FebriDx
The Science Behind the Accuracy

FebriDx® = 2 Biomarkers

FebriDx® produces a multiplexed result pattern combining C-reactive protein (CRP) and myxovirus resistance protein A (MxA).

Medical Professional with FebriDx

CRP is an acute phase inflammatory protein that is elevated in both viral and bacterial infections. Bacterial infection is a potent stimulus of marked CRP elevation. CRP is elevated within 4-6 hours of onset and is correlated with the severity of the infection. Normal CRP is less than 3 mg/L.1 It has been demonstrated that 38-56% of patients with viral acute respiratory infections (ARI) have CRP levels greater than 20 mg/L which may lead to unnecessary antibiotics being prescribed.2

MxA is an intracellular blood protein that is stimulated by interferon (IFN) alpha/beta cells.3 IFN cells are induced by viruses and form an essential part of the immune system’s defense against viral infections. MxA protein becomes elevated only in the presence of acute viral infections and not in bacterial infections.4

By combining an acute phase inflammatory protein, CRP, and a specific viral marker, MxA, the dual biomarker technology of FebriDx® improves the sensitivity and specificity of both markers. Neither CRP nor MxA alone is sensitive or specific enough to differentiate viral from bacterial infections. At low levels, CRP is very sensitive but non-specific at confirming bacterial infection. At high levels, the reverse is true. MxA is specific for viral infections only and will not be elevated in the presence of a bacterial infection.

FebriDx® optimises the sensitivity and specificity of both markers to accurately and reliably differentiate between viral and bacterial ARIs.

SENSITIVITY AND SPECIFICITY VALUES AT VARIOUS CUT-OFF LEVELS FOR CRP AND MxA
SENSITIVITY AND SPECIFICITY VALUES
AT VARIOUS CUT-OFF LEVELS FOR CRP AND MxA

FebriDx® Multi-Center
Clinical Study

Two prospective, multi-center clinical trials demonstrated high sensitivity and specificity of FebriDx® in differentiating clinically significant viral and bacterial ARIs.

These studies reveal a greater accuracy for differentiating viral and bacterial infections than CRP or procalcitonin alone. FebriDx® has a 97-99% NPV to assist in ruling out a bacterial infection.2,12

Clinical Trial Chart

ARIs are diagnosed and managed in GP settings solely by clinical signs and symptoms. Because viral and bacterial ARIs have similar symptoms, determining diagnosis and treatment by clinical observation alone may lead to misdiagnosis and unnecessary antibiotic treatment.

A FebriDx® test was performed on 21 patients (aged 3 years to 84 years) who had clinical diagnoses of an ARI (upper or lower respiratory tract infection). In each case, a clinical diagnosis was initially made by a GP.

FebriDx® improved the clinical management in 48% (10/21) of the patients including two patients that were clinically presumed viral but FebriDx® determined a bacterial infection. One of these patients was admitted to the hospital with sepsis.

FebriDx® reduced unnecessary antibiotics in 80% (8/10) of clinical cases without any adverse events.

FebriDx® was concluded to have high sensitivity and specificity for identifying a clinically significant infection and differentiating viral from bacterial cause.13

Physician and girl

Two UK studies prospectively evaluated the real-world diagnostic accuracy of FebriDx® for identifying COVID-19 in hospitalised adults.

STUDY 1 - Karim N, et al.14
A FebriDx® test was performed on 48 patients, of which 35 were confirmed to have a final diagnosis of COVID-19 using ECDC COVID-19 case definition.14-15

FebriDx® identified 35/35 (100%) of COVID-19 infections, whereas initial PCR SARS-CoV-2 test only identified 29/35 (82.9%). FebriDx® also identified 8/8 bacterial infections (100% sensitive and 92.5% specific).14

The use of FebriDx® as an initial triage test may have prevented COVID-19 negative patients being exposed to COVID-19 positive patients caused by the delay in molecular test results.14

FebriDx® can be successfully deployed as a reliable triage test amongst hospital or ED patients suspected to have COVID-19.

STUDY 2 - Clark TW, et al.16
FebriDx® was shown to be 93.2% (110/118) sensitive and 86.2% (112/130) specific for identifying COVID-19 infections compared to PCR.16

Seven FebriDx® viral patients (negative by PCR) had classical radiological features of COVID-19, and thus were likely true positives.16

By comparing FebriDx® to the ECDC COVID-19 case definition, FebriDx® would have been 93.6% (117/125) sensitive and 91.1% (112/123) specific, with PCR being 94.4% sensitive (118/125).15-16

The high sensitivity and NPV of FebriDx® enables viral negative patients to be rapidly cohorted in non-COVID-19 areas whilst viral positive patients are immediately isolated whilst awaiting confirmatory testing.

FebriDx® can be rapidly deployed as a front door triage tool in hospitals and urgent care centers to overcome current issues of delayed diagnosis from PCR testing.16

Study 1 - Karim N, et al. Study 2 - Clark TW, et al.

1. Okamura JM, Miyagi JM, Terada K, et al. Potential clinical applications of C-reactive protein. J Clin Lab Anal. 1990;4(3):231-5.
2. Shapiro NI, Self WH, Rosen J, et al. A prospective, multi-centre US clinical trial to determine accuracy of FebriDx point-of-care testing for acute upper respiratory infections with and without a confirmed fever. Ann Med. 2018;18:1-10.
3. Nakabayashi M, Adachi Y, Itazawa T, et al. MxA-based recognition of viral illness in febrile children by a whole blood assay. Pediatr Res. 2006;60:770-4.
4. Engelmann I, Dubos F, Lobert PE, et al. Diagnosis of viral infections using myxovirus resistance A (MxA). Pediatrics. 2015;135;e985-93.
5. Hatherill M, Tibby SM, Sykes K, et al. Diagnostic markers of infection: comparison of procalcitonin with C-reactive protein and leucocyte count. Arch Dis Child. 1999;81:417-21.
6. Andreola G, Bressan S, Callegaro S. Procalcitonin and C-reactive protein as diagnostic markers of severe bacterial infections in febrile infants and children in the emergency department. Pediatr Infect Dis J. 2007;26(8):672-7.
7. Moulin F, Raymond J, Lorrot M, et al. Procalcitonin in children admitted to hospital with community acquired pneumonia. Arch Dis Child. 2001;84:332-6.
8. Korppi M, Kroger L. C-reactive protein viral and bacterial respiratory infection in children. Scand J Infect Dis. 1993;25(2):207-13.
9. Kawamura M, Kusano A, Furuya A, et al. New sandwich-type enzyme-linked immunosorbentent assay for human MxA protein in a whole blood using monoclonal antibodies against GTP-binding domain for recognition of viral infection. J Clin Lab Anal. 2012;26:174-83.
10. Gendrel D, Rayond J, Coste J, et al. Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferonalpha for differentiation of bacterial vs. viral infections. Pediatr Infect Dis J. 1999;18(10):875-81.
11. Virkki R, Juven T, Rikalainen H, et al. Differentiation of bacterial and viral pneumonia in children. Thorax. 2002;57:438-41.
12. Self WH, Rosen J, Sharp SC, et al. Diagnostic accuracy of FebriDx: A rapid test to detect immune responses to viral and bacterial upper respiratory infections. J Clin Med. 2017;6(10):E94.
13. Davidson M. FebriDx point-of-care testing to guide antibiotic therapy for acute respiratory tract infection in UK primary care: A retrospective outcome analysis. J Infect Dis Preve Med. 2017;5:165.
14. Karim N, Ashraf MZ, Naseem M, et al. Utility of FebriDx in early identification of possible COVID-19 infection. Res Square. 2020;Epub ahead of print. https://www.researchsquare.com/article/rs-25802/v1
15. Case definition for coronavirus disease 2019 (COVID-19), as of 29 May 2020. European Centre for Disease Prevention and Control. Accessed 19 June 2020.
https://www.ecdc.europa.eu/en/covid-19/surveillance/case-definition
16. Clark TW, Brendish NJ, Poole S, et al. Diagnostic accuracy of the FebriDx host response point-of-care test in patients hospitalised with suspected COVID-19. J Infect. 2020;Epub ahead of print. doi: 10.1016/j.jinf.2020.06.051