Systematic literature review to understand whether SARS-CoV-2 cycle threshold (Ct) values correlate with clinical outcomes and therefore whether they could provide valuable information to clinicians as patients infected with SARS-CoV-2 display disparate disease severity. |
The results of this review indicate that lower Ct values are potentially associated with worse outcomes in COVID-19 patients. |
Low SARS-CoV-2 Ct values correlate with increased probability of progression to severe disease, increased disease severity, increased mortality and presence of biochemical and haematological markers. |
While reporting of qualitative SARS-CoV-2 test results as positive or negative is sufficient for diagnosis, the reporting of Ct values may offer benefit to clinicians in making clinical and patient-management decisions for patients with COVID-19 as well as guide infection control, public health and occupational health decisions. |
Introduction
Methods
Results
Included Studies
Outcome | Study | Country | Number of PCR + patients | Patients | Sample type | RT-PCR target | Timepoint of assessment | Lower Ct values associated with worse outcome | P value | Outcome measure |
---|---|---|---|---|---|---|---|---|---|---|
Mortality | Huang et al. [11] | China | 308 | Hospitalised adult patients | Nasal and pharyngeal swab | ORF1ab gene | Multiple time points after admission | Yes | < 0.001 | Average Ct values were lower in patients who died during the study than those who did not [discharged from hospital: median 37.43 (IQR 34.94–38.67); still hospitalised: median 36.97 (IQR 34.33–38.70); deceased: median 34.79 (IQR 25.46–37.65)] |
Disease progression | Yu et al. [17] | China | 92 | Hospitalised patients | Sputum from the lower respiratory tract | N and Orf1b genes | Hospital admission | Yes | 0.008 | Lower Ct values were observed in specimens from patients who became severe during hospitalisation than those did not (Ct values 24 vs. 29) |
NR | Ct values negatively correlated with the probability of progression to severe disease in patients representing mild-moderate disease at admission | |||||||||
Severity of disease | Arons et al. [25] | USA | 57 | Patients in a long-term skilled nursing facility | Nasopharyngeal and oropharyngeal swabs | N1 and N2 genes | 10 days after first patient within the facility tested positive | No | NR | Median Ct values for the four symptom status groups were similar (asymptomatic: 25.5; presymptomatic: 23.1; atypical symptoms: 24.2; typical symptoms: 24.8) |
He et al. [10] | China | 94 | Hospitalised patients | Throat swab | N gene | Symptom onset to day 32 | No | NR | Graphs of Ct values over time for patients with mild or severe disease and at least one positive test result (Ct value < 40) did not show any obvious difference in Ct value by disease severity | |
Huang et al. [11] | China | 308 | Hospitalised patients | Nasal and pharyngeal swab | ORF1ab gene | Multiple time points after admission | Yes | NR | Ct values of critical patients were much lower than general patients and severe patients in the early stages of hospitalisation. The overall Ct values of general patients were higher than severe patients | |
Kimball et al. [26] | USA | 23 | Patients in a long-term skilled nursing facility | Nasopharyngeal and oropharyngeal swabs | N1 and N2 genes | 12 days after an HCP within the facility tested positive | No | 0.3 | Mean Ct values in the four symptom status groups did not show any difference (typical symptoms: 18.6–29.2; atypical symptoms only: 24.3–26.3; presymptomatic: 15.3–37.9; asymptomatic: 21.9–31.0) | |
Liu et al. [14] | China | 12 | Hospitalised patients | Respiratory samples, including throat swabs | ORF1ab and N genes | Hospital admission | Yes | 0.01 | Ct value was positively linked to lung disease severity measured by Murray score (r = − 0.765) | |
0.018 | Ct value was positively linked to PaO2/FiO2 ratio (r = 0.663) | |||||||||
0.08 | There was no significant correlation of APACHE II scores with Ct values (r = − 0.503) | |||||||||
Liu et al. [13] | China | 76 | Hospitalised patients | Nasopharyngeal swab | Hospital admission | Yes | 0.017 | Patients with severe disease had significantly lower Ct values than mild-moderate cases at admission (25 vs. 28) | ||
Liu et al. [12] | China | 76 | Hospitalised patients | Nasopharyngeal swab | At diagnosis | Yes | < 0.00001 | ΔCt values (Ct of sample minus Ct of reference sample) of severe cases were significantly lower than those of mild cases at the time of admission (− 1.42 ± 3.62 vs. 4.44 ± 3.99); the mean viral load of severe cases was around 60 times higher than that of mild cases | ||
Schwierzeck et al. [23] | Germany | 12 | Paediatric dialysis patients | Nasopharyngeal swab | E and RdRP genes | > 5 days after contact with index case | Yes | 0.007 | Ct values of the symptomatic cases [22.55 (range 16.03–23.50); n = 6] were lower compared with asymptomatic cases [29.94 (range 21.89–37.49); n = 6], indicating an approximately 200-fold higher viral load | |
Shi et al. [15] | China | 114 | Hospitalised patients | Pharyngeal swab | N gene | Hospital admission | Noa | NR | Mean viral load was lower in cases with pneumonia (5.15 log10 copies/ml), followed by non-pneumonia cases (5.22 log10 copies/ml) and highest in severe pneumonia cases (5.58 log10 copies/ml), but the differences were not significant | |
< 0.05 | Among female cases, mean viral load in patients with severe pneumonia was higher and significantly differed from non-pneumonia patients and pneumonia patients | |||||||||
< 0.05 | Within the C-reactive protein- and serum amyloid A-positive group, mean viral load was higher in patients with severe pneumonia than in those without pneumonia (4.80 log10 copies/ml vs. 5.50 log10 copies/ml) | |||||||||
To et al. [21] | Hong Kong | 23 | Hospitalised patients | Early morning saliva from the posterior pharynx | RdRP gene | 0–29 days after symptom onset | Noa | 0.56 | Median initial viral loads in severe cases were higher than those in mild cases [log 10 copies/ml 6.17 (IQR 4.18–7.13) vs. 5.11 (IQR 3.91–7.56)] although the difference was not significant | |
0.52 | Median peak viral loads in severe cases were higher than those in mild cases [6.91 log10 copies/ml (IQR 4.27–7.40) vs. 5.29 log10 copies/ml (IQR 3.91–7.56)], although the difference was not significant | |||||||||
Xia et al. [16] | China | 10 | Hospitalised patients | Nasopharyngeal swab | ORF1ab and N genes | Hospital admission | Yes | NR | Ct values for severe cases (n = 3) were lower than those of other patients (n = 7) | |
Yu et al. [17] | China | 92 | Hospitalised patients | Sputum from the lower respiratory tract | N and Orf1b genes | Hospital admission | Yes | 0.017 | Severe patients had lower Ct values than mild-moderate cases at admission (25 vs. 28) | |
Zheng et al. [19] | China | 96 | Hospitalised patients | Respiratory | ORFab1 | Multiple time points after admission | Yesa | 0.03 | Patients with severe disease had significantly higher viral loads than patients with mild disease | |
Stool | ORFab1 | Noa | 0.83 | Viral loads in stool samples showed no significant difference between patients with mild disease and patients with severe disease | ||||||
Serum | ORFab1 | Noa | 0.09 | Viral loads in serum samples showed no significant difference between patients with mild disease and patients with severe disease | ||||||
Zou et al. [20] | China | 18 | Nasal and throat swabs | Orf1b | 0–21 days after symptom onset | No | NR | Viral load that was detected in the asymptomatic patient (n = 1) was similar to that in the symptomatic patients |
Outcome | Study | Country | Number of PCR + patients | Patients | Sample type | RT-PCR target | Timepoint of assessment | Lower Ct values associated with worse outcome | P value | Outcome measure |
---|---|---|---|---|---|---|---|---|---|---|
Clinical markers | Azzi et al. [22] | Italy | 25 | Hospitalised patients with severe disease | Saliva | 5′ Untranslated region | After hospital admission | Yes | 0.04 | There was an inverse correlation between LDH levels and Ct values |
0.07 | There was no significant correlation between ultrasensitive C-reactive protein levels and Ct values | |||||||||
Huang et al. [11] | China | 308 | Hospitalised patients | Nasal and pharyngeal swab | ORF1ab gene | Multiple time points after admission | Yes | < 0.0001 | Cases with Ct < median had higher neutrophil percentages than cases with Ct > median [62.4 (54.8–74.2) vs. 61.8 (52.6–70.5)] | |
0.0007 | Cases with Ct < median had lower lymphocyte percentages than cases with Ct > median [24.1 (16.1–30.2) vs. 25.7 (17.6–32.4)] | |||||||||
0.0002 | Cases with Ct < median had lower basophil percentages than cases with Ct > median [0.40 (0.20–0.70) vs. 0.60 (0.30–0.80)] | |||||||||
0.0001 | Cases with Ct < median had lower eosinophil percentages than cases with Ct > median [1.60 (0.50–2.80) vs. 2.00 (0.98–3.20)] | |||||||||
< 0.0001 | Cases with Ct < median had lower T cell counts than cases with Ct > median [783 cell/µl (466–1126) vs. 916 cells/µl (692–1132)] | |||||||||
< 0.0001 | CK-MB levels were increased in cases with Ct < median compared with cases with Ct > median [0.84 µg/l (0.53–1.66) vs. 0.65 µg/l (0.40–1.12)] | |||||||||
< 0.0001 | Myoglobin levels were increased in cases with Ct < median compared with cases with Ct > median [32.8 µg/l (25.0–68.2) vs. 26.4 µg/l (21.1–38.6)] | |||||||||
< 0.0001 | Ultrasensitive troponin-1 levels were increased in cases with Ct < median compared with cases with Ct > median [0.01 µg/l (0.01–0.03) vs. 0.01 µg/l (0.01–0.01)] | |||||||||
0.0005 | N-terminal pro-brain natriuretic peptide levels were increased in cases with Ct < median compared with cases with Ct > median [173.4 ng/l (43.3–646.1) vs. 91.4 ng/l (28.0–278.0)] | |||||||||
< 0.0001 | Cases with Ct < median had lower serum albumin compared with cases with Ct > median [36.3 g/l (32.9–39.2) vs. 37.7 g/l (34.8–40.0)] | |||||||||
< 0.0001 | Cases with Ct < median had lower inorganic phosphorus levels compared with cases with Ct > median [1.15 mmol/l (0.99–1.30) vs. 1.22 mmol/l (1.07–1.35)] | |||||||||
< 0.0001 | Cases with Ct < median had higher adjusted calcium levels compared with cases with Ct > median [2.47 (2.27–2.67) vs. 2.40 mmol/l (2.25–2.59)] | |||||||||
< 0.0001 | LDH levels were increased in cases with Ct < median compared with cases with Ct > median [220.0 mmol/l (187.0–287.5) vs. 204.0 mmol/l (174.0–240.0)] | |||||||||
Liu et al. [11] | China | 12 | Hospitalised patients | Respiratory samples, including throat swabs | ORF1ab and N genes | Hospital admission | Yes | 0.035 | Angiotensin II level in plasma samples was markedly elevated and negatively correlated with Ct value (r = − 0.669) | |
0.01 | Albumin levels correlated with Ct value (r = 0.717) | |||||||||
0.01 | Percentage of lymphocytes correlated with Ct value (r = 0.717) | |||||||||
0.05 | Percentage of neutrophils negatively correlated with Ct value (r = − 0.529) | |||||||||
0.03 | CRP levels negatively correlated with Ct value (r = − 0.584) | |||||||||
Liu et al. [13] | China | 76 | Hospitalised patients | Nasopharyngeal swab | Hospital admission | Yes | < 0.001 | ΔCt value (Ct of sample minus Ct of reference sample) was positively correlated with lymphocyte counts (r = 0.548) | ||
< 0.001 | ΔCt value was positively correlated with CD4 + T lymphocyte counts (r = 0.478) | |||||||||
< 0.001 | ΔCt value was positively correlated with CD8 + T lymphocyte counts (r = 0.525) | |||||||||
0.002 | ΔCt value was negatively correlated with interleukin-2R levels (r = − 0.323) | |||||||||
0.004 | ΔCt value was negatively correlated LDH levels (r = − 0.339) | |||||||||
< 0.001 | ΔCt value was negatively correlated with high-sensitivity troponin T levels (r = − 0.537) | |||||||||
Yuan et al. [18] | China | 217 | Paediatric patients | Throat swab | ORF1ab gene | 0–24 days after symptom onset | Yes | NR | Viral loads (assumed to be inversely related to Ct value) were positively correlated with myocardial zymogram, CK-MB, LDH and IL-10, while negatively correlated with neutrophils, CD8 + T cells and white blood cells | |
Anal swab | ORF1ab gene | Yes | NR | Viral loads (assumed to be inversely related to Ct value) were positively correlated with myocardial zymogram, CK-MB, LDH and CD4 + cell counts, while negatively correlated with neutrophils, Tregs, IgG and IgM | ||||||
Infectivity | Bullard et al. [27] | Canada | 90 | Nasopharyngeal or endotracheal samples | E gene | 0–21 days after symptom onset | Yes | < 0.001 | Positive culture samples had a significantly lower Ct values compared with culture-negative samples [17 (16–18) vs. 27 (22–33), respectively] | |
< 0.001 | Multivariate logistic regression using positive culture as a predictor variable and symptom onset to test, age and gender as independent variables showed Ct value as being significant (OR 0.64 [95% CI 0.49, 0.84]) | |||||||||
La Scola et al. [24] | France | 155 | Nasopharyngeal swab or sputum | E gene | Not reported | Yes | NR | An association between Ct value and culture positivity rate was observed: samples with Ct values of 13–17 all led to positive culture; culture positivity rate then decreased progressively according to Ct values to reach 12% at Ct = 33; no culture was obtained from samples with Ct > 34 |