Analysis Sheds Light on Biology of Serious COVID-19 Cases and Outlines Treatment Options

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US researchers have analyzed the available literature on COVID-19 infections to assess factors linked with severe cases and to inform medical professionals about drugs that could be repurposed to treat the disease.

Since the end of 2019, the SARS-CoV-2 virus behind COVID-19 has spread across the globe in a way that has not been seen since the 1918 flu pandemic. COVID-19 has a lower mortality rate than SARS and MERS – its two coronavirus predecessors – but a higher infection rate, which has led to more individuals experiencing severe acute respiratory symptoms than with either SARS or MERS.

While the large majority of patients infected with COVID-19 do not progress to severe disease, around 14% of people develop more serious symptoms that require hospitalization and can result in death.

It is not completely clear why some people are worse affected by the disease than others, but from the many papers published on this topic since the pandemic began it is possible to pick out some risk factors for more severe disease and to suggest some possible immune system differences that may contribute to more severe symptoms.

As outlined by Montserrat Puig, a researcher at the US FDA, and co-authors in the journal Frontiers in Immunology, some key risk factors for more severe disease include: male gender, older age – with increasing risk as age increases, and having at least one comorbidity. Other health conditions that have been shown to increase the risk for more severe COVID-19 are cardiovascular disease (including high blood pressure), diabetes, chronic kidney disease, and chronic obstructive pulmonary disease.

On a more cellular level, patients with more severe disease often have higher levels of a number of markers of inflammation such as C-reactive protein, interleukin 6 and ferritin; as well as increased N-terminal pro-brain-type natriuretic peptide and lactate dehydrogenase – both of which are linked with heart failure. D-dimer – a protein fragment in the blood associated with blood clots has also been observed to be significantly higher than normal in severe COVID-19 cases, as has the stroke-associated biomarker troponin.

The exact interaction between the virus and the human immune system is not yet completely clear. The authors write that if it uses a similar method to SARS or MERS to infect the body it probably compromises the body’s ability to fight the virus by preventing interferon 1 – one of the first proteins produced by the immune system to fight viruses — from functioning properly.

“A compromised RNA-specific innate immune response, at the beginning of the infection, could compromise control of virus replication, leading to a dramatic increase in the viral titer and the number of infected cells,” they suggest.

The authors also believe that problems with the complement system – which plays a critical role in the response to infection by the innate immune system – could be linked to increased inflammation in patients with the virus.  The release of cytokines from the innate immune system in response to infection and also the release of damage-associated molecular patterns (DAMPs) from dying cells have also been suggested as possible starting points for more severe symptoms.

As it could take some time to develop an effective vaccine or new drugs to treat COVID-19, a selection of drugs has been used off-label to try and combat some of the symptoms of the disease. These include the Ebola drug Remdesivir, which has shown benefits in some patients with severe disease and, more controversially, the malaria drug hydroxychloroquine – also suggested to have benefits for patients with the infection.

To try and help clinicians with decision making about use of these off-label drugs, the authors of this review decided to compile a table outlining the drugs that have been used to date, the evidence for their use and the stage of COVID-19 that they might be able to help treat. However, they caution that the information is “only for the purpose of helping make more informed decisions” and may change rapidly.

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