Retrospective case study of respiratory viral panel PCR testing in primary care

ABSTRACT

Respiratory illnesses are some of the most common reasons for visits to primary and urgent care yet their treatment is rarely guided by laboratory testing. A retrospective case review was performed on the use of an reverse transcription polymerase chain reaction (RT-PCR) respiratory viral panel (RVP) in a primary-care setting to assess its impact, particularly on antibiotic prescribing. Routine sick visits where an RVP was used were reviewed to compare presentations and outcomes. In this small study, positive RVP tests help reduce unnecessary antibiotic prescriptions by nearly one-third. Although currently expensive, RVPs are a valuable tool for the assessment of respiratory illnesses distinguishing between those that require antibiotics and those with potential public health implications, such as COVID-19.

Introduction

The United States averages over 500,000 primary-care visits for upper respiratory infections (URIs) each year which account for about half of all outpatient visits.[1] This figure does not include urgent or emergency-care visits. Despite the frequency of URI sick visits, treatment is seldom guided by diagnostic testing. Notable exceptions are rapid strep tests for sore throat, rapid influenza, and COVID-19. The benefit of rapid flu and COVID-19 testing is reduced, particularly when they are negative, given the overlap in symptomology and presentation of the various viruses which cause most URIs, rhinosinusitis, and viral infections.[2]

After ruling out lower respiratory tract pathology, such as pneumonia or exacerbations of underlying cardiopulmonary conditions, the primary question facing clinicians is whether or not to prescribe an antibiotic. This decision is usually made based on a mixture of the presentation (duration and severity of symptoms), patient characteristics (age, comorbidities), and exam findings. Overprescribing of antibiotics contributes to bacterial resistance, adverse events, and unnecessary costs. Each year in the United States, 23,000 deaths and 2 million illnesses are caused by drug-resistant bacteria with antimicrobial misuse costs estimated to be between $27 and $42 billion.[3,4] To date, numerous public health initiatives have sought to address the problem of unnecessary antibiotic use: from the centers for disease control (CDC), to hospital antibiotic stewardship programs, to Choosing Wisely Campaigns.[3,5] Several studies have looked at how respiratory viral panel (RVP) testing affects clinical outcomes including prescriptions, radiology, and other testing in average-risk individuals in the outpatient setting. The results of these studies are mixed but do show the potential for discontinuing or avoiding unnecessary antibiotic prescriptions when the RVP is positive and particularly for influenza or when combined with procalcitonin testing.[6,7,8,9,10] While the use of RVPs is already recommended to guide treatment of high-risk patients,[7] the COVID-19 pandemic has challenged this concept. In the context of evaluating a sick patient where COVID-19 is part of the differential, the risk of progression to serious disease is not just for immunocompromised patients but will also be impacted by COVID-19 vaccine status, underlying comorbid factors like diabetes, BMI and age.[7] This broadens the definition of high risk and presumably increases the potential benefit for RVP testing.

The purpose of this retrospective case study was to review in one urban primary-care office how the use of RVP testing during two years of the COVID-19 pandemic influenced the management of sick patients, particularly with regard to antibiotic prescriptions.

Materials and Methods

The study was conducted at an urban, multispecialty outpatient office affiliated with Maimonides Medical Center in Brooklyn, where 8 primary-care providers see an average of 160 patients a day. A review of the medical database was performed from March 2020 to June 2022 for every instance that an RVP was ordered. RVP testing was performed at the discretion of the provider, generally in the context of a sick visit. Sick visits presenting with any of the following symptoms were included in the study: cough, fever, chills, congestion, malaise, rhinorrhea, headache, pharyngitis, myalgia, and other routine symptoms of URIs or rhinosinusitis. Visits and testing took place at a single outpatient, primary-care office in Brooklyn. Multiplex PCR RVP was performed using the Roche (GenMark) platform through Northwell Laboratory. Details of the platform, including the list of pathogens detected, can be found at https://labs.northwell.edu/test/153255994. Turnaround time for results is typically 24–48 h. Each case was reviewed and demographic and clinical information extracted from the electronic medical record include patient age, comorbidities, history of present illness, and associated symptoms, the treatment plan focusing on whether antibiotics were prescribed, and the results of the viral respiratory panel.

Case definition

A respiratory illness was defined as an adult patient, 18 years of age or older presenting to the office with one or more of the following symptoms: fever, chills, fatigue, malaise, body aches, headache, pharyngitis, sinusitis, rhinorrhea, or cough. Cases were identified through a database search looking for every patient visit where an RVP test was ordered. The case visits were then stratified into one of six groups based on respiratory viral testing and prescription of antibiotics as follows:

1. Patient met respiratory illness sick visit definition, no antibiotic was prescribed (or antibiotics were recalled within 48 h of prescription) and a positive RVP was returned giving a likely diagnosis for symptoms (UA = unnecessary antibiotic avoided).

2. Patient met respiratory illness sick visit definition, an antibiotic was prescribed during the visit (based on clinicians’ assessment of patient), but a positive RVP was returned giving a likely viral etiology for symptoms. No evidence on chart review that antibiotic was subsequently stopped (UG = unnecessary antibiotic given).

3. Patient met respiratory illness sick visit definition, no antibiotic was prescribed and the RVP was negative giving no specific diagnosis for the symptoms. In each of these cases, the chart was reviewed to ascertain whether any follow-up calls or visits resulted in further action such as an antibiotic prescription (NEG = RVP − and no antibiotic given).

4. Patient met respiratory illness sick visit definition, the RVP was negative and an antibiotic was later prescribed on follow-up (NEG + ABX = RVP − and antibiotic prescribed later).

5. Patient met respiratory illness sick visit definition, the RVP was negative and an antibiotic was prescribed or had already been prescribed at the time of the visit (ABX = RVP − and antibiotic prescribed already or during visit).

6. An RVP was sent but not in the context of a usual URI or sick visit presentation (N/A = visit did not fit case definition).

Results

RVP testing results and cohort characteristics

Seventy-two RVP tests were performed, six of which were removed as erroneous (COVID-19 testing only performed or no data available) and eight visits were categorized as N/A and excluded from further analysis due to not fitting the case definition of a routine URI or sick visit. This left a total of 58 eligible cases for inclusion.

Table 1 describes the participant characteristics of the cases reviewed. Mean age was 44 years and 58% of patients were female and of diverse race and ethnicity [Table 1]. Many patients have been designated or self-designated their race as Unknown or Other in the database and these categories were combined into Other. There were many patients with comorbid conditions that, particularly for COVID-19, would be considered a risk factor for progression to severe disease. If a patient had more than one comorbid condition, each was tabulated as shown in Table 1.

Table 1.

Characteristics of the study population enrolled 2020–2022

	All Sites n=58
Mean age (years)	44
20–45 years, n (%)	33 (57)
46–65 years, n (%)	21 (36)
≥66 years, n (%)	4 (7)
Female sex, n (%)	34 (59)
Race, n (%)
White	13 (22)
Black or African American	25 (43)
Asian	3 (5)
Hispanic or Latinx	5 (10)
Other	12 (21)
Chronic comorbid conditions, n (%)
Asthma/COPD/OSA	10 (17)
CHF, CAD, cardiomyopathy	8 (14)
HTN	10 (17)
Obesity (BMI ≥30)	20 (34)
Diabetes mellitus	7 (12)
Chronic kidney disease	3 (5.2)
Other*	18 (31)

*Other included: HIV, rheumatoid arthritis, splenectomy, history of cerebral vascular accident, neuro-sarcoidosis, other auto-immune

Respiratory viruses were identified in 48% of the cases, including 13 cases of SARS-CoV-2 (one of which was coinfected with parainfluenza), 6 seasonal coronavirus infections (not COVID-19), 3 cases of human metapneumovirus, 3 cases of parainfluenza virus (one coinfected with COVID-19 as noted above), 2 cases of human enterovirus/rhinovirus, 1 case of adenovirus, and 1 case of respiratory syncytial virus. Of note, there were no cases of influenza found and none of the visits included rapid influenza, rapid strep tests, use of bacterial throat cultures, or procalcitonin testing.

Clinical presentations of respiratory illnesses

There was no significant difference between viral URIs with positive RVP tests and those from other sources in terms of the duration of symptoms [Table 2]. RVP + cases averaged five days and negative cases averaged seven days of symptoms (at time of presentation as taken from HPI). Notably, the range of symptom duration, 2–15 days for patients who had a positive RVP, went beyond the traditional 7–10 days clinicians often use when deciding if an infection might be bacterial.[11] Both positive and negative cases had an average of two-and-half symptoms with RVP + cases complaining of noticeably more cough and fever more than the RVP − cases (0.79 vs. 0.52 on average and 0.43 vs. 0.21).

Table 2.

Symptoms RVP (+) versus RVP (−) case presentations

	RVP (+) n=28	RVP (−) n=30	P
Mean symptom onset, days (range)	5.14 (2–15)	7.46 (1–30)	0.057
Mean number of symptoms, n (range)	2.5 (1–5)	2.52 (1–5)	0.46
Symptom, n (%)
Cough	22 (79)	15 (52)	0.03
Fever/Chills	12 (43)	6 (21)	0.08
Pharyngitis	9 (32)	12 (41)	0.59
Headache	1 (4)	6 (21)	0.10
Myalgias	3 (11)	3 (10)	1.0
Fatigue/Malaise	8 (29)	12 (41)	0.41
Congestion	13 (46)	10 (34)	0.59
Othera	2 (7)	7 (24)	0.14

^aOther symptoms included: GI, GU, chest pain, rash, eye or ear symptoms, and neuro

The presence of other symptoms (GI, GU, chest pain, neuro, etc.) made RVP testing much less likely to return a positive etiology; 24% of negative RVP cases presented with symptoms that did not fit with normal URIs compared to only 7% of the positive RVP. In this sample, the presence of malaise/fatigue or headache also favored a negative RVP test result: 41% versus 29% (P-value: 0.41) and 21% versus 4% (P-value: 0.10).

Case ascertainment and clinical outcomes

One-third of cases (19 [32.8%]) were found to have a positive RVP identifying a viral infection as the likely etiology of symptoms, 13 of which were COVID-19. Of these UA cases, 17 antibiotic prescriptions were avoided, and for two cases, antibiotics prescribed at the time of the visit were subsequently documented as discontinued within 48 h [Figure 1].

Figure 1.

Case visits stratified by RVP result and antibiotic prescription

Nine (15.5%) cases, or approximately one in six respiratory illness sick visits, were classified as UG for which antibiotics were prescribed and continued despite positive RVP identifying a viral etiology as the cause of illness. Four of these illnesses were due to COVID-19.

Sixteen cases (27.5%) had a negative RVP and also were not treated with antibiotics (NEG). No visit or phone notes were documented on follow-up to indicate these patients sought further treatment from the clinic or received antibiotic therapy. Two cases with negative RVP testing had follow-up appointments or phone calls documenting persistence of symptoms and an antibiotic was then prescribed (NEG + ABX). Finally, for 12 cases (20.6%), antibiotics were prescribed prior to the result of a negative RVP test and continued (ABX).

Discussion

From this small retrospective case study, it does appear that an RVP would be a useful diagnostic tool in the assessment and management of URIs and appropriate sick visits in primary and urgent care. Fully one-half of the tests sent came back positive, thus giving a presumptive diagnosis for the patient’s symptoms as a viral infection and helped confirm a provider’s decision not to prescribe antibiotics for one-third of patients.

In addition to cutting down on unnecessary antibiotic prescriptions, the more widespread use of RVPs could help other public health initiatives such as viral surveillance. It is not coincidental that the study period coincides roughly with the COVID-19 pandemic, a time when respiratory illness sick visits took on a heightened meaning and revealed a need for both patients and providers to make a microbiologic diagnosis. It has been well described that limitations in testing have been an impediment to the management of the current pandemic and one can envision partnerships between local laboratories and departments of health whereby the results of more widespread use of RVPs could be used for viral surveillance to help inform public health decisions.[12] Programs could also be implemented to sequence novel viruses that might threaten public health.

It can be argued that clinicians should be better at not prescribing antibiotics when they are not necessary, but reviewing the details of these cases, it becomes clear that many of the clinical tools traditionally used to help determine the need for antibiotic prescription such as duration of symptoms greater than 7–10 days and patient comorbid conditions were not predictive of RVP test results and therefore the need for antibiotics. This case review certainly underscores the point that most URIs and many common sick visits are indeed viral infections.

Most areas of medicine are driven by objective testing and diagnostics. Best practices in gastroenterology, for example, recommend PCR testing for patients who have symptoms of infectious diarrhea (a test which is also expensive, about $1,400 compared to up to $1,600 for the RVP).[13] Perhaps a similar approach should be considered for appropriate respiratory illness sick visits. Currently, RVP testing is discouraged by the American Society for Clinical Pathology unless the result would affect patient management.[14] Based on this study, it does appear that RVP testing can play a role in determining whether to start or hold empiric antibiotics for appropriate patients who present to primary care for a sick visit.

This study has a few important limitations. A positive RVP test does not rule out concomitant bacterial infection which is not uncommon in immunocompromised populations.[15] Additionally, the sensitivity of RVP testing can be affected by suboptimal swabbing technique.[15] The sample size of this study was small and more data would be needed to determine if respiratory illness sick visits where an RVP test is positive would be more likely to present with certain symptoms such as was seen here with cough and fever. It does appear that duration of symptoms of more than 7–10 days, which is often cited as a clinical predictor of the need for antibiotics, does not reliably predict RVP results; however, symptom duration and number of symptoms were extracted from the HPI as part of this retrospective case review and were not obtained as part of a structured intake as might be done in a different study design. Cost and turn-around time remain problematic and may have influenced antibiotic prescribing practices which could not be measured within the scope of this study. Finally, there may have been increased testing practices during the COVID-19 pandemic.

However, these data suggest that if integrated into larger stewardship programs involving clinician education, a test-before-treat protocol could have a positive impact on avoiding unnecessary antibiotic use. Finally, the use of RVP diagnostic testing may offer other intangible benefits such as increased patient and clinician satisfaction. Further study, ideally using a randomized controlled trial and with larger numbers, would be helpful and could better define algorithms for use of RVP in outpatient clinical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.