The LAVA (Lateral Flow Antigen Validation and Applicability) Study for COVID-19
Condition: This is a Pilot Study Which Aims to Assess the Validity and Applicability of Lateral Flow Assays (LFAs) Which Can be Used as a Point of Care Test for COVID-19; Covid19
MeSH terms: COVID-19
Study type: Interventional

Summary: 
      This is a pilot study which aims to assess the validity and applicability of lateral flow
      assays (LFAs) which can be used as a point of care test for COVID-19. The study will focus on
      children admitted to hospital or planned to have a procedure for which they require an
      anaesthetic. RT-PCR is the current gold standard test for COVID-19, but it usually takes
      approximately 24-48 hours for a test result to be returned which can slow the clinical care
      given to a patient and can potentially increase the risk of healthcare worker (HWC) exposure
      to COVID-19. LFAs are a point of care test which can identify children who have a high viral
      load of COVID-19 and are performed using a more acceptable method of swabbing for children,
      just inside the nostril. Using LFA potentially enables the identification of infectious
      children with COVID-19 to aid with immediate care of patients and limiting HWC and other
      patients' contact with the virus. This study aims to assess the test failure rate and
      identify reasons for this which can be addressed. It also aims to assess the discomfort of
      both tests for children, provide a comparison between the time to LCA and RT-PCR result and
      provide data for a trial to adequately power a prospective trial comparing RT-PCR and LFA.
    

Detailed description: 
      During the ongoing COVID-19 pandemic, testing of children for COVID-19 has become an area of
      substantial need and intense scrutiny. The current gold-standard method for SARS-CoV-2
      detection is the real time reverse transcriptase polymerase chain reaction (RT-PCR),
      performed on a sample from the respiratory system. This diagnostic test identifies fragments
      of viral RNA which are specific to SARS-CoV-2 and amplifies them. It can detect even
      relatively low levels of RNA in people who have contracted the virus but have not yet
      developed a high viral load or symptoms. It can also detect RNA after the live virus has
      cleared, but fragments of the virus' RNA remain. This test has a high analytical sensitivity
      and specificity. However, obtaining an adequate specimen is more difficult in children as the
      test is uncomfortable and not always well tolerated. This means that the diagnostic
      sensitivity is approximately 80%(1). Nevertheless, RT-PCR currently remains the most accurate
      method of detection of SARS-CoV-2. However, logistical issues around RT-PCR mean that the
      availability and usability of the test is reduced. This is due to a combination of factors
      including testing site capacity, processing capacity and the time taken to process and report
      the results by centralised laboratories. The net result is that the high sensitivity and
      specificity of PCR is offset by the time lag for result reporting. In acute hospitals, these
      delays can lead to poor patient flow through clinical areas, overuse of personal-protective
      equipment (PPE) or late recognition of nosocomial transmission. Thus, rapid testing is of
      particular importance in identifying highly infective individuals, for example people who are
      about to undergo a high-risk aerosol generating procedure, enter a crowded emergency room, or
      in rapid investigation of localised outbreaks.

      Alternative methods and modalities of testing have therefore been explored, in particular the
      use of anterior nasal swabs to detect the SARS-CoV-2. Salivary RT-PCR is also under
      investigation(2, 3) but is affected by some of the limitations of performing RT-PCR on any
      sample, as described above. An alternative method of detection of SARS-CoV-2 is the use of
      antigen testing using a lateral flow assay (LFA)(4). Antigen-detection diagnostic test are
      designed to directly detect SARS-CoV-2 proteins produced by replicating virus in respiratory
      secretions. Most antigen rapid diagnostic tests use a sandwich immunodetection method using a
      simple-to-use lateral flow test format similar to a pregnancy test. Antigen detection tests
      have several advantages compared to RT-PCR; 1) it can be performed on an anterior nasal
      swabs- a specimen which is much more acceptably obtained in children-, 2) the results can be
      rapidly processed using a commercial kit at the bedside, with a result being available within
      30 minutes of the sample being taken, and 3) it is less expensive to perform an antigen test
      compared to RT-PCR. The trade-off for ease-of-use and rapid turnaround time of antigen tests
      is a decrease in sensitivity compared to RT-PCR, particularly if the person has a low viral
      load (e.g. they are early or late in the disease) because the levels of antigens present in
      the upper respiratory tract might fall below the threshold for detection. The analytical
      sensitivity appears to be approximately 50% overall, but this increases during periods of
      anticipated infectivity when the viral load is >60,000 (RT-PCR cycle time threshold <27) to
      approximately 90%. The specificity of antigen tests has consistently been reported to be very
      high (>97%). Thus, if the antigen test is positive then it is very likely that it is a true
      result, and the person does have COVID-19. Antigen-detection tests are therefore primarily
      being used to detect infectivity of an individual, rather than being used as a clinical
      diagnostic test for COVID-19.

      The potential application of LFAs to defeat Covid-19 are evident, with several clinical
      scenarios below demonstrating areas where comparing the performance of RT-PCR to LFA could
      improve the care of children and improve the safety of staff in hospital. However, evaluation
      of the use of these tests in clinical settings is essential before full implementation in
      routine clinical practice is advised.

      At present, all children are tested for COVID-19 with RT-PCR when they are admitted to
      hospital, regardless of their symptoms. During the winter months, when more children with
      respiratory symptoms will seek medical care, current guidance recommends isolation or
      cohorting of these patients within hospital until their SARS-CoV-2 test is back(5). However,
      the majority of children are likely to have an alternative cause for their symptoms, such as
      respiratory syncytial virus, adenovirus or influenza. Early identification of infectious
      children with COVID-19 using a point of care test would allow for more effective cohorting or
      isolation to occur and potentially reduce the spread of COVID-19 in hospital settings, not
      just from children but their parents too who are likely to be infected as a household
      contact. Besides, early identification of children with COVID-19 using LFA will aid
      compliance with stringent use of PPE for healthcare workers caring for these children.

      Children being admitted for elective procedures are currently also routinely tested for
      COVID-19 with a nasopharyngeal swab prior to admission. This is performed to reduce the
      chance of them harbouring SARS-CoV-2 at the time of having a high-risk aerosol generating
      procedure (AGP), where the risk of transmission of SARS-CoV-2 to staff is increased.
      Generally, these children are asymptomatic, as the presence of ILI symptoms often precludes
      an anaesthetic being performed. In this population, LFAs could be used to identify children
      who were incubating SARS-CoV-2 at the time of swabbing but were not shedding the virus who
      have subsequently progress to start shedding the virus (Table 1). Performing LFA potentially
      enables infectious children to be identified and can be used to guide decisions around
      proceeding with a procedure and the use of PPE in children when the procedure goes ahead.

      Finally, LFAs could be used in 'high risk' hospital areas, particularly intensive care and
      high dependency units where high-risk AGPs are commonly performed and where children are more
      likely to have symptoms which are in-keeping with COVID-19. Surveillance of SARS-CoV-2 using
      RT-PCR is being performed routinely in some units, but a 24-48 hour delay in the result has
      minimal impact on practice around AGPs. LFAs may be utilised as a screening tool for
      infectious patients in these areas to support the use of appropriate PPE.

      Further use of these tests could also be considered within health care worker (HCW) screening
      for infectivity after known exposures to Covid-19 cases, to limit the number of HCW absences
      due to potential exposure both outside and inside the hospital. They could potentially also
      be used in the community, in settings such as schools and sports clubs, to identify
      infectious individuals. Validation and usability in a controlled clinical setting is
      recommended prior to use in the wider community. Mathematical analysis of LFAs shows that,
      due to their high specificity, the negative predictive value is good in times of both high
      and low prevalence, even when the sensitivity of the test is low.
    

Intervention name(s): Innova Lateral Flow Device
Intervention type(s): Device
Intervention description(s): The Innova Lateral Flow Device will be used on anterior nasal swab specimens and RT-PCR will be performed on nose and throat swabs.
Intervention model: Single Group Assignment
Intervention model description: Paired testing
Masking: None (Open Label)
Primary purpose: Diagnostic