The Practical Challenges of Making Clinical Use of the Quantitative Value for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load Across Several Dynamics

(See the Major Article by Magleby et al on pages e4197–205.) We are now approaching the half-year mark since the first case of coronavirus disease 2019 (COVID-19) was identified, and we have already learned a great deal about its viral dynamics but obviously need to continue to learn more. As the numbers of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to increase in the United States, so does access to diagnostic molecular testing, especially for hospitalized patients. Most of the molecular diagnostic platforms provide a polymerase chain reaction crossing time (Ct), indicative of the amount of viral RNA in the original sample. Most labs are not currently releasing the Ct value into the clinical result. However, based on the findings of Ct values tightly correlating with mortality rates and the need for mechanical ventilation when patients present for hospital admission with COVID-19 infection, this may need to change. From the very beginning of the pandemic, both the amount of viral RNA detected and the progression of illness have been striking those of us on the laboratory side. Here, Satlin et al. [1] demonstrate the prognostic value of the amount of SARS-CoV-2 RNA from a nasopharyngeal swab at the time of hospital admission for those who were sick enough to require hospitalization. These data clearly provide valuable means to assess the potential severity of illness to triage at the time of admission. Although similar, smaller data sets have hinted at this finding, it is shown clearly in a large number of patients, even though the analysis is retrospective [2, 3]. The Ct could be valuable data in determining a prognosis and the need for intensive care unit support. Predicting the location of admission is especially important in the setting of the pandemic, where we are frequently trying to allocate resources for optimizing medical care while trying to decrease the number of bed movements in a patient with a contagious respiratory illness. However, there are several hurdles and nuances which need to be addressed to deploy Ct value as a meaningful clinical metric. Laboratory results are static and capture a point in time, whereas the SARS-CoV-2 replication throughout an illness is dynamic [3]. There are a variety of contexts where clinical microbiology laboratories have been asked to provide SARS-CoV-2 diagnostic testing (e.g., asymptomatic screening, outpatient symptomatic, and clearance after infection). However, interpreting a low Ct value at the time of hospital admission can only be applied for the prognosis of patients in this context, while learning about the natural history of a novel infection. As the authors state, they were not testing patients whom they were planning to discharge from the emergency department; thus, it is important to note that the findings only apply to the hospitalized cohort. Others have established that early in symptom onset, the Ct value in the nasopharynx is the lowest 1–4 days after symptoms develop [2, 4]. In the cohort presenting for hospital admission, there were more days since symptom onset between the low, medium, and high viral load groups. Presumably, viral counts would have been initially higher for all patients had they presented earlier. But we do not know whether there would be the same prognostic value this early in the disease progression, and there is reason to believe that it would not be equivalent, with several descriptions of high initial viral loads even in mild illness [2]. We are learning that when replication is high in the nasopharynx early in infection, the later disease replication likely occurs lower in the lungs, which may be a sign of patients who cannot control the virus well into infection [3]. The highest viral loads are seen early in infections, when patients are more likely to be outpatients, and were not evaluated in this cohort [2]. Lastly, there may also be clinical value in using the Ct value late in disease to determine the level of contagion after symptom resolution. Obviously this will be a completely different setting, but it has been demonstrated that a low Ct value late in the disease progression correlates with recovery of a viable virus, which provides another potential clinical value for reporting the Ct [5]. In addition to the viral dynamics of infection, there are also several variables which may impact the amount of RNA detected in the sample. Because of the shortages in diagnostics, many laboratories are using more than 1 platform for SARS-CoV-2 molecular detection. Different diagnostic platforms have varying sensitivity and will likely have differences in the Ct values and methods. This likely means a laboratory would need to perform a Ct value equivalency study when releasing results, as clinicians typically assume that results from the same lab are roughly equivalent. Another factor potentially influencing Ct values has been the variability of specimen collection. In the setting of shortages of flocked nasopharyngeal swabs and viral transport media, many hospitals are substituting wrapped or 3D-printed swabs for flocked swabs and use variable media in place of viral transport media. The use of differing collection tools will likely also result in variable RNA recovery. Shortages in personnel, swabs, and the needed personal protective equipment for safe collection have also prompted health systems to explore anatomic site alternatives to nasopharyngeal collection (e.g., throat, nasal, and saliva), which will alter the test sensitivity and Ct values [5]. Because many of these factors are driven by the dynamics of shortages, it may be challenging for a lab to consistently report Ct values and have equivalent meaning across all of these variables within a single result. Even though there are many logistic challenges in comparing the Ct values from 1 platform, specimen type, and disease state, as demonstrated in this manuscript, there is value in understanding the viral burden. Our job now as infectious disease clinicians and laboratorians will be to work together to come up with reporting parameters across the various contexts in order to use the Ct value to maximum effect. Laboratorians will need to develop a standard equivalency across their own diagnostic platforms and specimen types to validate the numbers for accuracy and reproducibility. More critical will be for clinicians to interpret the reported Ct value in the context of the patient who is having the test. If a laboratory can only release the Ct values on inpatients, then maybe the Ct values will be interpreted as the data supports. It is not clear that a Ct <25 at Day 1 of symptom onset has the same mortality prediction that the data in Satlin et al does at Day 7 (the median for patients in the high viral load group in this study). As most laboratory reports are not context-aware, this may mean that additional information for the interpretation of the Ct value may need to be amended to the report, so that we can use this valuable data to understand how it can help us care for patients infected with SARS-CoV-2. We need to continue to work together to develop all the tools we possibly can to understand the disease progression, transmission risk, and recovery with a rapidly spreading novel infectious disease. Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.