Severe COVID-19 linked to genetic clotting predisposition

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed nearly 3.4 million lives already, with some scientists saying that the actual toll is likely to be more than double this number. The unpredictability of severe disease further complicates the management of this infection.

Thus, the need to stratify the risk of severe or critical disease in patients presenting with SARS-CoV-2 infection remains a crying necessity. A new preprint research paper posted to the medRxiv* server discusses the relationship between severe disease and pre-existing susceptibility to clots and other diseases of the cardiovascular system.

Severe COVID-19

The early symptoms of SARS-CoV-2 infection include dry cough, fever, anosmia with or without dysgeusia. However, the risk of progression and the speed of progression vary from person to person.

Severe COVID-19 is defined by the need for intensive care unit (ICU) admission and mechanical or non-invasive ventilation or supplementary oxygen. Hospitalized patients are mostly those with COVID-19 pneumonia due to inflammation of the lung alveoli.

The results of such pneumonia could be acute respiratory distress syndrome (ARDS), sepsis, and multi-organ failure, these being the leading causes of death in COVID-19 patients. Again, severe COVID-19 may also be defined by the presence of hyaline membranes in the lungs, caused by defective surfactant action and consequent alveolar collapse. These are found in pneumonia and thus indicate severe disease.

The root of severe COVID-19 is probably uncontrolled inflammation, as evidenced by the presence of a cytokine storm. This refers to a marked and persistent upregulation of inflammatory mediators, which in turn is responsible for the chronic overproduction of cytokines.

These signaling molecules recruit immune cells responsible for innate immunity, which forms the primary antiviral defense to the site of initial infection. When their levels are too high for too long, they lead to excessive vascular permeability, thus causing the lungs to be clogged, as well as mediating inflammatory injury to the lungs.

The cascade of cytokines also leads to the apoptosis or death of lung epithelial cells, which in turn compromises the delivery of oxygen to the body, causing ARDS. Higher cytokines and inflammatory molecules are related to more severe disease.

Type I interferon suppression is also found to be reduced during the early phase of the disease. This being a primary antiviral pathway, its absence also contributes to an overactive inflammatory response.

Genetic approaches

Various genomic and genetic approaches have been used to pick out risk factors, to select potentially useful interventions. These have been employed to identify the potential of baricitinib, a monoclonal antibody used to treat rheumatoid arthritis, now repurposed to reduce the cytokine storm in severe COVID-19.

Again, the downregulation of the interferon receptor encoding gene IFNAR2 in severe COVID-19 has led to the trial of interferon therapy to bring down the mortality rate. Additionally, such studies could help find new therapeutic targets to help develop useful drugs.

The approach called genome-wide association studies (GWAS) has led to the identification of genetic loci that indicate a higher susceptibility to infection as well as severe disease following exposure to SARS-CoV-2. These genes include both downregulated (IFNAR2 and OAS1) and upregulated genes (TYK2).

The first set allows viral replication to proceed unhampered, while the second promotes severe inflammation.  

Again, a set of genes on chromosome 3 is associated with variants that increase the odds of hospitalization in COVID-19 by 60%. This haplotype is prominently found in people of Bangladeshi origin and may be responsible for their relatively higher mortality compared to White males.

This haplotype is thought to be like that found in Neanderthal Vindija genomes.

Other risk factors

Other risk factors identified in patients with severe COVID-19 include chronic lung disease and cardiovascular disease. Age also plays a role, with the risk of hospitalization and death increasing five-fold and 90-fold in people aged 60-74 years compared to those between 18 and 29 years.

Body mass index (BMI) is also related to severe COVID-19, probably because a high BMI predisposes to other independent risk factors, such as heart disease and diabetes. Obesity has a genetic basis and increases the likelihood of poor lung function, higher baseline levels of cytokines from adipose tissue, and other cytokines, which increase the risk of ARDS.

Cardiovascular disease also predicts a poor outcome following COVID-19. The inflammatory milieu in a patient with this infection promotes hypercoagulability, which in turn triggers multi-organ dysfunction and other complications of severe disease.

Again, hypertension may increase the risk of severe disease because the host cell angiotensin-converting enzyme 2 (ACE2) receptors are part of the renin-angiotensin-aldosterone system, which causes inflammation of the lung, followed by fibrosis. Smoking also increases ACE2 expression in the lung, which may also explain the higher risk of hospitalization among smokers.

Findings of the present study

In the current study, the researchers found that several genetically determined traits were associated with COVID-19 susceptibility and severity. These include lymphocyte counts, blood clots, thrombocytopenia, lower levels of some hormones, poor lung function and obesity.  

Higher lymphocyte counts were reported with severe COVID-19, though numerous studies have shown lymphopenia in this subclass.

Lymphopenia is rare in children who have a very low risk of death from COVID-19. Further work is required to elucidate the role of this set of cells, especially the atypical cells found in less ill COVID-19 patients.

Lower platelet counts also indicate severe disease in association with microvascular clots and coagulation defects. ICU patients show platelet aggregates and large platelets, while another study reported higher platelet gene expression, and higher platelet activity, in COVID-19 patients.

A lower score on lung function tests also reflects an increased risk of severe COVID-19, while post-recovery patients continue to show impairment in lung physiology.

Clotting in superficial and deep veins in the leg and lungs was also linked to 12% increased susceptibility to the infection. This significant association is concordant with existing meta-analyses in moderate to severe COVID-19, which also show the presence of blood clots to predict a higher mortality rate.  

Lower levels of insulin growth factor 1 (IGF-1) and sex hormone binding globulin (SHBG) are also associated with severe COVID-19, with the latter being involved in binding serum testosterone at higher levels compared to estrogen. Testosterone levels are lower in male COVID-19 patients in the ICU and could be useful in detecting high-risk patients.

The role of obesity was confirmed, with a higher risk of hospitalization linked to the increased trunk and arm fat, as well as lower sitting and standing height.

Conclusion

These findings should help identify patients at high risk of SARS-CoV-2 infection, as well as stratify the relative risk of COVID-19 patients.

Further work will be required to better understand the biological and clinical value of these findings, including long-term complications after infection.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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