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Coronavirus: ‘Promising new treatments must be explored immediately’

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The major effort in coping with the new coronavirus has been around isolation etc (short-term) and finding a vaccine (long-term), but international experts argue in The Lancet that there are other promising treatments that should be explored immediately, writes MedicalBrief.

Reducing mortality from 2019-nCoV: host-directed therapies should be an option. The number of confirmed cases of the 2019 novel coronavirus (2019-nCoV) reported to World Health Organisation (WHO) continues to rise worldwide, write researchers at the University College London, University College London Hospitals NHS Foundation Trust, Chinese University of Hong Kong, Prince of Wales Hospital, King Abdulaziz University, Jeddah, Alfaisal University, Riyadh, Saudi Arabia, Champalimaud Centre for the Unknown, Lisbon and the University of Mainz, in The Lancet.

They write: As with two other WHO Blueprint priority coronaviruses, SARS-CoV and MERS-CoV, 2019-nCoV is lethal. The mainstay of clinical management is largely symptomatic treatment, with organ support in intensive care for seriously ill patients.

The unprecedented flurry of activity by WHO and other global public health bodies has mainly focused on preventing transmission, infection control measures, and screening of travellers. The development of vaccines has received immediate funding; however, as with SARS-CoV and MERS-CoV, support for developing treatments for 2019-nCoV that reduce mortality has not been forthcoming. There is an urgent need for focusing funding and scientific investments into advancing novel therapeutic interventions for coronavirus infections.

All three coronaviruses induce excessive and aberrant non-effective host immune responses that are associated with severe lung pathology, leading to death. Similar to patients with SARS-CoV and MERS-CoV, some patients with 2019-nCoV develop acute respiratory distress syndrome (ARDS) with characteristic pulmonary ground glass changes on imaging. In most moribund patients, 2019-nCoV infection is also associated with a cytokine storm, which is characterised by increased plasma concentrations of interleukins 2, 7, and 10, granulocyte-colony stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and tumour necrosis factor α. In those who survive intensive care, these aberrant and excessive immune responses lead to long-term lung damage and fibrosis, causing functional disability and reduced quality of life.,

Specific drugs to treat 2019-nCoV will take several years to develop and evaluate. In the meantime, a range of existing host-directed therapies that have proven to be safe could potentially be repurposed to treat 2019-nCoV infection. Several marketed drugs with excellent safety profiles such as metformin, glitazones, fibrates, sartans, and atorvastin, as well as nutrient supplements and biologics could reduce immunopathology, boost immune responses, and prevent or curb ARDS.

Zinc and other metal-containing formulations appear to have anti-viral activity, are safe, cheap, and readily available. These formulations could be used as adjuncts to monotherapy or as combinational therapies with cyclosporine, lopinavir–ritonavir, interferon beta 1b, ribavirin, remdesivir, monoclonal antibodies, and anti-viral peptides targeting 2019-nCoV. Tocilizumab, a monoclonal antibody that targets the interleukin 6 receptor, has a good safety profile. Monoclonal and polyclonal antibodies to 2019-nCoV could be developed for post-exposure prophylaxis.

Ongoing trials of cellular therapies for treatment of ARDS could be expanded to treatment of seriously ill patients with 2019-nCoV infection. Cellular therapy, using mesenchymal stromal cells from allogeneic donors, has been shown to reduce non-productive inflammation and affect tissue regeneration and is being evaluated in phase 1/2 trials in patients with ARDS. Infection with 2019-nCoV appears to be initially associated with an increased Th2 response, which might reflect a physiological reaction to curb overt inflammatory responses, a clinical phenomenon that guided the optimal timing of interferon treatment in patients with sepsis, resulting in increased survival. Interleukin 17 blockade might benefit those patients who have a 2019-nCoV infection and increased plasma concentration of interleukin 17.

The isolation and short-term expansion of anti-viral directed T cells has been proven to be a life-saving procedure in patients after autologous hematopoietic stem-cell transplantation with cytomegalovirus infection. Expansion of anti-2019-nCoV-specific T cells, as cellular drugs, could aid to prepare T-cell products for the adjunct treatment of patients with severe 2019-nCoV infection.

Several unique opportunities to evaluate a range of treatment interventions at the peak of the SARS-CoV and MERS-CoV outbreaks were missed due to avoidable delays and subsequent decline of the numbers of cases, leaving numerous questions about coronavirus pathogenesis unanswered. Disappointingly, treatment trials registered for MERS-CoV are still not complete. As the 2019-nCoV continues to spread and evolve, and the numbers of deaths rise exponentially, advancing new therapeutic development becomes crucial to minimise the number of deaths from 2019-nCoV infection.

We declare no competing interests. Alimuddin Zumla is co-principal investigator of the Pan-African Network on Emerging and Re-emerging Infections (PANDORA-ID-NET), funded by the European & Developing Countries Clinical Trials Partnership, supported under Horizon 2020, the EU’s Framework Programme for Research and Innovation, and a National Institutes of Health Research senior investigator. Markus Maeurer is a member of the innate immunity advisory group of the Bill & Melinda Gates Foundation, and his work is funded by the Champalimaud Foundation.

Authors
Alimuddin Zumla, David S Hui, Esam I Azhar, Ziad A Memish, Markus Maeurer

Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced , write researchers led by Justin Stebbing at Imperial College London in The Lancet. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins, have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination.

BenevolentAI‘s knowledge graph is a large repository of structured medical information, including numerous connections extracted from scientific literature by machine learning. Together with customisations bespoke to 2019-nCoV, we used BenevolentAI to search for approved drugs that could help, focusing on those that might block the viral infection process. We identified baricitinib, which is predicted to reduce the ability of the virus to infect lung cells.

Most viruses enter cells through receptor-mediated endocytosis. The receptor that 2019-nCoV uses to infect lung cells might be ACE2, a cell-surface protein on cells in the kidney, blood vessels, heart, and, importantly, lung AT2 alveolar epithelial cells (figure). These AT2 cells are particularly prone to viral infection. One of the known regulators of endocytosis is the AP2-associated protein kinase 1 (AAK1). Disruption of AAK1 might, in turn, interrupt the passage of the virus into cells and also the intracellular assembly of virus particles.

Of 378 AAK1 inhibitors in the knowledge graph, 47 have been approved for medical use and six inhibited AAK1 with high affinity. These included a number of oncology drugs such as sunitinib and erlotinib, both of which have been shown to inhibit viral infection of cells through the inhibition of AAK1. However, these compounds bring serious side-effects, and our data infer high doses to inhibit AAK1 effectively. We do not consider these drugs would be a safe therapy for a population of sick and infected people.

By contrast, one of the six high-affinity AAK1-binding drugs was the janus kinase inhibitor baricitinib, which also binds the cyclin G-associated kinase, another regulator of endocytosis. Because the plasma concentration of baricitinib on therapeutic dosing (either as 2 mg or 4 mg once daily) is sufficient to inhibit AAK1, we suggest it could be trialled, using an appropriate patient population with 2019-nCoV acute respiratory disease, to reduce both the viral entry and the inflammation in patients, using endpoints such as the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia.

Authors
Peter Richardson, Ivan Griffin, Catherine Tucker, Dan Smith, Olly Oechsle, Anne Phelan, Justin Stebbing

The 2019 novel coronavirus (2019-nCoV) outbreak is a major challenge for clinicians, write researchers at the Roslin Institute at the University of Edinburgh and the Queen’s Medical Research Institute Edinburgh in The Lancet. The clinical course of patients remains to be fully characterised, little data are available that describe the disease pathogenesis, and no pharmacological therapies of proven efficacy yet exist.

Corticosteroids were widely used during the outbreaks of severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, and are being used in patients with 2019-nCoV in addition to other therapeutics. However, current interim guidance from WHO on clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected (released Jan 28, 2020) advises against the use of corticosteroids unless indicated for another reason. Understanding the evidence for harm or benefit from corticosteroids in 2019-nCoV is of immediate clinical importance. Here we discuss the clinical outcomes of corticosteroid use in coronavirus and similar outbreaks.

Acute lung injury and acute respiratory distress syndrome are partly caused by host immune responses. Corticosteroids suppress lung inflammation but also inhibit immune responses and pathogen clearance. In SARS-CoV infection, as with influenza, systemic inflammation is associated with adverse outcomes. In SARS, inflammation persists after viral clearance. Pulmonary histology in both SARS and MERS infections reveals inflammation and diffuse alveolar damage, with one report suggesting haemophagocytosis. Theoretically, corticosteroid treatment could have a role to suppress lung inflammation.

In a retrospective observational study reporting on 309 adults who were critically ill with MERS, almost half of patients (151 [49%]) were given corticosteroids (median hydrocortisone equivalent dose [ie, methylprednisolone 1:5, dexamethasone 1:25, prednisolone 1:4] of 300 mg/day). Patients who were given corticosteroids were more likely to require mechanical ventilation, vasopressors, and renal replacement therapy.

After statistical adjustment for immortal time and indication biases, the authors concluded that administration of corticosteroids was not associated with a difference in 90-day mortality (adjusted odds ratio 0·8, 95% CI 0·5–1·1; p=0·12) but was associated with delayed clearance of viral RNA from respiratory tract secretions (adjusted hazard ratio 0·4, 95% CI 0·2–0·7; p=0·0005). However, these effect estimates have a high risk of error due to the probable presence of unmeasured confounders.

In a meta-analysis of corticosteroid use in patients with SARS, only four studies provided conclusive data, all indicating harm. The first was a case-control study of SARS patients with (n=15) and without (n=30) SARS-related psychosis; all were given corticosteroid treatment, but those who developed psychosis were given a higher cumulative dose than those who did not (10 975 mg hydrocortisone equivalent vs 6780 mg; p=0·017). The second was a randomised controlled trial of 16 patients with SARS who were not critically ill; the nine patients who were given hydrocortisone (mean 4·8 days [95% CI 4·1–5·5] since fever onset) had greater viraemia in the second and third weeks after infection than those who were given 0·9% saline control. The remaining two studies reported diabetes and avascular necrosis as complications associated with corticosteroid treatment.

A 2019 systematic review and meta-analysis identified ten observational studies in influenza, with a total of 6548 patients. The investigators found increased mortality in patients who were given corticosteroids (risk ratio [RR] 1·75, 95% CI 1·3–2·4; p=0·0002). Among other outcomes, length of stay in an intensive care unit was increased (mean difference 2·1, 95% CI 1·2–3·1; p<0·0001), as was the rate of secondary bacterial or fungal infection (RR 2·0, 95% CI 1·0–3·8; p=0·04).

Corticosteroids have been investigated for respiratory syncytial virus (RSV) in clinical trials in children, with no conclusive evidence of benefit and are therefore not recommended. An observational study of 50 adults with RSV infection, in which 33 (66%) were given corticosteroids, suggested impaired antibody responses at 28 days in those given corticosteroids.

Life-threatening acute respiratory distress syndrome occurs in 2019-nCoV infection. However, generalising evidence from acute respiratory distress syndrome studies to viral lung injury is problematic because these trials typically include a majority of patients with acute respiratory distress syndrome of non-pulmonary or sterile cause. A review of treatments for acute respiratory distress syndrome of any cause, based on six studies with a total of 574 patients, concluded that insufficient evidence exists to recommend corticosteroid treatment.

Septic shock has been reported in seven (5%) of 140 patients with 2019-nCoV included in published reports as of Jan 29, 2020. Corticosteroids are widely used in septic shock despite uncertainty over their efficacy. Most patients in septic shock trials have bacterial infection, leading to vasoplegic shock and myocardial insufficiency., In this group, there is potential that net benefit might be derived from steroid treatment in severe shock.

However, shock in severe hypoxaemic respiratory failure is often a consequence of increased intrathoracic pressure (during invasive ventilation) impeding cardiac filling, and not vasoplegia. In this context, steroid treatment is unlikely to provide a benefit. No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV. The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors. If it is present, the effect of steroids on mortality in those with septic shock is small, and is unlikely to be generalisable to shock in the context of severe respiratory failure due to 2019-nCoV.

Overall, no unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids, and they might be more likely to be harmed with such treatment. We conclude that corticosteroid treatment should not be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a clinical trial.

Authors
Clark D Russell, Jonathan E Millar, J Kenneth Baillie

The Lancet correspondence

The Lancet article

The Lancet article

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