COVID-19: pathogenesis and treatment 

Simon Collins, HIV i-Base

The keynote talk for Glasgow 2020 was an excellent review on current understanding of COVID-19 and strategies for treatment, including the implications for HIV care, given by Professor Karine Lacombe from Saint-Antoine Hospital, Paris. [1]

Part of the response to COVID-19 developed from experience with two earlier coronaviruses responsible for SARS-1 and MERS. However, although both were more pathogenic (with 7% and 35% mortality respectively), unlike SARS-CoV-2, neither were transmitted during asymptomatic infection.

This resulted in the extensive spread of the current coronavirus (> 35 million cases and >1 million deaths), which has so far been reported most severely in terms of both cases and mortality in North and South America and western Europe. While most countries experienced the first peak in March and April the widely predicted second wave is now established in most European countries, although so far with lower mortality.

The original early concern over a viral infection also rapidly expanded as it was quickly recognised that SARS-CoV-2 is a systemic disease with a complex pathology. Understanding this pathway is critical to the development of effective treatment.

Initial infection targets immune cells expressing ACE-2 receptors in the nose and throat that enable viral replication and then epithelial cells and marcrophages in lung tissue. In people where the infection progresses, this then produces an inflammatory response with overproduction of cytokines including IL-6, IP-10, MIP-1a, MIP-1b and MCP1 and resulting massive cell death restricting oxygenation.

The transmission timeline includes being infectious from an average of three days before symptoms to seven days after, and is complicated by a large percentage of people being asymptomatic but still infectious. Viral RNA is increasingly difficult to identify and culture from day ten, especially in mild and moderate disease, and, except in rare cases, is only detectable for a few days longer in severe disease.

Early clinical signs are now well described, most commonly fever, dry cough, shortness of breath, loss of taste and/or smell, fatigue, nausea and diarrhoea etc. X-ray shows multifocal ground glass opacities with peripheral and sub-pleural localisation but are not present in 18% of minor and 3% of severe infections. Extra pulmonary disease can be extensive and affect nearly all other organs including neurologic, renal, hepatic, GI, cardiac, endocrine and dermatological, including thrombosis and pulmonary embolism.

Neurological complications have also become an unexpected challenge – where people underestimate the severity of symptoms, continuing daily life even with severely depleted blood-oxygen levels, or focusing on daily responsibilities while about to be intubated. Mood instability and anxiety, similar to PTSD, are also commonly reported, sometimes for many months, after discharge from hospital.

Although surrogate markers for severe disease are not widely established, with similar presenting symptoms, four recent papers have suggested immune markers that might be predictive. [2, 3, 4, 5]

The three stages in the natural history – viral, pulmonary and hyperinflammation phases – have different targets for potential interventions. That these phases overlap and vary between individual patients, clearly suggest a role for combination therapy, for example, to include both antiviral and anti-inflammatory compounds. A fourth stage is also increasingly recognised of delayed recovery lasting many months, called ‘long COVID’.

Early targets for treatment include ACE-2 and angiotensin-II blockers, fusion inhibitors (baricitinib), endosomal acidification inhibitors (hydroxychloroquine), antiviral polymerase inhibitors (remdesivir, favipiravir, ribavirin, TDF/FTC), protease inhibitors (lopinavir/r), more than 20 immunomodulators (corticosteroids, tocilizumab etc) and passive immunisation. There is already considerable well-publicised evidence to support the efficacy of some of these compounds (remdesivir and dexamethasone), or the definitive lack of benefit (hydroxychloroquine, lopinavir/r).

Of the two approved treatments, remdesivir is associated with faster recovery but only dexamethasone has reduced mortality, and then only in people with advanced disease who are already requiring supportive oxygen.

Although promising, with ongoing studies, there have been conflicting results from using the IL-6 inhibitor tocilizumab. Of three randomised trials, the CONVICTA study reported no benefit, CORIMUNO-TOCI reported reduced mortality or need for oxygen at day 14 and EMPACTA has reported both reduced mortality and need for intubation. However, several meta-analyses have supported efficacy, though this might only be in a subset of patients, perhaps before the increase in proinflammatory proteins. [6]

Research importantly covers many other aspects of care including different strategies for oxygen support and intubation and prevention of thrombosis.

A French study from 2015 reported a positive effect on 90-day mortality of nasal high flow oxygen on ARDS compared to other methods of oxygen delivery and a recent paper from New York on higher responsiveness to prone position in COVID-19 in order to delay mechanical ventilation in ICU. [7, 8]

The limited evidence on anticoagulation includes no benefit on 28-day mortality in a preventative randomised study in China (although a benefit was seen in those with coagulopathy). [9] Reduced mortality was reported in a large retrospective US cohort analysis (29% vs 62%) in people who were intubated (but not in others). [10]

Promising, or preliminary results on other compounds include MK-4428 (potentially active against remdesivir resistance), baricitinib, immunomodulators (anti-IL-1, anti-C5a), passive transfer of immunity (convalescent plasma), monoclonal and polyclonal antibodies – and, of course, vaccines.

Of these, another French study recently reported benefits of convalescent plasma in 17 participants with B-cell depletion with protracted COVID-19. [11]

Finally, the talk referred to the difficulty during COVID-19 of reduced services for other infectious diseases including suspension of many STI services and restricting hospital care to emergency services. Among many others, this has led to delayed diagnosis of acute HCV and hepatic cancer, or support for people living with TB or HIV who need support for adherence.

The Q&A after the talk included little likelihood that vitamin D would have any significant effect and the comment included above that tocilizumab might be more likely to work if used before the pro-inflammatory cytokine response. Also, although reinfection cases have been reported, these have often been in those who might have generated low antibody responses to their initial mild infection.

References

1. Lacombe K. COVID-19: where are we now and what next? Keynote lecture. HIV Therapy Glasgow 2020, 5-8 October 2020.
   https://virtual.hivglasgow.org/webcast/covid-19-where-are-we-now-and-what-next
2. Laing AG et al. A dynamic COVID-19 immune signature includes associations with poor prognosis. Nature Medicine. DOI: 10.1038/s41591-020-1038-6. (17 August 2020).
   https://www.nature.com/articles/s41591-020-1038-6
3. Atyeo C et al. Distinct early serological signatures track with SARS-CoV-2 survival  Author links open overlay panel. Immunity 53(3);524-532.e4. DOI: 10.1016/j.immuni.2020.07.020. (15 September 2020).
   https://www.sciencedirect.com/science/article/pii/S1074761320303277
4. Carvelli J et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature (2020). DOI: 10.1038/s41586-020-2600-6. (29 July 2020).
   https://www.nature.com/articles/s41586-020-2600-6
5. Bastard P et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science: eabd4585. DOI: 10.1126/science.abd4585. (24 September 2020).
   https://science.sciencemag.org/content/early/2020/09/23/science.abd4585
6. Malgie J et al. Decreased mortality in COVID-19 patients treated with Tocilizumab: a rapid systematic review and meta-analysis of observational studies. CID, ciaa1445. DOI: 10.1093/cid/ciaa1445.
   https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1445/5910379
7. Frat et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015; 372:2185-2196. DOI: 10.1056/NEJMoa1503326. (4 June 2015).
   https://www.nejm.org/doi/full/10.1056/nejmoa1503326
8. Berrill et al. Evaluation of oxygenation in 129 proning sessions in 34 mechanically ventilated COVID-19 patients. J Int Care Med 2020. DOI: 10.1177/0885066620955137. (30 September 2020).
   https://journals.sagepub.com/doi/full/10.1177/0885066620955137
9. Tang J et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020. DOI: 10.1111/jth.14817 (27 March 2020).
   https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14817
10. Parantjpe I et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Card. 76(1). DOI: 10.1016/j.jacc.2020.05.001. (July 2020).
    https://www.onlinejacc.org/content/76/1/122
11. Hueso T et al. Convalescent plasma therapy for B-cell depleted patients with protracted COVID-19 disease. Blood . 2020 Sep 21;blood.2020008423.  DOI: 10.1182/blood.2020008423.
    https://pubmed.ncbi.nlm.nih.gov/32959052

This report was first published online on 6 October 2020.