Considering the outcomes of RT-PCR as reference, in our meta-analysis, the sensitivity and specificity of initial chest CT scan for detecting patients, who were highly suspicious for nCoV, were 86% and 43% respectively. The positive predictive value and negative predictive value of CT scan were 67% and 84% respectively. In a boarder sense, 67% of individuals with positive chest CT scan had positive RT-PCR and 84% of individuals with negative chest CT scan had negative RT-PCR. Despite numerous studies have been conducted on various subjects of nCoV, the early diagnosis of patients who were infected with nCoV and also, suitable quarantine of them are under the debate. In accordance with previous studies, chest CT scan when it compares to RT-PCR, may have a variety of beneficial features including, but not limited to, less time- consuming and more availability, that makes doctors to take it into consideration as an adjuvant diagnostic tool (61, 62).
Tao Ai and his colleagues performed a study on 1014 patients and 888 (88%) of them had positive chest CT scan and 601 patients had positive RT-PCR for nCoV, and the sensitivity, specificity, PPV, and NPV of CT scan were about 97%, 25%, 65%, and 83% respectively that compare to our result sensitivity and specificity were much different. The possible reason behind relatively high sensitivity and low specificity in this study is the odds ratio of positive RT-PCR was low, which was considered as the reference (61).
There have been a number of patients with typical chest CT scan findings and symptoms for nCoV that their initial RT-PCR results were negative according to previous literatures (4, 18, 61). For instance, following Y Fang et.al., study that showed that the result of initial RT-PCR in 15 out of 51 patients were negative while their chest CT scan were positive (4, 47, 61). Hence, negative result of RT-PCR is not able to roll out nCoV and it is very important to pay attention to chest CT scan, epidemiologic features, and clinical symptoms. Diagnostic approach with favorably sensitivity and specificity is needed to control the rapid distribution of this disease. Therefore RT-PCR is suggested as a method for diagnosis of SARS-CoV–2 by World Health Organization (WHO) (63). The swabs are commonly taken from sputum, nasopharyngeal, pharyngeal and throat which were included in our meta-analysis. Although WHO recommends examining stool specimens, together with nasopharyngeal swabs (63). Furthermore, combination of humoral and cellular immunity, for instance IgG-IgM antibody, alongside RT-PCR could possibly refine the detection of COVID–19 (25, 68).
According to Chen W., and his colleagues research, positive results based on blood samples, represent deterioration of the disease. Additionally, positive results of anal swabs are related to the severe phase of the disease and the RNA load was higher in anal swabs indicates that the virus may replicate in the digestive system (53). Stool swabs were positive in 8 out of 9 confirmed patients but urine and blood samples were negative in all (8). Also, plasma and urine samples caused negative result in the study by Jasper Chan et al, as well (15). A prospective case series including 30 confirmed COVID–19 patients (21 common type, 9 severe type and one of them had conjunctivitis) underwent RT-PCR test for both tear and conjunctival secretions specimens. Surprisingly, the results of the two specimens were positive the only conjunctivitis patient and the other 58 samples were negative. Therefore, tear and conjunctival secretions samples could possibly yield result for RT-PCR test in COVID–19 infected patients with conjunctivitis(23). Based on distinctly targeted genomes, the sensitivity of RT-PCR would be various. The results of Chan et al indicated that among 273 specimens from 15 positive COVID- 19 patients, RdRp-P2 test showed 77 positive specimens and RdRp/Hel test showed 42 positives, more and revealed RdRp/Hel assay has higher sensitivity. Moreover, RdRp/Hel analysis did not cross reacted with any human coronaviruses or other respiratory pathogens while RdRp-P2 analysis reacted to SARS-CoV, either (64). Another study expressed that the sensitivity of N gene assay in finding the positive samples, is 10 times more than ORF–1b gene assay(65).
In February, 280 suspected patients with clinical manifestations were enrolled in a hospital in Marseille, RT-PCR assay was conducted. About 51% of the patients were negative for all the common viruses, additionally none of the patients were positive for SARS-COV–2 (66). As reported by Guo-Qing Qian et al. 88 out of 91 suspected patients, were confirmed at least one time by RT-PCR assay in 2 sequential tests with 24 hour interval, and 3 patients with negative outcome reported as confirmed due to clinical manifestation (17). In the study by Tao Ai et al (N.1 in the table), from total 1014 patients, 601 patients were confirmed by Positive RT-PCR test and 308 patients with negative results were strongly perceived infected by clinical manifestations and CT scans approval. From total 909 patients, the percent of positive first, second, third and fourth test were 37.7%, 22.6%, 5%, and 0.9%, retrospectively. Additionally, about 33.9% of the patients could not be diagnosed with four repeating tests. Whereas CT scans were positive in 580 of 601(97%) confirmed RT-PCR test and 308 in 413(74.6%) patients with negative RT-PCR assay, as well(36). On the report of Xingzhi Xie (N.2), from total 167 patients, 162 patients were confirmed by the first test (7 of them had normal CT), while 4 patients turned positive after the second and third test and the other patients became positive after multiple tests. Whereas all these patients had clinical symptoms in addition to GGO pattern on their CT scans(47). In the third study, more than two-thirds of the patients had abnormal CT scans(22). In a retrospective analysis(N.5), in the group of 51 patients, 98% (50/51) had abnormal CT, besides 70.6% (36/51) had positive PCR assay, initially, about 30% of the tests became positive after second, third and fourth scanning(4). from the report of a family cluster (N.7), 4 patients were confirmed by RT- PCR, one patients with negative PCR had GGO patterns in her CT and the other two with the same test result, had mild cough and fever for few days(54). On the report of 5 children (N.9), 4 of them had positive PCR outcome within first assay but one with CT findings turned positive after six times of examining (41). As specified by Li Ni (N.10), from 3 suspected patients, 2 patients showed negative PCR result after 3 repeated tests in 11 days and finally affirmed to be infected by typical CT features and clinical manifestations (55). On a report of 2 children, one of them had positive and the other had negative RT-PCR result which became positive in the day after, and at the same time, both had CT symptoms (56). In a case report represented a 56 years old man (N.12), RT-PCR assay was negative for 3 times and the fourth time became positive while CT demonstrated typical features such as ground-glass opacification (GGO) (57). Another case report(N.13) presented a patient with negative PCR result but typical features of COVID–19 in CT. finally RT-PCR result became positive in the third examination (58).
What stands out from table 2 is that, 62.7% of the infected COVIED–19 patients could be recognized in the first test and about 21.2%, 6.3%, 0.7% could be diagnosed in the further second, third and fourth tests, retrospectively. Actually, about 9% of the infected patients have not been detected, even after the fourth test. According to the results and due to the PCR’s cost and time consumption, it seems repeating the test for 3 times is reasonable in patients with initially negative results (with 24hrs to 3 days’ time interval based on literatures).
In fact about forth/ fifth of infected patients with COVID–19 virus have mostly mild and just about 15% of them may have severe ones. Usually patients who have the worse clinical symptoms like fever, dry cough, and low saturation are candidate for RT-PCR testing. Positive RT-PCR results usually have high positive predictive value, but negative RT-PCR should be repeated for three times in order to increase the negative predictive value equal to 98% (57% first test, 34% second one, and 7% third times). If the patient’s death is due to Covid–19 but their PCR indicated to the negative presence of virus and their chest CT is positive no death as the result of Covid–19 is reported. In fact, some patient with negative PCR result dies, but based on our results, 86% of them are covid positive and their disease should be confirmed by repeating PCR for three times. So the exact place of chest CT is staging the COVID–19 disease as the mild, moderate, and severe, but not screening and diagnosis of the disease. Serological tests can complement the PCR results because the negative value of chest CT can be due to the early stages of the disease. So PCR does not compete with chest CT but is used as a supplementary test.
We acknowledge that our study had some limitations: 1. the specificity of CT scan was not as reliable as the sensitivity of that as a result of the majority of studies’ nature, which were case- series and the number of true negative patients in those studies were zero. 2 it has been postulated in A Bernheim et al’s study that chance of detecting lung involvement in chest CT scan will be increased if the duration between symptom onset and initial chest CT scan rises and this duration was different among 47 studies. So, the different outcomes would have emerged if the duration between studies were equal.