An interesting article by Moran and others published in The Lancet Infectious Diseases August 16th discusses this issue.

The management of patients presenting to healthcare service with SARS-CoV-2 infection has developed rapidly over the past year, driven by the findings of high quality randomised trials. 

These trials have been justifiably focused on preventing severe disease in patients with very early infection and on the treatment of acutely unwell patients.  However, it has become apparent that there are specific patient cohorts not well served by these studies, to whom their conclusions might not apply and who, as a consequence, risk missing out on access to potentially beneficial treatments. 

Patients with persistent SARS-CoV-2 infection are one such cohort.  Persistent SARS-CoV-2 infection can occur in certain immunocompromised people, such as those with primary immunodeficiency or recipients of immunosuppressive therapy, for example B cell depleting anti-CD20 treatment or chimeric antigen receptor T-cell therapy following bone marrow transplantation.  

These individuals are well known to be at risk of other chronic viral infections, including Norovirus and rhinovirus.

Although some patients might experience severe disease and fatal outcomes, many others might not require hospitalisation, but are unable to clear their coronavirus infection.

They can experience months of cough, fever, breathlessness and debilitation, often with episodes of apparent clinical recovery followed by deterioration.  

The reports have confirmed the viable virus can be cultured from these individuals, many months after the initial infection, and they commonly do not develop an anti SARS-CoV-2 antibody response.  

The antiviral drug Remdesivir can ease symptoms and has been associated with viral clearance and sustained improvement in some patients, yet in others it appears to produce only a transient drop in viral load, with recrudescence once treatment stops.  

Antibody therapy, whether with convalescent plasma or synthetic monoclonal antibody cocktails, holds promise.  There are convincing reports of complete symptom resolution and sustained viral clearance often after receipt of these therapies in patients will have many months of illness.  

Over 30 such cases have been reported in the UK, but the total number of affected individuals is not known.  Data collected from these cases confirmed the clinical impression that Remdesivir monotherapy is associated with frequent relapses or PCR persistent positivity, but monoclonal antibody therapy combined with Remdesivir has been associated with near universal viral clearance and clinical recovery.  

Currently, there is no access to these treatments in the UK for patients with persistent infection.  There does not appear to be any support for their compassionate use from pharmaceutical companies, and convalescent plasma has been withdrawn following demonstration that is ineffective in immunocompetent hospitalised patients.  

Synthetic antibody therapy has already been authorised for emergency use in the EU and USA for patients with mild or moderate disease, and work is in progress to define the criteria for access to these therapies in the UK, in light of the preliminary results of the casirivimab plus imdevimab arm of the RECOVERY trial.  

These results, however, do provide a way forward.  Although this trial was not designed to address treatment strategies in patients with persistent infection, it did find a mortality benefit in seronegative patients.  

This finding supports the rationale for benefit in patients who are unlikely to generate an antibody response, although no randomised controlled trial conducted specifically within this patient group has been published, and such a trial will be challenging given small patient numbers.

It is important that any potential benefit for this small but important cohort is not overlooked.  Beyond treatment of sick individuals trapped in hospital or at home in perpetual self-isolation with a risk of developing chronic lung disease, there are compelling public health arguments for attempting a cure.  

Analysis of viral sequences obtained from such patients over time suggests ongoing viral evolution within immunosuppressed individuals, potentially facilitating the emergence of new strains within the wider population. 

It has been suggested that such treatments could themselves risk driving the selection of resistance, and thus any treatment regime would require close monitoring of viral evolution and early recognition of any unintended consequences.  

The authors of this paper agree that such monitoring is mandatory and deliverable for these patients regardless of treatment.  However, rapid viral elimination using a combination of antivirals and high titre antibody based therapy would prevent any further evolution.  

The small patient numbers need not be an impediment to deliver well designed trials of potential therapies.  

In the absence of such trials, a rigorously overseen national treatment protocol incorporating the collection of virological and clinical outcomes data could be delivered safely.

Whatever route is chosen to develop and deliver therapies, a strategy to reduce morbidity and protect public health is needed urgently.  

The London General Practice, the leading London doctors’ clinics provides a full diagnostic, treatment and management programme for patients with all aspects of COVID infection and SARS-CoV-2 diagnosis.

Dr Paul Ettlinger

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