with more severe disease in 7 (64%) of these (Table 2).11-14,16,17,23 Three studies (with numbers of PCR-positive patients ranging from 23 to 114) reported on the correlation between viral load determined via Ct values and disease severity15,19,21 and one of these (which included 96 patients) reported that higher viral loads were significantly associated with more severe disease (Table 2).19
Of the 15 studies reporting on the correlation between Ct value or viral load determined via Ct value and disease severity, 11 were performed in hospitalised patients10-17,19,21,23 and three included non-hospitalised patients.20,25,26 Of the eleven studies performed in hospitalised patients only, eight (73%) reported an association between Ct value and disease severity,11-14,16,17,19,23 of which six showed statistical significance.12-14,17,19,23 None of three studies that included non-hospitalised patients reported that patients with severe disease had higher viral loads compared with those with mild disease. 20,25,26
Biochemical and haematological markers
All five studies (with numbers of PCR-positive patients ranging from 12 to 308) reporting on the correlation of Ct value with biochemical and haematological markers showed a correlation with at least one marker (Table 2).11,13,14,18,22 Lower Ct values were significantly associated with: higher lactate dehydrogenase levels (n = 4);11,13,18,22 lower lymphocyte counts and/or percentages (n = 3);11,13,14 lower T-cell counts (n = 3);11,13,18 lower serum albumin levels (n = 2);11,14 increased levels of creatinine kinase myocardial band (n = 2);11,18 and increased levels of high-sensitivity troponin 1 (n = 2).11,13 Two studies showed that lower Ct values were associated with higher neutrophil counts and/or percentages,11,14 whereas one study showed a negative correlation.18 One study in 12 patients showed that C-reactive protein levels negatively correlated with Ct value (r = −0.584; p = 0.03),14 whereas another in 25 patients showed no significant association (p = 0.07).22 Associations were also reported between Ct values and angiotensin II,14 IL-2R,13 basophil and eosinophil counts, and levels of myoglobin, N-terminal pro-brain natriuretic peptide, inorganic phosphorus and calcium.11
Two studies reported on the correlation between Ct value and infectivity and showed that lower Ct values were associated with higher probability of a positive viral culture (Table 2).24,27 In one study of 155 patients, 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 (OR 0.64 [95% confidence interval 0.49–0.84], p < 0.001) suggesting that for every one unit increase in Ct, the odds of positive culture decreased by 32%.27 The results demonstrated that infectivity (defined as growth in cell culture) was significantly reduced when RT-PCR Ct values were greater than 24 (p < 0.001).