Q&A: Negative PCR tests 'should not preclude evidence-based COVID-19 treatment'

Physicians should practice clinical judgment when treating patients who have a negative PCR test despite clear COVID-19 signs or symptoms and no alternative diagnosis, according to researchers.

“Among the ongoing threat of highly infectious variants and emergence of new evidence-based COVID-19 therapies, these findings suggest a critical role for clinically-diagnosed COVID-19, whereby a negative [PCR] test should not preclude evidence-based COVID-19 treatment in the presence of clinical suspicion and no potential alternative diagnosis,” Yingda L. Xie, MD, an assistant professor of medicine in the division of infectious diseases at Rutgers New Jersey Medical School, and colleagues wrote in BMC Infectious Diseases.

Xie and colleagues conducted a study to investigate the likelihood of COVID-19 among patients with signs and symptoms of COVID-19 who repeatedly received negative PCR test results. Between April 2020 and October 2020, the researchers conducted serologic testing in patients with suspected (n = 15) or probable (n = 20) COVID-19, individuals who had PCR-confirmed COVID-19 (n = 40) and individuals without signs or symptoms of COVID-19 (n = 43).

Despite investigating for other clinical causes, patients with probable COVID-19 had higher antibody and neutralization rates compared with the control patients, according to the researchers. Moreover, their seropositivity, antibody levels and neutralization potency were similar to those of patients with PCR-confirmed COVID-19. Yet, PCR-confirmed patients were twice as likely to receive COVID-19 treatment compared with patients who had probable COVID-19.

“This discrepancy implicates missed potential opportunities to prevent early progression of mild-to-moderate disease in high-risk patients, and potentially reduce morbidity and/or mortality in severe disease,” the researchers wrote. “We incidentally observed that 43% of the [patients with probable COVID-19] who presented with mild-to-moderate disease progressed to severe hypoxic disease.”

Healio spoke with Xie to learn more about how physicians should be balancing clinical judgment with PCR test results.

Healio: What is the key takeaway from your study?

Xie: Individuals with COVID-19 signs or symptoms and no alternative diagnosis can have a high likelihood of COVID-19, even if their PCR test is negative. Clinicians should therefore listen to their clinical judgment in the absence of a positive PCR test, especially when the stakes are high and effective treatments are available.

Healio: How should physicians manage symptomatic patients with a negative PCR test?

Xie: In our study, which focused on patients in the hospital and emergency rooms, we broadly defined COVID-19 clinical signs as having at least three COVID-19 symptoms or chest imaging consistent with viral or multifocal pneumonia to encompass the diverse range of COVID-19 clinical presentations. If a patient who meets these criteria is sufficiently severe or high-risk to potentially warrant treatment, we suggest to first determine the possibility of an alternative diagnosis (eg, assess comorbidities, exposures, chest radiography, testing for flu and other respiratory viruses). In the absence of an obvious competing diagnosis, our findings support the diagnostic consideration of evidence-based interventions for COVID-19 disease.

Healio: How should physicians manage asymptomatic patients with a positive PCR test?

Xie: While not directly addressed in our study, asymptomatic patients who have a positive PCR test are generally assumed to have COVID-19. False-positive PCR tests are infrequent (roughly 5% or less) whereas there are multiple lines of evidence of considerable asymptomatic and pre-symptomatic COVID-19 infection. Beyond following public health guidelines to prevent transmission, any role for preventive treatment would be based on the individual’s risk factor for disease progression.

Healio: How do PCR test results compare with clinical judgment when presented in these conflicting scenarios?

Xie: A positive PCR test can generally be trusted, but if the PCR test is negative, clinical judgment should heavily weigh into the diagnosis of COVID-19.

Healio: How should physicians weigh PCR test results when deciding whether to prescribe antiviral or other therapies?

Xie: This comes down to risk/benefit ratio of the therapy and what is at stake. While our study suggests a likelihood of COVID-19 in PCR-negative individuals with signs or symptoms and no alternative diagnosis, at an individual level there is still a degree of uncertainty of their COVID-19 diagnosis compared to individuals who are PCR-confirmed. We suggest that the decision to prescribe therapies for these PCR-negative individuals without an obvious alternative diagnosis should be based on disease severity and/or risk for disease progression, the strength of evidence for the therapy, and contraindications to the therapy. For example, we would suggest from this study that the threshold for prescribing steroids, which reduces mortality in severely ill individuals, should be lowered among PCR-negative patients with signs of severe COVID-19 and no obvious alternative diagnosis.

Healio: What is the danger of refusing treatments to symptomatic patients with a negative PCR test?

Xie: For severely ill or high-risk patients, this can translate to disease progression, disability and even mortality that may have been averted with effective treatment. The costs of missed treatment are even higher as more evidence-based therapies and interventions emerge.

Healio: Anything else to add?

Xie: I would like to offer two more points:

First, although we used comparative seroprevalence as a marker of COVID-19 probability in the early pre-vaccination era when background seroprevalence was low, the study does not support any role for serologic testing in the individual diagnosis of acute COVID-19, particularly in this high seroprevalence era.

Additionally, while we found a high likelihood of PCR-negative COVID-19 in our study setting, this likelihood of PCR-negative COVID-19 may vary in other settings depending on rates of COVID-19 and clinically overlapping conditions. For example, in settings with less COVID-19 and more competing diagnoses (eg, high prevalence of other respiratory viruses), a thorough workup for alternative diagnoses should be considered to increase the confidence of PCR-negative COVID-19.

Reference:

Parmar H, et al. BMC Infect Dis. 2022;doi:10.1186/s12879-022-07095-x.