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18th January 2021
It has become recognised that increasing age and a higher number of co-morbidities such as hypertension, obesity and diabetes are associated with higher levels of mortality among those infected with COVID-19.
Given that the prevalence of diabetes is often very high among this ethnic group, a team from the Hugh Kaul Precision Medicine Institute, University of Alabama, US, sought to determine the effects of different anti-diabetic treatments on mortality among an ethnically diverse population infected with COVID-19. The team retrospectively reviewed all electronic health records of subjects consecutively tested for COVID-19 between February and June 2020 at a single tertiary hospital in their area. In an effort to make the results more generalisable, the researchers included all patients within the five month period with the only exclusion criterion being a lack of available outcome data. The team sought to focus their attention on the diabetic treatments and in particular, insulin and metformin because these were the most commonly prescribed and there were too few patients prescribed other medicines to provide a meaningful statistical analysis. The primary outcome for the study was overall mortality and the researchers used logistic regression to explore the association between mortality and known risk factors and diabetic treatments.
There were 604 patients who tested positive for COVID-19 during the study period. The majority of those testing positive (43%) were aged 50 to 70 years and just over half (51.5%) were Black Africans, giving a highly significant odds of testing positive compared to those of white ethnicity (odds ratio, OR = 2.6 95% CI 2.19–3.10, p < 0.001). Overall mortality among those testing positive for COVID-19 was 11% and the presence of diabetes dramatically increased the risk of mortality (OR = 3.62 95% CI 2.11–6.2, p < 0.001). In fact, 67% of all deaths occurred among those with diabetes. Focusing on diabetic treatments, the researchers observed that use of metformin reduced the odds of dying by 62% (OR = 0.38 95% CI 0.17–0.87, p = 0.0221) although no such effect was seen with insulin. Moreover, after adjusting for the covariates age, race, sex, obesity and hypertension status, the odds ratio remained significant (OR = 0.33 95% CI 0.13–0.84, p = 0.0210). The researchers also observed that neither BMI or HBA1C levels were lower in those taking metformin thus discounting these as explanatory factors.
The authors noted that while the presence of type 2 diabetes was associated with an increased mortality risk in those with COVID-19 (as reported in other studies) there appeared to be a protective effect among diabetic patients treated with metformin although they were unable to explain their findings and called for more research to understand how metformin conferred these effects.
Crouse AB et al. Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. Front Endocrinol 2021.
30th November 2020
The precise reasons why obesity enhances the risk of a more severe outcome in COVID-19 remains unclear. Nevertheless, obesity is associated with several other additional risk factors such as cardiometabolic, thromboembolic and pulmonary disease and it is likely that it is this combination of factors that raises the overall risk. For example, obese patients have higher levels of pro-inflammatory cytokines and oxidative stress which can impact on both the innate and adaptive immune system, all of which may contribute to a worse prognosis. Metabolic surgery in obese patients leads to improvements in cardiovascular risk factors and the amelioration of the pro-inflammatory state linked with obesity.
In a retrospective study of patients testing positive for COVID-19, researchers from the Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Ohio, US, set out to examine the relationship between prior metabolic surgery and the severity of COVID-19 in severely obese patients. A total of 33 individuals who had prior metabolic surgery (the surgical group) were identified and were matched 1:10 to non-surgical patients to create a cohort with a body mass index (BMI) greater than or equal to 40kg/m2 at the time of testing. The pre-specified endpoints examined were: admission to intensive care, need for mechanical ventilation, dialysis during their hospital stay and mortality.
Data on a total of 363 patients, including the 33 who had prior metabolic surgery were available for analysis. The surgical group had a mean age of 46.1 years (78% female) with a mean BMI of 37.2±7.1 compared to 46.7± 6.4kg/m2 in the control group. A subsequent univariate analysis showed that 18.2% of those in the surgery group and 42.1% in the control group were admitted to hospital because of their infection with COVID-19. A prior history of metabolic surgery was associated with a statistically lower odds of being admitted to hospital (odds ratio = 0.31, 95% CI 0.11 – 0.88, p = 0.028). Furthermore, none of the surgical group patients experienced one of the four pre-specified endpoints. In contrast, 13% of those in the control group were admitted to intensive care, 6.7% required mechanical ventilation, 1.5% dialysis and 2.4% died. The authors suggested that prior metabolic surgery was associated with a lower severity of COVID-19 infection but recognised that these observations were based on a small sample size and they were also unable to account for their findings.
They concluded by calling for more research to understand the mechanistic role of both obesity and intentional weight loss on COVID-19 infection.
Aminian A et al. Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity. Surg Obes Relat Dis 2020. https://doi.org/10.1016/j.soard.2020.10.026
Mutations in RNA viruses can arise through copying errors, genomic variability when two viral lineages infect the same host and finally because of host-induced RNA-editing systems. Any mutations that have a deleterious effect on the virus will be quickly removed from the population although those which provide an advantage are retained. Researchers have been closely monitoring mutations in COVID-19 because any such changes could affect the ability of the virus to replicate and may even increase transmissibility.
A study by a team from the Genetics Institute, University college, London, have been cataloguing mutations in the virus and assessing whether or not these mutations have the potential to increase the transmissibility of COVID-19. They assessed the difference in transmissibility by estimating the relative fractions of descendants produced by a particular genotype. The rational for this approach was based on the notion that the worldwide distribution of the virus is likely to introduce a high level of genetic diversity which might increase the potential for greater transmissibility.
The researchers analysed 46,723 SARS-CoV-2 genome assemblies although none of these were found to deviate by more than 32 single-nucleotide polymorphisms from the reference genome, Wuhan-Hi-1. The team estimated a mutation rate of 9.8 x 10-4 substitutions per site per year and this finding is in line with work on other coronaviruses. The team also explored viral homoplasies, i.e., nucleotide changes that have not arisen through simple inheritance and identified a total of 185 such cases. However, none of these were associated with an increased risk of viral transmission or, interestingly, a reduced risk of transmission and all were effectively neutral changes.
Commenting on these findings, the authors noted that COVID-19 has only acquired moderate generic diversity since its jump to humans and concluded that there is currently no a priori reason to suspect that any lineage might arise with an increased potential for transmissibility.
Van Dorp Let al. No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2 Nat Commun 2020;11:5986.
On 19 November, 2020, the FDA gave emergency use authorisation for the baricitinib combination therapy to be used in patients hospitalised with either confirmed or suspected COVID-19, from 2 years of age and who require mechanical ventilation, supplemental oxygen or extracorporeal membrane oxygenation.
The approval is based on preliminary results from the ACCT-2 trial, which compared the recovery time in patients receiving either remdesivir alone or in combination with the JAK STAT inhibitor, baricitinib at a dose of 4mg. Remdesivir is already approved by the FDA as an antiviral drug for hospitalised COVID-19 patients, aged 12 years and over. Baricitinib is currently only licensed for use in rheumatoid arthritis but since the drug blocks the JAK-STAT intracellular messaging system, which is an important inflammatory pathway, there was a potential benefit from combining the two drugs. ACCT-2 was a Phase III trial that enrolled 1033 participants, who were randomised to either intravenous remdesivir alone plus matching placebo (518) or oral baricitinib (515). Remdesivir was given as a loading dose of 200mg, followed by 100 mg daily while in hospital, for up to 10 days. Baricitinib was given at a dose of 4mg per day and limited to a maximum of 14 days. All patients were assessed daily and if discharged, they were followed-up at home on days 15, 22 and at the study endpoint, day 29. Recovery from COVID-19 was defined as either being discharged from hospital, no longer requiring supplemental oxygen or needing ongoing medical care.
Preliminary data published from the trial showed that the median time to recovery with remdesivir and baricitinib was one day shorter (7 vs 8 days) than using remdesivir alone and this difference was statistically significant. In addition, the odds of a clinical improvement at day 15 using the combined therapy was also found to be significantly lower. Under the emergency use authorisation, the manufacturer of baricitinib, Eli Lilly, is required to provide both health professionals and patients, fact sheets which include information on dosing, side-effects and drug interactions. The full results of the ACCT-2 trial will be published in due course.
Furthermore, the presence of hypercoagulation and thrombotic complications appeared to correlate with a worse prognosis.
Although COVID-19 is principally a respiratory infection, studies have shown that the virus also leads to coagulatory dysfunction and which increases the risk of both arterial and venous thromboembolism (TE) and ultimately mortality. In fact, the presence of TE correlates with a more severe form of infection. However, studies to date have shown that the association between TE and mortality in patients with COVID-19 is poorly characterised. This prompted a team from the Department of Surgery, University of California, US, to undertake a systematic review and meta-analysis of available studies to provide a more precise estimate of TE rates in COVID-19 and to determine the association between TE and mortality. They searched all the major databases in June 2020 and included studies where the thromboembolic event could be calculated. The primary outcomes were venous and arterial TE (ATE), deep vein thrombosis (DVT) and pulmonary embolism (PE) as individual endpoints and mortality in those who develop TE.
The review identified 42 studies with 8271 patients which were included in the meta-analysis. The overall rate of venous TE was 21% but this increased to 31% among patients admitted to an intensive care unit (ICU). Similarly, the rate of DVT was 20% but this increased to 28% among patients admitted to ICU. The overall rate of PE was 19% among patients in ICU. The pooled rate of ATE was much lower at 2%. The researchers calculated that the pooled odds of mortality among patients who developed a TE was 74% higher than those without the condition (odds ratio = 1.74, 95% CI 1.01 – 2.98, p = 0.04). Commenting on these findings, the authors stated how their observed rate of venous TE was much higher than expected for hospitalised patients with acute infections, which were estimated from previous work as been only 15.5%.
They concluded by noting that studies on the value of thromboprophylaxis and the optimal dosing in COVID-19 patients are currently ongoing but eagerly awaited given the higher risk of mortality due to TE.
Citation Malas MB et al. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. Clin Med 2020. https://doi.org/10.1016/j.eclinm.2020.100639
25th September 2020
This was the question posed in a new study by a team from the Department of Population Medicine, Harvard Medical School who sought to determine the incidence of COVID-19 in a large, 793-bed hospital in Boston. They identified all patients who were hospitalised from 7 March 2020 through to 17 June 2020, including those who were admitted because of COVID-19, which was defined as a positive test during hospitalisation or within 14 days prior to admission. When assessing the extent of nosocomial infection, the authors reviewed medical records and only included those who tested positive on day 3 of their hospital stay or within 14 days after hospital discharge.
A total of 9149 patients with a mean age of 46.1 years (57.3% female), were admitted to the hospital during the study period, for whom 7394 COVID-19 tests were performed and of which 697 tested positive. However, of the 697 patients, only 12 (1.7%) were diagnosed on day 3 (or later) and the median time from admission to the first positive test result in these patients was 4 days (range 3 to 15 days). Interestingly, none of the 12 patients had known exposure to either staff or other patients who had tested positive for COVID-19. Analysis of medical records suggested that infection was definitely acquired before hospitalisation in 4 of the 12 cases and very likely for 7. Only a single patient was definitely infected in hospital because symptoms began on day 15. Post-discharge, among 8370 patients hospitalised with non-COVID-19-related conditions, 11 (0.1%) tested positive within 14 days and again, only a single case was deemed to have acquired the virus during their hospital stay and developed symptoms 4 days after discharge.
The authors concluded that the hospital had robust and rigorous infection control practices and suggested that these results should reassure patient that nosocomial infection is a rare event.
Rhee C et al. Incidence of nosocomial COVID-19 in patients hospitalised at a large US academic medical center. JAMA Netw Open 2020; 3(9):e2020498. doi:10.1001/jamanetworkopen.2020.20498
In this new study by a team from the Division of Rheumatology, New York University School of Medicine, the authors speculated that patients with inflammatory arthritis (IA), prescribed immunosuppressants may be protected to some extent against the worse outcomes for COVID-19, that is, the need for hospitalisation and/or mechanical ventilation. They recruited patients with a range of IA including rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease-associated arthritis. All patients had either confirmed COVID-19 (based on a positive test result) or were strongly suspected of being infected, based on having a new fever or known positive contact plus one or more respiratory symptoms.
A total of 103 patients, of whom 80 had confirmed COVID-19 infection were included in the analysis. All were followed for a mean of 42 days from the time of symptom onset which was established through a series of on-line questionnaires, telephone calls or a review of medical records and hospital charts. The mean age of participants was 53 years (72% women) and in terms of their disease state prior to the onset of COVID-19, nearly a quarter (23%) said that their disease was in remission and 38% stated that they had mild and 34% moderate disease severity with the remainder having severe disease. Overall, 26% of patients required hospitalisation due to COVID-19 and 4% (4/103) of patient died. Interestingly, chronic use of corticosteroids was significantly more common among those hospitalised (37% vs 4%, p < 0.001) compared to those on maintenance anti-cytokine therapies. In addition, older patients with comorbidities such as hypertension, were more likely to be hospitalised.
In conclusion, the authors called for further studies to determine whether immunomodulatory therapy can prevent COVID-19 or ameliorate its clinical outcomes.
Haberman RH et al. COVID-19 in patients with inflammatory arthritis: a prospective study on the effects of comorbidities and DMARDS on clinical outcomes. Arthritis Rheumatol 2020; doi: 10.1002/ART.41456