Guidance

Investigation and management of suspected SARS-CoV-2 reinfections: a guide for clinicians and infection specialists

Published 15 March 2021

Applies to England

Purpose and scope

This guidance is intended for clinicians (primary and secondary care) who may encounter individuals suspected to have been reinfected with SARS-CoV-2.

The purpose of this guidance is to inform clinicians:

• when to suspect SARS-CoV-2 reinfection
• how to initially investigate patients with suspected SARS-CoV-2 reinfection
• how to perform a risk assessment and who does this
• what further investigation is needed for SARS-CoV-2 reinfection and how to interpret testing
• what public health and surveillance actions are required

Additional information is also provided for infection specialists.

This guidance does not cover clinical or infection prevention and control management of patients with COVID-19 infection.

Background – what SARS-CoV-2 reinfection is and why it’s important

Reinfection refers to a new infection with SARS-CoV-2 following previous confirmed (SARS-CoV-2 RT-PCR positive) infection and is distinct from persistent infection and relapse of infection. Reinfection with SARS-CoV-2 remains rare, though especially in the context of high prevalence, cases will occasionally occur.

Identification of reinfection is challenging for several reasons including:

• there is currently no standard case definition for a SARS-CoV-2 reinfection
• SARS-CoV-2 PCR positivity may persist for prolonged periods (frequently up to 90 days, sometimes beyond) following initial infection without necessarily indicating viable virus
• PCR may also be intermittently negative
• asymptomatic infection is common
• there is limited availability of diagnostics to routinely identify reinfection to inform clinical and public health practice in real time

It is important to promptly identify individuals with suspected SARS-CoV-2 reinfection to initiate public health actions to reduce risk of onward transmission and ensure appropriate and clinical management.

When to suspect SARS-CoV-2 reinfection

Reinfection should be considered in the following circumstances:

• a repeat positive SARS-CoV-2 PCR test 90 days or more after a previous positive PCR test
• new COVID-19 symptoms in a patient with previous SARS-CoV-2 PCR positive infection after apparent full recovery (resolution of previous symptoms) AND a repeat positive SARS-CoV-2 PCR test (including within 90 days after a previous positive PCR test)

Clinical and public health management of suspected SARS-CoV-2 reinfection

Patients with suspected reinfection should be managed as if they are infectious, as for a new or first infection and should be instructed to self-isolate pending further investigation and clinical risk assessment.

Inform the individual that a COVID-19 illness due to reinfection (if confirmed) may not necessarily follow the same clinical course as the last time they had the infection; the illness could range from asymptomatic to severe and they should seek medical support as appropriate for their clinical condition.

How to investigate patients with suspected SARS-CoV-2 reinfection – initial steps

You should take a full history from the patient to capture both clinical and epidemiological information including:

• nature of symptoms (consistency with COVID-19) if present
• onset or timing of symptoms relative to prior confirmed infection and whether acute or new versus persistent
• any underlying immunosuppression
• recent contact with a recently confirmed case
• overseas travel history in the last 10 days
• vaccination status (including the number and timing of doses)

If a suspected reinfection case has been identified in the community (for example through Pillar 2 testing), you should organise an additional PCR test via pillar 1 specifically to enable measurement of cycle threshold (Ct) values.

If the patient has presented with COVID-19 or other upper respiratory symptoms, an alternative diagnosis should be excluded:

• for example, consider testing with a full respiratory viral panel profile, in addition to taking bacterial respiratory samples, an atypical pneumonia screen, and other serology tests as appropriate (consider seeking advice from infection specialist if or as required)

If after initial assessment you still suspect an individual has SARS-CoV-2 reinfection, please contact your local infection service (infectious disease, microbiology, virology) to collectively perform initial risk assessment (see below) and discuss further investigation and sample collection.

How to perform a risk assessment for SARS-CoV-2 reinfection and who does this

A risk assessment involves reviewing available clinical, diagnostic and epidemiological information to inform whether reinfection with SARS-CoV-2 is likely and to inform further investigation and management.

A risk assessment is primarily the responsibility of the diagnosing or treating clinician though will need to be performed with the support of an infection specialist.

Risk assessment is not currently formalised though it is expected that the principles described should guide decision making and be documented.

The following factors should be considered in a risk assessment:

• index of clinical suspicion for reinfection (considering onset and nature of symptoms relative to previous confirmed infection)
• cycle threshold (Ct) value if available (see below)
• epidemiological factors which might increase suspicion of reinfection such as: close contact with a recently confirmed case or if the patient is considered a ‘person at risk from SARS-CoV-2 variants of concern or variants under investigation’
• related factors such as prior vaccination (prior vaccination should not rule out further investigation, however should the case be confirmed as reinfection, further steps may be required as outlined in the post-implementation vaccine surveillance strategy)

The following factors make reinfection much less likely:

• if the second PCR test is within 90 days from the initial infection and the individual is asymptomatic, it is more likely to be a persistent positive result
• persistent rather than new symptoms (aside from fever) since previous positive test

If after risk assessment SARS-CoV-2 reinfection is still suspected, further investigation is indicated.

Further investigation for SARS-CoV-2 reinfection and interpretation of testing

Further investigation following initial risk assessment should be informed by an infection specialist.

Cycle threshold (Ct) value should be ascertained and reviewed as part of, or after, initial risk assessment. Viral load is estimated by the Ct value, with an inverse relationship e.g. a high Ct value reflects a low viral load:

• a low Ct value is suggestive of recent infection (whilst a value of 35 is often referred to as an appropriate threshold to differentiate low and high, a cut-off is not proposed here in view of operational considerations and may be dependent on the platform used)
• a high Ct value of can be more indicative of a prolonged PCR positive result – repeat positives can hover around the threshold limit of detection so do not necessarily reflect reinfection even with an intermediary negative result
• the infection specialist will liaise with the relevant laboratory team to ascertain the reliability, the analytical sensitivity and specificity of the tests, and to determine which SARS-CoV-2 PCR targets were positive over time

Further investigation may include serological testing and whole genome sequencing as advised by your local infection service subject to clinical risk assessment.

Diagnosing SARS-CoV-2 reinfection

A compatible clinical presentation together with diagnostic evidence (such as low Ct value) may be sufficient to diagnose SARS-CoV-2 reinfection.

A diagnosis of SARS-CoV-2 reinfection should be made in conjunction with an infection specialist following risk assessment.

Confirmation of reinfection will be obtained through whole genome sequencing of paired specimens, if available, which will be organised via an infection specialist but should not delay implementation of infection prevention and control and self-isolation measures.

Surveillance actions for SARS-CoV-2 reinfection

Cases of COVID-19 infection are statutorily notifiable. Ensure the case is notified. When reinfection is suspected, it is particularly important to notify the reinfection as such; the notification form allows free text ‘reinfection’ in the ‘Disease, infection or contamination’ section.

Additional notes for infection specialists

Investigation of suspected SARS-CoV-2 reinfection

If prolonged PCR positivity and alternative diagnoses have been excluded and there remains a high clinical suspicion or risk of reinfection, discuss what serological assays are available with laboratory services and how they may assist in clarifying the diagnosis.

Investigate, where relevant, for severe immunosuppression as defined in the Green Book on Immunisation.

If prolonged positivity or an alternative diagnosis have been excluded, inform the individual that the laboratory will be undertaking further work to determine if this is a definite reinfection.

Where SARS-CoV-2 reinfection is suspected

Consider follow up antibody tests conducted 14 to 28 days after the second infection to determine if there has been a change in the antibody profiles, if they have an initial test performed. If not, please ensure antibody tests are performed on this occasion. Antibody tests against both the spike and N protein should be performed.

Whole genome sequencing should be conducted to identify phylogenetic similarity by COG-UK (COVID-19 genomics UK consortium) centres, or locally if available. This will also identify whether the new infection is due to a different variant and will provide additional information on the epidemiology of the new variants of concern or under investigation. If possible, forensic analysis using human genotyping can ensure the samples originate from the same individual and therefore there is no possibility of laboratory mix-up.

If the individual has been vaccinated please ensure the steps outlined for enhanced surveillance have been undertaken, including completion of the online form and sending of the minimal sample set to the reference lab.

Consider suitability for entry into clinical characterisation studies for example, the Humoral Immune Correlates of COVID-19 (HICC) consortium study.