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Take a look at a selection of our recent media coverage:

Infliximab attenuates COVID-19 antibody response

29th March 2021

Immunosuppressant therapy affects an individual’s immune response but how this impacts on the COVID-19 antibodies is uncertain.

The production of an effective immune response after infection with COVID-19 is of paramount importance in preventing further bouts of infection. Moreover, biologicals such as infliximab, which target tumour necrosis factor (TNF), are known to impair protective immunity following a number of viral infection vaccinations including influenza, viral hepatitis and pneumococcus, thereby increasing the risk of serious infection. Hence in the early part of the COVID-19 pandemic, patients prescribed immunosuppressant therapy were advised to shield. Fortunately, information derived from international registry data indicates that the rates of severe infection among patients prescribed immunosuppressants are similar to the background population rates. However, whether anti-TNF drugs actually impair the immune response in those who have already been infected with COVID-19 is uncertain. This prompted a team from the Department of Gastroenterology, Royal Devon and Exeter Trust, UK, to examine the subsequent immune response in those with inflammatory bowel disease (IBD) after infection with COVID-19 and treated with infliximab. In an effort to test whether the immune response was blunted, the team retrospectively compared antibody responses in those treated with either infliximab or vedolizumab, a gut selective anti-integrin alpha4beta7 monoclonal antibody, for at least 6 weeks. Consecutive patients at the hospital were recruited when attending their infusion appointments and those who had participated in any of the COVID-19 vaccine trials were excluded. The primary outcome was the proportion of patients with a positive COVID-19 test and a secondary outcome was the magnitude of the antibody response between the two treatment groups, in those who tested positive. The team collected several additional pieces of information including demographics as well as information on IBD disease activity and mental health wellbeing and anxiety assessment and used this to construct multivariate logistic regression analysis.

Findings
A total of 6935 patients were included in the analysis of whom, 67.6% were prescribed infliximab with a mean age of 37.1 years (45.5% female). The majority of those prescribed infliximab had Crohn’s disease (66.6%) or ulcerative colitis (31.1%). In contrast, most of those (60.1%) prescribed vedolizumab had ulcerative colitis. There were a similar proportion of patients in both groups who either reported COVID-19 symptoms (8.3% vs 8.9%, infliximab vs vedolizumab) or tested positive (5.2% vs 4.3%) or who were hospitalised (0.2% vs 0.2%) because of their infection. Overall, the prevalence of COVID-19 antibodies was 4.3% but this was significantly lower in those using infliximab (3.4% vs 6%, p < 0.0001). Additionally, among those with PCR confirmed COVID-19 infection, seroconversion was observed in fewer patients treated with infliximab (48% vs 83%).

In a discussion of their findings, the authors noted how infliximab appeared to attenuate the subsequent serological response to the virus despite a similar level of rates of either symptoms or positive tests. They also described how as the action of TNF is to stimulate B cells, the effect of infliximab was biologically plausible.

They concluded that their work had important implications for vaccinating those prescribed infliximab and called for serological surveillance to detect suboptimal vaccine responses.

Citation
Kennedy NA et al. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut 2021

Latest REACT-1 data show no decline in COVID-19 prevalence in England

25th January 2021

REACT-1 study is an ongoing COVID-19 prevalence study in England and round 8a suggests there was no evidence of a decline in the prevalence of COVID-19 during the third national lockdown.

The Real-time Assessment of Community Transmission (REACT-1) is a longitudinal study of the community prevalence of COVID-19, led by a team from Imperial College, London. The study regularly reports on the prevalence of COVID-19 collected from a random sample of more than 120,000 people in England, identified from national health service records linked to a patient’s GP. Invited participants, who vary in age from 5 years to over 65, are sent a nasopharyngeal swab kit for home testing and which is then collected and analysed for COVID-19. The study has been collecting data since June 2020 and provides an important snapshot of the prevalence of COVID-19 in the community.

Findings

The REACT-1 (8a) covers the period 6-15 January 2021. Researchers found a total of 1962 positive swabs from 142,909 individuals giving a weighted prevalence of 1.58% (95% CI 1.49-1.68%). Interestingly, they note that this represents the highest prevalence since the study began in May 2020, when the prevalence was 0.16%. Moreover, it is more than 50% higher than round 7 (the previous data collection period), between November to December 2020). However, using a growth model, the team could not find any evidence of either a growth or decay in prevalence and estimated the transmission rate, R to be 1.04. In analysing mobility data from the Facebook app, the team found a decreased activity at the end of December 2020 that began to rise again in January 2021. As a result, they speculated that this increased activity might have caused the rise in cases. Across the country, the prevalence more than doubled in the London area from last round 7 (1.21%-2.47%) and in the East of England (0.59%-1.74%). However, infection rates decreased in Yorkshire and The Humber and remained broadly similar to round 7 in the East Midlands. The age-related prevalence showed an increase among those aged 18 to 24 (0.99%-2.51%) and among those aged 65 years and over (0.41%-0.94%). In discussing their findings, the authors noted that there was no continued decline in prevalence during the third national lockdown but rather a slight initial decline followed by a plateau or possible increase. They also cautioned that if rates do not fall there will be an increase in hospitalisations, which will negatively impact on healthcare delivery.

Citation
REACT-1 round 8 interim report; SARS-CoV-2 prevalence during the initial stages of the third national lockdown in England.

Smokers are at a higher risk of COVID-19 and have a greater symptom burden

18th January 2021

Tobacco smoking increases the risk of viral infections, so researchers sought to examine the relationship between smoking, symptom burden and risk of developing COVID-19.

Since March 2020, members of the public in the UK have been able to download and register with a smartphone app as part of an ongoing COVID-19 symptom study. Individuals who register with the app self-report demographic and healthcare data (i.e., co-morbidities) as well as any COVID-19-related symptoms. The app has been downloaded by over 2.4 million people and for the present analysis, researchers collected COVID-19-related symptom data between March and April 2020. Participants were asked to report if they felt ‘physically normal’ and those answering no were invited by the app to record the presence of 14 symptoms that have been associated with COVID-19. The main outcome for the study was the development of ‘classic’ symptoms of COVID-19, i.e., fever, new persistent cough and breathlessness and the association of this symptom triad with current smoking status. They also explored the relationship between smoking, a positive PCR test result and hospital attendance.

Findings
During the study period there were 2,401,982 registered users (63.3% female) with a mean age of 43.6 years, of whom, 834,437 (35%) reported not feeling ‘physically normal’. The team then classified all registered participants into one of four groups; those who had tested positive for COVID-19, (SC2P); those who tested negative (SC2N); those self-reporting COVID-19 symptoms and who thus believed they had the virus (SC2S); the remainder who made up a group termed ‘standard users’. Among standard users, current smokers were more likely to report developing the COVID-19 triad symptoms, suggesting a diagnosis of infection (odds ratio, OR = 1.14, 95% CI 1.10 – 1.18, p < 0.001) and to report a higher symptom burden (defined as reporting > 5 of the 14 symptoms), than non-smokers. Smoking was also associated with a higher symptom burden in both the SC2S and SC2P groups. Interestingly, while smoking rates were lower among those testing positive for the virus, i.e., in the SC2P group (thus suggesting a protective effect against the virus from smoking), their reported symptom burden was higher than non-smokers. Furthermore, smokers in the SCP2 group had a higher risk of attending hospital due to COVID-19 compared to non-smokers (OR = 2.11 95% CI 1.41 – 3.11, p < 0.001) and this association remained even after adjusting for co-morbidities (OR = 1.87).

Summarising these findings, the authors made the following observations. Smoking was associated with an increased risk of developing self-reported COVID-19 symptoms and a greater symptom burden. A higher symptom burden was also evident among smokers testing positive for the virus and that these individuals were more likely to visit hospital because of their symptoms.

The authors concluded by calling for smoking cessation to be a part of public health campaigns during the current pandemic.

Citation
Hopkinson NS et al. Current smoking and COVID-19 risk: results form a population symptom app in over 2.4 million people. Thorax 2021

Prolonged viral shedding not associated with viable COVID-19 virus

26th November 2020

Both viral load and the duration of viral shedding of COVID-19 have a significant impact on disease transmission.

Early data have suggested that peak COVID-19 viral load occurs at the time of symptom onset although viral shedding can persist much longer.

Nevertheless, there is considerably heterogeneity in studies with some suggesting that viral shedding continues much longer after the initial acute illness. There is also a lack of data concerning how both viral load and shedding relate to factors such as age and disease severity.

In an effort to gain a better understanding of viral load kinetics, a team from the Division of Infection and Global Health Research, University of St Andrews, Fife, UK, conducted a systematic review in order to characterise these factors for COVID-19 and compared the results with two other coronaviruses: SARS-CoV and Middle East respiratory syndrome (MERS-CoV).

Findings

The systematic search identified 79 relevant studies with 5340 participants on COVID-19, 8 studies (1858 participants) on SARS-CoV and 11 studies (799 participants) on MERS-CoV. Analysis of the data revealed how the mean duration of RNA viral shedding for COVID-19 varied considerably depending on the part of the body tested. For example, the average shedding time was 17 days in the upper respiratory tract (maximum 83 days), 14.6 days in the lower respiratory tract (maximum 59 days), 17.2 days in stool samples (maximum 126 days) and 16.6 days in serum samples (maximum 60 days). Viable COVID-19 levels peaked within the first week of infection and but could not be detected after 9 days of illness. In contrast, for SARS-CoV and MERS-CoV, viable virus levels peaked after 10 -14 days and 7 – 10 days respectively although the authors were unable to detect a consistent relationship between viral shedding and disease severity for COVID-19. There was a positive and significant association between the duration of shedding and age (p = 0.0016) but not sex (p = 0.28).

In discussing these findings, the authors concluded that while viral particles continue to be shed for extended periods of time, the presence of viable COVID-19 virus is short-lived and suggested that isolation should commence at the first onset of symptoms.

Citation Cevik M et al. SARS-CoV-2, SARS-Co-V and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe 2020 https://doi.org/10.1016/S2666-5247(20)30172-5

Inhaled interferon-beta shows promise as COVID-19 treatment

20th November 2020

Type 1 interferon (interferon-beta) is one of the first cytokines induced by a host’s innate immune system in response to infection by a virus in the lungs.

It is known that COVID-19 is able to suppress the release of interferon-beta in vitro and recent work has shown how there is a significant reduction in interferon activity in patients who develop a more severe infection. SNG001 is a recombinant interferon-beta in development for the treatment of virus-induced lower respiratory tract infections and has been formulated for inhalation via a nebuliser in an effort to achieve sufficient concentrations in the lungs. The drug has been shown to increase lung antiviral defences in patients with asthma and COPD and in this Phase II trial, a team from Southampton General Hospital, UK, decided to explore whether the drug had the potential to reduce the severity of respiratory symptoms in patients with COVID-19.

The researchers randomised patients, admitted to hospital because of COVID-19, to either interferon-beta or placebo which was given once daily for up to 14 days with a 28-day follow-up. The primary outcome for the study was a change in the clinical condition of patients as assessed by the WHO ordinal scale for clinical improvement (OSCI), which ranged from 0 (no evidence of infection) to 8 (death). A secondary outcome was the breathlessness cough and sputum scale (BCSS) as well as measures of the safety and tolerability of the drug.

Findings
A total of 101 patients with a mean age of 57.1 years (59% male) were randomised to SNG001 or placebo. Patients in the SGN001 group had more severe disease (OSCI >4) although those in the placebo group had more comorbidities. Patients receiving SNG001 had a two-fold higher odds of achieving a greater improvement on the OSCI scale (odds ratio, OR = 2.32, 95%CI 1.07-5.04, P = 0.033) on day 15 or 16 which increased to a three-fold on day 28 (OR = 3.15, 95% CI 1.39-7.14, p = 0.006). Only three patients died in the study, all from the placebo group. Furthermore, SNG001 reduced the odds of developing severe disease by 79%. The most frequent treatment-related side-effects were headache, 15% vs 10% (SNG001 vs placebo).

The authors concluded that their initial findings warrant a Phase III trial of the drug and suggest that SNG001 may also be of value against other seasonal respiratory viruses.

Reference
Monk PD et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNGOO1) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 2020 https://doi.org/10.1016/ S2213-2600(20)30511-7

Rapid COVID-19 breath test can help differentiate between other infections

2nd November 2020

With the onset of influenza season and the potential overlap of influenza and COVID-19 symptoms, there is a need to be able to quickly differentiate between the two viruses to ensure that patients are appropriately managed.

Current COVID-19 diagnostics rely on a PCR test, which can only be undertaken via laboratory analysis and, in some cases, the result is not available for a few days. Now researchers from the UK and Germany have reported their preliminary findings on the use of a device that analyses a breath sample to identify infected patients within 10 minutes. The study makes use of exhaled volatile organic compounds (VOCs) in breath which are subjected to gas chromatography and either mass spectrometry (GC-MS) or ion mobility spectrometry. The researchers based their study on the fact that there are distinct breath biochemistry derangements in respiratory illness and that this could be utilised for the detection of those infected with COVID-19 compared to other viral illnesses. The study recruited participants who presented with respiratory symptoms consistent with COVID-19 and this was confirmed with a PCR test. Participants then exhaled through a disposable tube and a sample of breath withdrawn and placed in the GC-MS.

Findings
A total of 98 patients were recruited of whom 79% had confirmed COVID-19. Differentiation of COVID-19 from other conditions was possible in 81.5% of patients. Exhaled breath compounds were attributed to a combination ketosis, impaired gastrointestinal function and inflammatory responses. A distinct panel of compounds including ethanal, octanal, acetone, butanone, methanol, heptanal and one unidentified compound, provided the basis to rule in COVID-19.

The authors reported that the instrument can be easily used in emergency departments for a quick assessment of whether a patient has COVID-19 and that the sampling technique does not pose a risk for clinicians performing the task. They called for further and larger studies to validate these preliminary findings.

Reference
Ruszkiewicz DM et al. Diagnosis of COVID-19 by analysis of breath with gas chromatography-ion mobility spectrometry – a feasibility study. EClinical Medicine 2020; https://doi.org/10.1016/j.eclinm.2020.100609

COVID-19 vaccine: Will there be enough to go around?

30th October 2020

There is an urgent and global wait for an effective COVID-19 vaccine with over 240 currently in development.

In fact, there is much anticipation that a vaccine will offer an exit strategy from the pandemic and the UK government has established a vaccine taskforce to drive forward the development of a vaccine. However, writing in the Lancet, Kate Bingham, the head of this taskforce, has cautioned that we should guard against what she termed “complacency and over-optimism”. She notes that the first vaccine is likely to be imperfect, will not prevent infection and only reduce the symptoms and might not be effective for everyone. Given that COVID-19 preferentially kills patients over the age of 65, any vaccine needs to offer protection in this group and Bingham states that the UK has secured access to at least six vaccines, each with a different format, for example, adenoviral vectors, mRNA, adjuvant proteins and whole inactivated viruses. Furthermore, she emphasises that while the most advanced vaccines from AstraZeneca and the university of Oxford have demonstrated immunogenicity, these are based on novel formats and for which there is little experience as vaccines. In fact, vaccines using the more traditional format, for example, adjuvant proteins and whole inactivated viruses are unlikely to be available until late 2021.

The first Phase III efficacy data from the leading vaccines will be available by the end of 2020, provided that enough patients are recruited and the taskforce is attempting to accelerate recruitment in disease hotspots. The current primary outcome measure for these vaccines is protection against COVID-19 and a reduction in symptom burden. Bingham describes how the taskforce has options to purchase enough doses of each vaccine type to use in adults over the age of 50, health and social care workers and people with underlying comorbidities.

Bingham also makes the rather sobering point that even if an effective vaccine is developed, global manufacturing is currently and quite simply inadequate, to meet the demand for the billions of doses that will be required. She concludes by calling for international collaboration to not just ensure a high degree of readiness to meet the challenges posed by the current pandemic, but to help prepare for any possible future pandemics.

Reference
Bingham K. The UK Government’s vaccine taskforce: strategy for protecting the UK and the world. Lancet 2020. https://doi.org/10.1016/ S0140-6736(20)32175-9

FDA approves remdesivir for COVID-19

The US Food and Drug Administration (FDA) approved remdesivir (brand name Veklury) on 22 October 2020 for use in adults and paediatric patients aged 12 years and over and weighing at least 40kg for the treatment of COVID-19 in patients requiring hospitalisation.

The approval requires that remdesivir is only used in a hospital or healthcare setting capable or providing acute care which is comparable to hospital care. This new approval does not however, include the entire population that was originally included via the emergency use authorisation (EUA) issued on 1 May 2020. In order to allow continued use in paediatric patients the EUA was amended for use only in laboratory confirmed COVID-19 cases for patients weighing 3.5 to less than 40kg less or hospitalised children under 12 years of age weighing at least 3.5kg. However, the FDA makes clear that this is NOT an approved use of the drug and that this authorisation is only temporary and could be revoked.

The approval in adults was based on three randomised clinical trials which showed that treatment with remdesivir lead to clinically meaningful improvements across multiple outcomes compared to placebo. For instance, in the most recent ACTT-1 trial, published in the New England Journal of Medicine, remdesivir significantly improved time to recovery by 5 days and reduced disease progression among patients requiring oxygen. It also showed an improved time to recovery among patients not requiring oxygen in the SIMPLE-Moderate trial conducted in hospitalised patients. Moreover, adverse effects with remdesivir were similar to placebo.
Remdesivir was approved under the early access to medicines scheme in the UK in May 2020.

Reference
FDA News release. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19

Latest REACT-1 data show rapid growth in COVID-19

As the number of infections of COVID-19 rise across the UK in the so-called ‘second wave’, the latest data from the Real-time Assessment of Community Transmission-1 (REACT-1), which was established to specifically track the course of infection, quantifies the extent of the spread of the virus and provides some alarming estimates.

The REACT-1 study was established in May 2020 by a team from Imperial College, London and involves obtaining nose and throat swabs from non-overlapping random samples of the population of England, at ages 5 years and above, obtained from a list of GP registered patients as the sampling frame. The swabs are sent to patient’s homes and collected via courier and PCR tested. To date there have been five rounds of data collection and the team use this data to analyse trends in swab positivity and provide weighted and unweighted population estimates. The latest publication includes data from round 6, collected from 16 to 25 October 2020 and is therefore as current as possible.

Findings
In the latest round there were 863 positive swabs from a total of 85,971, giving an unweighted prevalence of 1% and a weighted prevalence of 1.28% (95% CI 1.15–1.41%). Compared to round 5 (18 September to 5 October 2020) where the weighted prevalence of was 0.60%, the latest figures suggest that the prevalence of COVID-19 has more than doubled. Putting the data into perspective, the authors estimate that around 960,000 individuals have the virus on any one day and that this will lead to approximately 96,000 new infections per day. Interestingly, this latest weighted prevalence is the highest recorded compared to earlier rounds. For instance, the paper reports that in round 1 (1 May to 1 April 2020), the weighted prevalence was 0.16%. Additionally, the latest figures indicate that the prevalence was highest in Yorkshire and the Humber at 2.72% and lowest in the East of England at 0.55%. Epidemic growth is no longer fastest in the North of England but is increasing in the South East, East of England, London and the South West. Furthermore, prevalence has increased across all age groups with the greatest increase now among those aged 55–64, up threefold from round 5 although the highest weighted prevalence remains in the 18–24-year-olds at 2.25% an increase from 1.59% in round 5.

This increased prevalence gave an average R number of the period of rounds 5 and 6 of 1.20. The authors note that their most recent data suggests a national doubling of infection rates every 9 days and that this corresponds to an R value of 1.56. They conclude by stating that the epidemic has now reached a critical stage and that it is time to introduce more stringent measures to control the virus and thus avoid more hospital admissions and deaths.

Reference
Riley S et al. High prevalence of SARS-CoV-2 positivity and increasing R number in England during October 2020: REACT-1 round 6 interim report. MedRxiv 2020. https://doi.org/10.1101/2020.09.30.20204727

Plasma therapy ineffective for COVID-19

23rd October 2020

Given the current limited treatments available for COVID-19, one area of interest has been convalescent or plasma therapy, which represents a form of passive immunity and has been successfully used to treat other viral infections.

To date only two clinical trials have examined the value of convalescent plasma therapy (CP) in patients with COVID-19 though both were stopped early and did not appear to show any significant benefit. For this new study, researchers from the Indian Council of Medical Research have undertaken a randomised trial in over 400 patients but the results also suggest that CP is of limited value. The study recruited 464 adult patients (aged 18 and over) with a median age of 52 years (75% male) from 39 public and private hospitals across India who were admitted to hospital with confirmed moderate COVID-19, based on a positive PCR test. Included patients had a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (Pa02/FiO2) ratio between 200mmHg and 300mmHg, or a respiratory rate of more than 24/minute and an oxygen saturation < 93%. Eligible CP donors were required to have had a PCT positive test for COVID-19 and symptom resolution for 28 consecutive days before donation or a 14-day period which included two negative PCR tests collected 24 hours apart.

Patients were randomised to either CP and best standard of care (intervention group) or care lone (the control group) and intervention patients received two doses of 200ml CP transfused 24 hours apart. The primary outcome as a composite of progression to severe disease Pa02/FiO2 ratio < 100mmHg, anytime within 28 days of enrolment or mortality at 28 days.

Findings
Progression to severe disease occurred in 19% vs 18% (intervention vs control) and 28 day mortality occurred in 15% vs 14% (intervention vs control) of patients. There was a statistically significant higher proportion of patients receiving CP with a resolution of shortness of breath after 7 days (76% vs 66%) and fatigue (73% vs 60%), there was no difference for fever or cough. In addition, significantly more patients (68% vs 55%) had a negative PCR test at day 7. The authors concluded that as a treatment for COVID-19, CP appeared to be of limited value.

Reference
Agarwal A et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020;371:m3939.