Sensitivity of PCR Assay
Currently the CDC states that a negative result does not exclude SARS-CoV-2 infection. Sources of false negative testing include patient misidentification, collection of inappropriate or inadequate material, improper specimen transportation, low viral density in pre-symptomatic patients, and lab errors. In addition to these factors, the location of testing in the aerodigestive tract plays a large role in the sensitivity to detect SARS-CoV-2. As was shown by Zou et al.,3viral loads in the upper respiratory tract of 18 patients varied according to sub-site, with about 64 fold higher viral loads detected in the nasal cavity than in the pharynx. In a study of 213 patients with confirmed COVID-19, the authors found that sputum samples showed the highest positive rate in both severe (88.9%) and mild (82.2%) cases, followed by nasal swabs (73.3%, 72.1%), and then throat swabs (60.0%, 61.3%).2 In a similar study consisting of 205 patients, Wang et al. found that bronchoalveolar lavage had the highest positive rates (93%), followed by sputum (72%), nasal swabs (63%), bronchoscope brushings (46%), pharyngeal swabs (32%), feces (29%), and blood (1%).1 From these studies, it appears that the highest positive detection rate is from lower respiratory tract specimens. A plausible explanation is that SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (ACE2), found predominantly in the lower respiratory tract.23 However a potential confounder is that invasive lower respiratory tract sampling would be primarily performed on patients that have been intubated, which suggests that these patients overall may have higher viral load. Finally, to add further complexity to diagnosis, there may be variable viral load and shedding over time, even when the patient is asymptomatic. There currently is no consensus on when PCR testing should be performed, and this is an area that needs further study.