Acute respiratory tract infection (ARTI) is a common illness presenting to General Practice in the United Kingdom. General practitioners (GPs) regularly assess patients presenting with symptoms suggestive of ARTI, which can include otitis media, sinusitis, pharyngitis, acute bronchitis and pneumonia [1]. Viral and bacterial infections clinically present similarly and are frequently misdiagnosed.

The decision to prescribe antibiotics for ARTI is challenging [2,3] and is frequently based solely on clinical symptoms and signs, which is known to be of limited value [4-6] because of their inherent low sensitivity and specificity [7,8]. Diagnostic uncertainty and patientrelated factors, such as patient expectations and pressure, often lead GP’s to unnecessarily prescribe empiric antibiotic treatments.

The use of antibiotics in a population is the primary driver of the development of resistant bacteria and it is estimated that more than 25,000 patients die annually in the European Union due to multidrugresistance (MDR) in bacterial infections [9]. A reduction in the excess antibiotic use is critical for combating the growing number of resistant infections [10]. Moreover, antibiotics are the second most common cause of adverse drug events in the elderly and account for 20% of all drug-related emergency department visits in the United States of which 80% of which are for allergic reactions [11]. Furthermore, antibiotics lead to diarrhoea in 2-25% and C. difficile infection is the major identifiable cause of antibiotic-associated diarrhoea and is responsible for 15–25% of all cases of diarrhoea [12]. Unnecessary antibiotic use for ARTI is an important public health problem [13] that not only contributes to the selection of resistant microorganisms [14] but also increases the frequency of adverse events and subsequently results in higher medical expenditures [15].

Improving diagnostic certainty may help identify those patients that will benefit from antibiotic treatment [16-18]. A meta-analysis that looked at 13 studies of upper respiratory tract infection (URI) and lower respiratory tract infection (LRTI) on the association between point-of-care (POC) C-reactive protein (CRP) testing and antibiotic prescribing for ARTIs in general practice found that CRP testing significantly decreased antibiotic prescribing at the initial consultation [19]. Any reduction in antibiotic consumption will have a relatively higher impact when done in a primary care setting [20,21]. Excessive use of antibiotics drives the development of antimicrobial resistance, medicalisation of patients and increases health care costs [22,23].

A five-year United Kingdom national antimicrobial resistance strategy, comprising seven areas for action aimed at controlling and ideally reducing the burden of resistance was initiated [24]. Two key parameters of the national antimicrobial resistance strategy, improved diagnostics and improved antibiotic stewardship both may be positively impacted with FebriDx, a new rapid POC test that can identify clinically significant infections and aid in the differentiation of viral from bacterial ARTIs. An outcome analysis was performed to confirm the clinical impact of FebriDx testing.

A retrospective chart review was performed on 21 patients that presented to an outpatient general practice and were administedred the FebriDx test. The objective was to determine if the FebriDx test results impacted therapeutic decisions that would have been otherwise determined based solely on clinical exam findings. In each case, a suspected clinical diagnosis was identified, the FebriDx test recorded, antibiotic prescriptions analysed, and the response to therapy evaluated. The patient’s history and medical chart was reviewed to confirm any medical consultations or hospital admissions in the month period following the use of the FebriDx test. This was a retrospective analysis based on a chart review, and does not involve any new studies of human or animal subjects performed by the author, and deemed exempt from IRB approval.

Each patient underwent testing with FebriDx^® (RPS Diagnostics; Sarasota, FL), which is a rapid, qualitative, single-use, disposable, whole blood immunoassay with a turn-around time of 15 min [25] Sambursky 2015. FebriDx requires 10 μL of whole blood obtained by capillary (“finger”) stick. It provides a qualitative red test line result line for elevated levels of myxovirus resistance protein A (MxA) (≥ 40 ng/ml), and a black test line result for CRP with separate CRP thresholds of 20 mg/L (“low CRP” threshold) and 65 mg/L (“high CRP” threshold), and the presence of test lines in both control positions indicated a valid test result. FebriDx results indicating an elevated MxA, with or without an elevated CRP test line, was interpreted as a viral infection and the presence of any CRP test results without an associated elevated MxA, was interpreted as a bacterial infection.

FebriDx testing was performed on 21 patients with a mean age of 46.3 years, ranging in age from 3 years to 84 years old, including 12 males and 9 females. Patients had clinical diagnoses of nonspecific URTI and LRTI (Table 1).

Table 1: Patients tested with FebriDx.

FebriDx altered clinical management in 48% (10/21) and reduced antibiotics in 80% (8/10) clinical cases of possible bacterial infection. In two cases, the physician prescribed an antibiotic despite the test result including 1) a 3 year old patient that presented with sudden lethargy and respiratory signs tested negative within 4 h after symptoms began and was prescribed antibiotics despite the negative FebriDx test; 2) an immunocompromised patient with 10 days of persistent symptoms and was prescribed antibiotic despite the negative FebriDx test. All patients, inclusive of those patients given antibiotics or withheld antibiotics, demonstrated full clinical recovery at 1 month without additional unscheduled medical consultations or subsequent newly initiated antibiotic prescriptions. One FebriDx positive patient for bacterial infection was subsequently diagnosed with bacterial sepsis and admitted to the hospital (Table 2).

Table 2: Diagnostic demographic analysis and impact on clinical management.

The current standard of care for the management of patients with acute respiratory tract symptoms in the United Kingdom outpatient setting are diagnosed by general practitioners clinically without the additional aid of ancillary laboratory testing such as rapid antigen testing, bacterial cell cultures, or molecular tests. In this retrospective chart review, use of the FebriDx test lowered the rate of antibiotic prescriptions without leading to increased morbidity, mortality, increased consultations, or increased complications. FebriDx results altered the clinical management plan in 48% of the patients tested including two patients that were clinically presumed viral infection that FebriDx determined a bacterial infection and led to antibiotic therapy. Of note, one of these patients was admitted to the hospital with sepsis. Of the 21 patients tested with FebriDx, 81% (17/21) were determined to be nonbacterial, 29% viral (6/21) and 52% negative (11/21) with the FebriDx test. Two patients were tested within several hours of symptom onset while several others were tested up to 10 days later. The FebriDx negative patients were thought to possibly represent illness too early in the course of the infectious process, illness that already transitioned from the acute phase to the recovery phase of infection to stimulate a systemic response, or suggested a clinically insignificant illness. Symptomatic patients presenting more than a week after symptom onset may have a component of reactive airway disease contributing to their lingering symptoms. Antibiotics were withheld in 80% (8/10) patients that were clinically a possible bacterial infection but tested either as viral positive or negative with the FebriDx test. Clinically, these patients had a high enough clinical suspicion for a bacterial infection that an antibiotic prescription would have been prescribed without the FebriDx result.

A single case of a 3 year old patient that presented with sudden lethargy and respiratory signs tested negative within 4 h after symptoms despite the negative FebriDx test. This physician discretion was due to the age of the patient, his sudden physical deterioration, and the physician’s lack of experience with the FebriDx test. Also, an immunocompromised patient with a 10 day history of symptoms was prescribed antibiotics despite the FebriDx negative result. Given that ancillary laboratory testing should be viewed in the context of the clinical condition, confronted with similar clinical circumstance in the future, antibiotics would likely be withheld and a watchful waiting strategy instituted.

All 96% (20/21) of the patients recovered completely without any clinical complications. One patient, confirmed positive for bacterial infection with FebriDx, was admitted with sepsis to the hospital. Two patients presented for routine scheduled follow up including a patient with a bacterial positive FebriDx result that was confirmed bacterial positive Group A Streptococcus with oropharyngeal cell culture that required an extended course of antibiotics and a patient with a viral diagnosis with FebriDx was seen with improvement obviating any need for prescribing antibiotics.

It is known that the patients’ perceived expectations can influence the decision to prescribe antibiotics [26]. Further, patients seen on a Friday that might be developing a significant ARI when follow up access to the practice would not be possible for several days, typically would result in the temptation to prescribe an antibiotic. However, the availability of the FebriDx results at the office visit helped support the clinical decision to withhold antibiotics in 3 patients presenting on Friday and pursue a watchful waiting strategy.

POC CRP testing is a cost-effective part of the routine evaluation of patients with LRTI in general practice in Scandinavia [27,28]. A normal CRP in a patient with symptoms of respiratory infection usually indicates a self-limiting infection that does not require referral to hospital or antibiotic treatment, although it may also be observed early in the presentation of an illness [29]. A systematic review and meta-analysis of 13 studies in primary care demonstrated CRP testing led to significantly reduced antibiotic prescribing at the index consultation [19]. Patient recovery without antibiotics at the same speed and with comparable rates of complications (hospitalisation, mortality, and number of re-infections), suggest that the infection was of non-bacterial origin or so mild that the immune defense could clear the infection unassisted [30].

CRP testing may help to identify respiratory tract infections that have a higher likelihood for a complicated course and support a delayed prescribing strategy for low risk patients [31]. Delayed prescriptions based on CRP assistance resulted in an absolute 50% lower fill rate compared with delayed prescription in the control group [31]. As a single biomarker, CRP is less sensitive but more specific for confirming the presence of a bacterial infection at high concentrations but at lower concentrations of CRP is frequently observed during both viral and bacterial infections [32]. Certain viral infections, such as influenza, adenovirus, and others have been shown to cause substantial increases in CRP [33-36]. Using only CRP as a single biomarker at a cut off of 20 mg/L will reduce the risk of missing a clinically significant bacterial infection but simultaneously lead to overtreatment of viral infections that do not necessitate any antibiotic therapy.

MxA protein expression in peripheral whole blood is a specific biomarker for viral infection [25,37-42]. Higher levels of MxA level are seen in viral infections compared to bacterial infection and this can be explained by the fact that the MxA protein is induced exclusively by type I IFN and not by IFN-gamma, IL-1, TNF-alpha, or any of the other cyotokines induced by bacterial infections [43].

Independently, neither MxA nor CRP alone is sensitive or specific enough to differentiate viral from bacterial infection. FebriDx testing results improved clinical management decisions and resulted in a reduction in antibiotic therapy without any adverse events. The simultaneous identification of both MxA and CRP, allows MxA to confer enhanced specificity onto the CRP biomarker [44]. FebriDx has high sensitivity and specificity for identifying a clinically significant infection and aiding in the differentiation of viral from bacterial infection. Since the test has a 97% NPV for bacterial infection, this supports watchful waiting prior to initiating antibiotics and supports antibiotic stewardship [45].

POC testing should be viewed as an aid to the clinical exam that can increase the selectivity for determining the infectious etiology. This strategy may be demonstrated for patients with pharyngitis and bronchitis. Since group A or C beta-haemolytic Streptococcus is the most frequent, and arguably the only common cause for bacterial pharyngitis requiring initial antibiotic treatment, patients presenting with symptoms of pharyngitis without a significant cough or rhinitis that test positive for bacterial infection could be treated presumptively for Streptococcus with Penicillin. Patients presenting with cough consistent with bronchitis who test positive for a bacterial infection may have one of a range of common pathogens including Haemophilus influenzae, Streptococcus pneumoniae, Mycoplasma or Chlamydophila , for which a Macrolide or Tetracycline may be considered. Amidst influenza season, a viral positive test within the first 24 h of presentation would suggest an influenza infection and could justify antiviral therapy. Those patients negative for a clinically significant infection or confirmed viral positive, may be initially treated without antibiotics and only with supportive measures.

This study has three primary limitations including the small sample size, single centre and the lack of prospective, randomised controlled trial results, which can result in selection bias. The data supports pursuing larger outcome studies.

POC testing is not the current standard of care in the United Kingdom today and acute respiratory tract infections are routinely managed based only on clinical symptoms and signs. POC diagnostic testing with the FebriDx test may help primary care general practitioners cost-effectively manage patients presenting with clinical evidence of an ARTI. FebriDx test results improved clinical management decisions and resulted in a significant reduction in antibiotic therapy without any subsequent testing related adverse events. Larger antibiotic outcome studies should be performed to evaluate FebriDx’s potential to mitigate against antibiotic resistance and save healthcare costs.

No funding or sponsorship was received for this study.

Author declares no financial interest or conflict of interest.

Editorial assistance in the preparation of this manuscript was provided by John Clague and supported by Prospect Diagnostics LTD.