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24th January 2022
Inhaled unfractionated heparin can be safely used in hospitalised patients with COVID-19 and improves oxygenation according to a retrospective analysis by researchers from Saint George Hospital, Intensive Care Unit, Sydney, Australia.
There is a strong rational for the use of inhaled unfractionated heparin (IUH) in the treatment of patients with COVID-19, given the evidence that heparin blocks spike protein binding and/or infection by pseudo-typed virus and authentic COVID-19.
Moreover, in a preliminary and pre-pandemic study, the use of IUH in patients with or at risk of acute respiratory distress syndrome, the drug was was well tolerated and there was less progression of lung injury and an earlier return home.
For the present study, the Australian team recruited hospitalised patients infected with COVID-19 and who had shown clinical deterioration despite standard of care and offered them treatment with IUH. The drug was nebulised and given at a dose of 5000IU every 8 hours or initially at 10,000 IU every four hours and if tolerated increased to 25,000 IU every six hours.
The outcomes of interest were activated partial thromboplastin time (APTT) and the highest level achieved during treatment. Efficacy outcomes were oxygenation which was assessed by the ratio of oxygen saturation to the fraction of inspired oxygen (S/F ratio).
Findings
A total of 98 patients with an average age of 66 years (52% male) were enrolled in the study, 79 of whom were intubated and the median time from COVID-19 symptom onset to use of IUH was 6.7 days for non-intubated patients compared to 8 days among intubated patients.
In 3 patients on UFH, APTT levels did not significantly increase from a baseline of 72 to a peak of 84 seconds (p = 0.17).
The S/F ratio decreased by an average of 9.2 units each day prior to IUH, suggesting a deterioration of oxygenation although after commencement of therapy, this began to increase compared to baseline in all patients and for each of the doses used (p < 0.001) with intubated patients showing the greatest improvement.
In discussing these results, the authors noted that the use of IUH was associated with improved oxygenation. However, an important caveat was that the study did not have a control group and that IUH was administered at different doses and durations, together with the fact that COVID-19 severity was also not uniform.
Nevertheless, they argued that this heterogeneity was a potential advantage, demonstrating that the use of IUH was safe across the COVID-19 disease spectrum. While based on a case series, the authors added that there are several ongoing trials examining the value of IUH in patients hospitalised with COVID-19 and which should report in the future.
Citation
van Haren FMP et al. Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID‐19: A multicentre case series of 98 patients Br J Clin Pharmacol 2022.
28th October 2021
Increasing the dexamethasone dose from 6 mg to 12 mg/day in hospitalised patients with COVID-19 and severe hypoxia, has no effect on overall mortality. This was the conclusion of a randomised trial undertaken by researchers from the COVID STEROID 2 Trial group, Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark. The value of dexamethasone in hospitalised patients with COVID-19 was shown in an open-label trial published in February 2021, which found that dexamethasone 6mg/daily for 10 days, resulted in a lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen. Guidance from the World Health Organisation also recommends a dexamethasone dose of 6 mg/daily either orally or intravenously.
Whether a higher dexamethasone dose would be more beneficial to those with severe COVID-19 is uncertain. However, some evidence suggests that in patients with acute respiratory distress syndrome (which can be induced by infection with the virus) initial dexamethasone doses of 20 mg for five days, could reduce the duration of mechanical ventilation and overall mortality. Thus, the purpose of the COVID STEROID 2 trial was to evaluate the efficacy and safety of a higher dose of dexamethasone in hospitalised adult patients with COVID-19 and severe hypoxia. The researcher’s working hypothesis was that a higher dexamethasone dose would increase the number of days alive without life support. The study was conducted at 26 hospitals in four countries and included patients who required supplemental oxygen, and both non-invasive and invasive mechanical ventilation. Participants were randomised 1:1 to receive either 6 or 12 mg of dexamethasone daily as a bolus injection for up to 10 days after randomisation. Patients were assessed after 28 days with the primary outcome set as the number of days alive without life support (i.e., invasive mechanical ventilation, circulatory support or kidney replacement therapy) after 28 days. There were several secondary outcomes, including the number of days alive without life support at 90 days.
Findings
A total of 982 randomised patients were included in the final analysis with a median age of 65 years (31% female). The most common co-morbidities were diabetes (27% in the 12 mg dexamethasone group, 34% in the 6 mg group) and ischaemic heart disease or heart failure (14% in both groups). After 28 days, the median number of days alive without life support was 22 days in those with a dexamethasone dose of 12 mg and 20.5 days in the dexamethasone 6 mg group (adjusted mean difference, aMD = 1.3 days, p = 0.07). The 28-day mortality was 27.1% and 32.3% (dexamethasone 12 mg vs 6 mg). Similarly after 90 days the corresponding number of days was 84 and 80 days (dexamethasone 12 mg vs 6 mg) and this difference was not statistically significant.
The authors concluded that doubling the dexamethasone dose did not improve the number of days alive but suggested that they trial might have been underpowered to identify a significant difference.
Citation
The COVID STEROID 2 Trial Group. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomised Trial. JAMA 2021
6th October 2021
According to an interim analysis, Merck and Ridgeback’s investigational anti-viral drug, molnupiravir (MPV), halved the risk of hospitalisation in patients with mild-to-moderate COVID-19. MPV is a pro-drug that is incorporated by RNA polymerase into COVID-19 and which has been shown in preliminary studies, to reduce nasopharyngeal COVID-19 infectious virus and viral RNA.
The results come from the Phase III MOVe-OUT trial, designed to evaluate the safety, tolerability and efficacy of MPV in non-hospitalised patients with COVID-19. Enrolled patients had laboratory-confirmed mild-to-moderate COVID-19 and with an onset of symptoms within 5 days of study randomisation. In addition, all patients were required to have at least one risk factor associated with poor disease outcome. A second trial, examined the value of MPV in hospitalised patients although this was halted after it became apparent that molnupiravir was unlikely to demonstrate a clinical benefit in hospitalised patients.
MOVe-OUT is evaluating molnupiravir at a dose of 800mg twice daily and while the results are yet to be published, the interim analysis seems positive. According a joint press release from the companies, 7.3% (28/385) of patients receiving MPV were either hospitalised or died through to Day 29 following randomisation (28/385), compared with 14.1% (53/377) of placebo-treated (p=0.0012). In addition, after 29 days, there were no deaths were reported in patients who received MPV compared to 8 deaths in the placebo arm.
The incidence of drug-related adverse events was shown to be comparable (12% and 11% MPV vs placebo). Fewer subjects discontinued study therapy due to an adverse event in the molnupiravir group (1.3%) compared to the placebo group (3.4%).
Merck plans to submit an application for Emergency Use Authorisation (EUA) to the FDA as soon as possible and plans to submit marketing applications to other regulatory bodies worldwide.
21st September 2021
The available evidence clearly shows that infection with COVID-19 is disproportionately higher in adults compared with children. Nevertheless, emerging data suggests that in children infection with COVID-19 can induce multisystem inflammatory syndrome and lead to serious illness. While the pandemic has revealed how several clinical factors such as older age, various co-morbidities and ethnicity, are all associated with a higher level of COVID-19 severity, much less is known about which factors lead to more severe disease in children.
This lack of information prompted a group of US researchers from the Division of Hospital Medicine, Monroe Carell Jr, Children’s Hospital, Vanderbilt, Nashville, Tennessee, US, to undertake a retrospective cohort study across 45 US children’s hospitals to assess factors associated with COVID-19 severity in paediatric patients. The researchers included patients as young as 30 days old to 18 years of age, discharged from either an emergency department (ED) or inpatient setting with a primary diagnosis of COVID-19. The researcher collected demographic data and information on the presence of any co-morbidities, particularly those which appeared to result in a worse prognosis among adults. The outcome of interest was COVID-19 severity which was categorised as mild (i.e., ED discharge), moderate (in-patient admission) and severe (intensive care (ICU) admission) and very severe (ICU admission with mechanical ventilation, shock or death). The results were analysed using regression analysis and presented as odds ratios adjusted for various factors including ethnicity and co-morbidities.
Findings
The study included 19,976 ED encounters of children with a median age of 6 years (51.2% male) with the most common ethnicities being Hispanic (48.8%) and non-Hispanic White (21.1%). In the majority of cases (79.9%) COVID-19 severity was mild (79.7%) and these individuals were discharged from the ED. However, among the 4063 (20.3%) patients who were hospitalised, the majority had moderate COVID-19 severity (79.3%) with 11.3% classed as severe and 9.4% as very severe. When compared with those who were discharged from the ED, the clinical factors associated with an increased odds of hospitalisation included obesity/type 2 diabetes (adjusted Odds ratio, aOR = 10.4, 95% CI 8.90 – 13.3), asthma (aOR = 1.40, 95% CI 1.3 – 1.60), cardiovascular disease (aOR = 5.0), an immunocompromised condition (aOR = 5.9) and pulmonary disease (aOR = 3.2). Only Black ethnicity impacted on the risk of hospitalisation compared to those of White ethnicity, (aOR = 1.52, 95% CI 1.20 – 1.93). With respect to age, compared to children aged 0 – 4 years, the risk of hospitalisation was lower among those aged 5 – 11 years (aOR = 0.50, 95% CI 0.45 – 56) and 12 – 17 years (aOR = 0.75, 95% CI 0.69 – 0.82). However, once hospitalised, the risk of higher COVID-19 severity increased in both groups: 5 – 11 group (aOR = 2.66) and 12 – 17 years (aOR = 2.09).
The authors concluded that while older children were at a lower risk of hospitalisation with COVID-19, once hospitalised, they appeared to be a higher risk of more severe disease. In addition, as with adults, similar co-morbidities were associated with a greater risk of hospitalisation and higher COVID-19 severity once admitted.
Citation
Antoon JW et al. Factors associated with COVID-19 disease severity in US children and adolescents. J Hosp Med 2021
16th August 2021
During the first wave of the COVID-19 pandemic there were a huge number of patients admitted to hospital. Ensuring minimal hospital-acquired infection was therefore of paramount importance, especially as earlier research with SARS and MERS had shown that human-to-human transmission occurred mainly within the healthcare setting. In a letter to the Lancet, a team from Lancaster Medical School, Lancaster University, UK, have examined the extent to which nosocomial, i.e., hospital-acquired, COVID-19 infections occurred during the first wave of the pandemic. The researchers used records contained in the International Severe Acute Respiratory Emerging Infection Consortium (ISARIC) and which has already reported on the clinical characteristics of 20,133 hospital in-patients during the initial phase of the pandemic. For the current analysis, the team examined records of patients enrolled in the UK arm of ISARIC and who had an onset of symptoms before the beginning of August 2020. In trying to determine whether patients were likely to have a hospital-acquired infection, the team considered both their admission date and the date of symptom onset. They used the recorded infection date for a patient and identified those who were admitted before infection, as likely candidates for a hospital-acquired infection.
Findings
The researchers estimated that there were 82,624 patients admitted to hospital before the beginning of August 2020 and found that 11.3% (95% CI 11.1 – 11.6) of these became infected with COVID-19 after admission to hospital. When restricting their analysis to the middle of May 2020, this proportion increased to 15.8% (95% CI 15.8 – 19.6). Using a more conservative estimate of symptom onset at least 14 days after hospital admission, the proportion reduced to 6.8%. An interesting additional finding was how there was marked heterogeneity between hospital trusts. For example, in cases where the trust provided both acute and general care, the incidence of infections was 9.7% (95% CI 9.4 – 9.9) whereas this was substantially higher in residential community care hospitals (61.9%, 95% CI 56.4 – 68) and in mental health hospitals (67.5%). The authors were unable to account for this extreme variation and called for an urgent investigation to identify and promote best practice for infection control.
In discussing these findings, they identified that a recognised limitation of the ISARIC dataset was that it was unable to identify patients infected during admission or those who were discharged before developing symptoms and who might have acquired their infection within the hospital. In other words, the authors felt that their overall estimate of the nosocomial infection rate is probably an underestimate. The concluded that with lessons learnt from the first wave coupled with the development of vaccines, NHS infection control policies should now be sufficiently robust to prevent the burden of hospital-acquired infections.
Citation
Read JM et al. Hospital-acquired SARS-CoV-2 infection in the UK’s first COVID-19 pandemic wave. Lancet 2021
19th July 2021
The mortality rate from infection with COVID-19 is high at approximately 26% and it has also become recognised that COVID-19 complications can occur in a large number of patients. Information on the incidence and type of COVID-19 complications is important for both patients and healthcare providers. For instance, patients need to know the likely time course of any complications whereas healthcare providers require this data to help with resource allocation and long-term planning for the delivery of services. Moreover, a sizeable number of patients with COVID-19 are admitted to intensive care units and while mortality is widely used as an outcome measure in many of the COVID-19 clinical trials, it fails to adequately capture the fact that survivors experience significant morbidity upon discharge.
A better understanding of the range and incidence of COVID-19 complications among those who are critically ill with the virus, is therefore critical to an assessment of the long-term burden on healthcare systems. In an effort to determine the range and prevalence of immediate complications of infection with COVID-19, a team from the Centre for Medical Informatics, Usher Institute, Edinburgh, Scotland, undertook a prospective, multi-centre cohort study in 302 UK which included adults, aged 19 years and older, with confirmed COVID-19 and admitted to hospital. Data was captured upon admission and after days 1, 3 and 9 and at discharge or the patient’s status after 28 days and included demographics and co-morbidities. The team set the primary outcome as the incidence of in-hospital complications and which was defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness.
Findings
A total of 75,276 patients were included in the analysis with a mean age of 71.1 years (56% male) and with the majority (73.5%) being of white ethnicity. The existence of one or more comorbidities was present in 81% of participants. and the overall rate of COVID-19 complications was 49.7%. The most common complications reported affected the renal system (24.3%), systemic effects (16.3%), gastrointestinal (10.8%), cardiovascular (12.3%), neurological (4.3%) and respiratory (18.4%). Males aged 60 years and over, suffered the highest rate of complications (54.5%) although COVID-19 complications were common across all demographics. For example, among patients aged 19–29 years and without any comorbidities, 21.1% experienced at least one complication, whereas in those aged 50 years and older, the complications occurred in 51.3% of patients. Interestingly, among patients who survived 28 days from first symptoms to discharge, 44% suffered complications and 26.6% of whom, had a worse ability to self-care than prior to their illness.
In discussing their findings, the authors noted the high level of complications experienced by survivors. The most common were renal and in particular acute kidney injury which is known to be associated with substantial long-term morbidity. They also remarked upon how COVID-19 complications had developed in young and previously healthy individuals and how such complications are known to have a negative impact on long-term morbidity.
Citation
Drake TM et al. Characterisation of in-hospital complications associated with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study. Lancet 2021.
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