When “Rhinovirus” May Not Just Be a Cold: The Diagnostic Blind Spot in RhV/EV Reporting

Molecular respiratory diagnostics have reshaped the evaluation of influenza-like illness (ILI), enabling fast identification of possible viral and bacterial etiologies for acute respiratory infections (ARIs) and informing clinical decision-making. Broad syndromic respiratory PCR panels for ILI have become widely used across emergency departments and inpatient settings. Yet these advances have also hard-coded a persistent diagnostic blind spot: the routine reporting of rhinovirus (RhV) and enterovirus (EV) as a single, undifferentiated result.

At first glance, this compromise appears reasonable. Rhinoviruses are ubiquitous, often benign, and lacks specific therapies. Enteroviruses are generally not reported separately in respiratory testing panels.¹ However, accumulating clinical and epidemiologic evidence suggests that conflating these related viruses obscures important differences in terms of disease severity, prognosis, and implications for public health.

A diagnostic compromise rooted in biology

Commonly used respiratory testing cannot reliably distinguish RhV from EV because both share significant homology in targeted genomic regions, particularly the 5′ untranslated region that is a common target for diagnostics.^1-7 As a result, laboratories often report a combined “RhV/EV” result. Interestingly, there are on-market tests like the SPOTFIRE R/ST Panel Mini^© that report a "rhinovirus"-only result even though their Instructions for Use (IFU) state: "Due to the genetic similarity between human rhinovirus and enterovirus, the SPOTFIRE R/ST Panel Mini cannot differentiate them and will report both as Human rhinovirus."² From a clinical perspective, doing so could lead to a presumption of clarity when ambiguity is actually present.

Rhinovirus: frequent detection, limited actionability

Rhinoviruses are consistently cited as the most detected respiratory virus in both symptomatic and asymptomatic populations. They are found in healthy children, adults with mild upper respiratory infections, and hospitalized frail elderly patients alike.^8.9

However, no approved antivirals exist, and treatment remains supportive. In part due to the difficulty of distinguishing true RhV infection, evidence is conflicting whether RhV, alone or detected with other respiratory pathogens, predicts disease severity. This mixed picture has led some to question whether routine rhinovirus testing adds value in otherwise healthy ambulatory populations.^8.9

As Dr. Melissa Miller at UNC-Chapel Hill notes, “RhV/EV is at times the coagulase-negative Staph[ylococcus] of the viral world.”

In addition, cases of spurious RhV detection have been reported for CLIA-waived assays, even when used in a controlled laboratory setting, possibly due to the ubiquity of RhV.¹⁰

Enterovirus: clinically important yet incompletely seen

Enteroviruses present a different risk profile. While many cause gastrointestinal illness, multiple species exhibit respiratory tropism and may also initially present as ILI, clinically indistinguishable from RhV early on. Enterovirus D68 (EV-D68) is the most important of these respiratory EVs, which has been associated with more serious respiratory illness, but also aseptic meningitis, myocarditis, neonatal sepsis and acute flaccid myelitis (AFM)—a fortunately rare but potentially devastating neurological disorder that affects the spinal cord, causing a polio-like syndrome that can result in varying degrees of paralysis, often following a respiratory prodrome.^11,12

During the initial 2014 U.S. epidemic and subsequent European one when EV-D68 first came to widespread attention, many EV-D68 infections were initially presumed to be RhV on broad panel testing, which may have complicated early recognition of the outbreak. Subsequent analyses demonstrated higher rates of ICU admission, mechanical ventilation, and the association with AFM.¹³

The clinical picture is further complicated by the pattern of biennial circulation exhibited by EV-D68, being much more prevalent in even years. From a public health perspective, lumped RhV/EV reporting blunts epidemiologic resolution, obscuring awareness of true enterovirus activity. For instance, in one academic medical center, almost 1 in 10 RhV/EV-positive cases (9,0%) were actually found to be EVs over one near-complete calendar year (Jan-Nov 2024).¹⁴

A combined RhV/EV result presumed to be RhV may lead to underrecognition of potential enterovirus infection, potentially when careful monitoring—or additional evaluation—may be warranted.

The red herring problem

Co-infections further complicate interpretation. RhV is sometimes detected alongside other clinically significant pathogens such as RSV, adenovirus, parainfluenza viruses, and human metapneumovirus. In such cases, an isolated RhV/EV result may draw attention away from the real possibility another pathogen more often linked to severe outcomes could also be present. ^9,14

And in the absence of comprehensive testing or clear differentiation, clinicians may anchor on an incidental finding of what they presume to be RhV, rather than the true driver of illness. “RhV/EV can be a bystander in a patient with an alternative infectious diagnosis that is not included in a molecular panel, and may lead a clinical provider to stop looking for that alternative diagnosis,” Miller adds.

Limited evidence of antimicrobial stewardship benefit

Testing of additional viruses like RhV/EV that lack specific treatments (unlike flu or COVID-19) is often justified on antimicrobial stewardship grounds. However, three U.S.-based studies of the impact of broad syndromic respiratory panels on prescribing behavior have shown mixed results. Two done in the ED reported lower antibiotic prescribing rates, but one compared patients with positive versus negative results; rates were actually higher than in clinically matched controls. The second compared testing plus a robust antimicrobial stewardship intervention with usual care.^15,16 A third study in urgent care found patients who were tested with a broad panel reported higher rates of antibiotic prescribing in some point-of-care testing settings without robust stewardship interventions.¹⁷ At this time no published studies were found specifically examining the incremental benefit of RhV/EV detection alone.

These findings suggest that the additional availability of an RhV/EV result alone may not reliably improve antibiotic prescribing practices.

Conclusion: Rethinking RhV/EV testing

Together, these considerations highlight a possible mismatch between what RhV/EV testing provides and what clinicians need. Rhinoviruses are common but not often actionable. Enteroviruses can be clinically consequential yet remain hidden within a combined result.

In point-of-care and other ambulatory settings, a combined RhV/EV result that is reported as “rhinovirus”-only in isolation can complicate interpretation. Providers may be unaware that the test cannot reliably distinguish between RhV and EV, and could obscure the possible presence of other pathogens. Thus, in these settings, the “answer” provided may not guarantee the peace of mind that patients and their families naturally seek.

Rather, given the limits of the current testing paradigm, a combined RhV/EV result can probably be more appropriately understood as part of a broader panel administered in higher acuity care settings (e.g., inpatient or ED and/or specialist-directed care) and when paired with provider education (e.g., through careful annotation of results).¹⁸

The example of RhV/EV also highlights the ongoing need for greater precision, intentionality, and awareness in testing—in short, for diagnostic excellence.¹⁹ Testing strategies should prioritize pathogens that meaningfully change management today, while emerging diagnostics should aim to resolve—rather than perpetuate—RhV/EV ambiguity tomorrow.¹³ Until then, clinicians should continue to interpret an innocuous-seeming “rhinovirus” result with caution, and not allow it to lead them away from what they do best: treating the patient—not a test result.