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3rd August 2020
How can these drugs be discontinued without giving rise to glucocorticoid withdrawal syndrome?
These were the questions addressed by the SEMIRA study, a large European trial led by Charité – Universitätsmedizin Berlin. According to the trial’s findings, continuous glucocorticoid regimens were better at controlling disease activity. However, discontinuation also proved successful in the majority of cases, and could be used to prevent the long-term side effects associated with glucocorticoid treatment. Results from this trial have been published in The Lancet.
Glucocorticoid are highly effective in controlling inflammatory diseases. Their long-term use, however, is associated with severe side effects, including cardiovascular disorders, osteoporosis and infections. These drugs also suppress the adrenal glands, thereby impairing the body’s ability to produce its own cortisone. This can lead to fatigue, nausea and low blood pressure, and can even prove life-threatening. An appropriate period of gradual dose reduction – known as tapering – is essential to enable the body to adapt to a reduced supply of this substance and prevent withdrawal syndrome. Tapering glucocorticoids without triggering a recurrence of inflammation is a common challenge faced by many medical specialties.
“We had not previously had access to data from double-blind, randomised, placebo-controlled trials which compared a tapering regimen for low-dose prednisone – the most common glucocorticoid used – with continued use of low-dose prednisone. In the SEMIRA trial, our comparative analysis focused on rheumatoid arthritis, a condition commonly treated with glucocorticoids,” explains the article’s first author, Prof Dr Gerd-Rüdiger Burmester, Head of the Medical Department, Division of Rheumatology and Clinical Immunology on Campus Charité Mitte. He and his Deputy Head of Department, Prof Dr Frank Buttgereit, form part of the team responsible for conducting the Steroid Elimination In Rheumatoid Arthritis (SEMIRA) study, a trial including more than 250 participants recruited from close to 40 trial centres in six different countries.
All recruited patients had been receiving glucocorticoids for a minimum of six months, meaning their disease-related inflammation was well-controlled. Patients in the control group continued to receive prednisone at a similar dose for a duration of six months, while patients on the dose reduction regimen had their treatment tapered down to zero over the course of four months. Both groups received the anti-interleukin-6 receptor antibody tocilizumab as adjunctive therapy. Treatment successfully prevented disease flare-ups in 77% of patients on the continued prednisone regimen. The same outcome was achieved in 65 percent of patients on the tapering regimen. Fortunately, neither of the two groups had to contend with clinically relevant changes in their laboratory parameters, disease-related inflammation or other severe problems.
“The fact that glucocorticoid tapering was associated with a treatment success rate of 65% is of enormous significance for shared decision-making involving patients. It will now be possible to decide, on a case-by-case basis, whether glucocorticoid treatment should continue or whether tapering should be attempted,” says Prof Burmester. He adds: “Our results also set the scene for studies to investigate glucocorticoid tapering in other clinical settings – for instance in the fields of allergology, neurology and dermatology – where these drugs are also used, and where there is a certain level of uncertainty regarding the risks and benefits of discontinuing treatment.”
31st July 2020
Using a fixed-dose triple antihypertensive pill improved blood pressure (BP) control more than usual care according to the results of a study by a team from the University of New South Wales, Australia.
The fixed-dose pill (FDP) contained half standard doses of telmisartan 20mg, amlodipine 2.5mg and chlorthalidone 12.5 mg.
Researchers assessed the ability of the triple pill compared to what they termed “therapeutic inertia”, that is, failure to intensify treatment despite poor blood pressure (BP) control. The study recruited 700 patients (mean age 56 years) of whom 57% were women, with mild-to-moderate hypertension (systolic blood pressure > 140mmHg and/or diastolic > 90mmHg) or greater than 130/80 mmHg among those with either diabetes or chronic kidney disease. Individuals were randomised to the FDP once daily or usual care for a period of 6 months. Clinicians in the usual care group were asked to follow local prescribing guidance to achieve blood pressure targets of a BP of <140/90mmHg or <130/80mmHg (in diabetics/kidney disease).
The primary outcome was the proportion with therapeutic inertia. After 6 months, therapeutic inertia occurred in 86.8% of the FDP vs 63.9% in the usual care group (p < 0.01) and 69.5% vs 55.3% (FDP vs usual care) had achieved the BP target.
The authors concluded that initiation of the FDP simplified prescribing and improved BP control compared to usual care.
Reference
Wang N et al. Association of Low-Dose Triple Combination Therapy With Therapeutic Inertia and Prescribing Patterns in Patients With Hypertension: A Secondary Analysis of the TRIUMPH Trial. JAMA Cardio 2020; Jul 22 doi:10.1001/jamacardio.2020.2739
The guideline (NG179) is for adults, young people and children in hospitals and diagnostic settings having planned care, for example, day surgery, inpatient stays or other procedures and seeks to help patients make decisions about their planned care.
Advice and support for shared decision-making for planned care
NG179 suggests that hospitals and services providing planned care in the current COVID-19 pandemic should:
When deliberating the risks of getting COVID-19, NG179 advises staff to discuss any individual factors that may increase a patient’s risk of infection or of becoming severely ill, for example, their age, gender, ethnicity, any possible occupational factors before and after the planned care, as well as the presence of relevant underlying conditions which makes them clinically extremely vulnerable. NG179 also directs patients to the UK government local and national prevalence data on COVID-19 which might impact on a patients’ risk.
Prior to planned care
The guidance recommends that patients receive timely health and wellbeing advice (such as the patient advice from the centre for perioperative care). It is also useful to follow the NICE guidance on lifestyle and wellbeing. Additionally, inform patients that planned care may be brought forward or even postponed especially if they test positive for COVID-19, have symptoms of the virus or need to self-isolate and if they are clinically unwell for any other reason.
Patients (and their family or carers) should be informed of what they can or cannot bring with them for example, type of clothes, mobile phones etc. They will also need to follow social distancing and good hygiene measures before, during and after the planned care, paying attention to the UK government guidance on staying alert to stay safe. In cases where transport services are not available, patients should use private transport to planned care setting and where this is not possible to use public transport, provided they follow government advice on travel.
Minimising the risks of COVID-19
NG179 advises that for children and young people having elective surgery, the guidance from the Royal College of Paediatrics and Child Health should be followed for the recovery after elective surgery. Similarly, maternity and antenatal services should follow the Royal College of Obstetricians and Gynaecologists guidance.
In general terms, all patients (and family/carers) should minimise contact with others to reduce the risk of becoming infected with COVID-19. NG179 strongly recommends that patients are assessed for COVID-19 the day before planned care either by telephone or video call. Patients will apparent symptoms of COVID-19 should self-isolate before a planned procedure.
Patients requiring anaesthesia (both general, regional and local) or sedation
All patients requiring any form of sedation should following social distancing and hand hygiene for 14 days prior to admission. It will also be necessary to have a test for COVID-19 3 days before admission and to self-isolate from the day of the test until admission.
All other planned procedures
NG179 advises patients to follow social distancing and hand hygiene as above (that is, those requiring sedation).
Planning and scheduling
NG179 recommends that departments develop flexible measures to ensure efficient delivery of care. This should involve:
The amount of time spent in the hospital should be minimised by careful scheduling of appointments, discouraging early attendance and by texting patients to inform them that they are ready to be seen.
During planned care
NG179 advises staff following advice infection prevention and control and guidance on personal protective equipment and make efforts to minimise the potential for transmission of COVID-19. Keep visitors to a minimum during inpatient stays and ensure that visits are in line with the government guidance on infection prevention and control. If a patient’s stay exceeds five days, follow NHS England and improvement guidance on testing.
Ongoing care and support
The guideline also suggests staff test inpatients to ensure that they do not have COVID-19 before being discharged to other settings. In addition, to making arrangements for post-operative care, patients should be inform staff if they develop COVID-19 symptoms within 3 weeks of having their planned care.
Healthcare workers
NG 179 suggests that staff working in planned care are offered individualised COVID-19 risk assessments. In cases where staff are known/suspected of having COVID-19, or live in a household where another person is known/suspected of having the virus, they should self-isolate and arrange to be tested in line with local policies. Such staff should only return to work in accordance with the government advice on management of staff and exposed patients or residents in health and social care setting.
Service organisation
The final part of NG179 requests that service providers maintain effective communication with NHS England and NHS Improvement Regional teams to monitor the current COVID-19 prevalence in their areas and be in a position to adapt processes to increase or decrease service provision. Service providers are directed to the weekly COVID-19 surveillance reports produced by NHS England.
NG179 is available online and interested readers should check this version for further updates.
In a change to the current NHS advice, the Chief Medical Officers for the four nations of the UK have agreed that the period of self-isolation should increase from seven to ten days.1
The new advice is for people who are either symptomatic or who have had a positive test for COVID-19. This brings the UK in line with advice from both the US and the World Health Organization (WHO). For example, in the US, the centres for disease control advice is that for most people with COVID-19, isolation can be discontinued 10 days after symptom onset.2 On 27 May, the WHO updated its own guidance on self-isolation, The WHO advice defines the criteria for discharging patients from isolation, which for symptomatic patients is “10 days after symptom onset, plus at least 3 additional days without symptoms” and for asymptomatic cases “10 days after positive test for SARS-CoV-2.”3
But where have these figures come from and how robust is the evidence? The basis for these recommendations comes from a series of studies and while some indicate that viral shedding is no longer detectable after 10 days (see reference 2 for details), other data suggest that shedding can continue for longer than 30 days.4 In a more recent review exploring the detection pattern and viral load of COVID-19, researchers identified 113 studies conducted in 17 countries.5 Their analysis revealed that viral RNA becomes undetectable from upper respiratory tract specimens after about 2 weeks of symptom onset, with a median of 14.5 days though for patients with more severe disease and lower respiratory tract infections, it seems that this period may increase to 15.5 days.
Nonetheless, the connection between viral load and infectivity is still not completely understood and a further concern is the potential for the virus to be transmitted prior to the onset of symptoms which in theory should prolong the self-isolation period even further. The pre-symptomatic transmission of COVID-19 was identified in some early work from China6 and also acknowledged as being the most likely cause of infection in a study from Singapore. In this latter study which included 243 infected cases, the authors identified 7 clusters of pre-symptomatic transmission.7 For example, in four of these clusters, pre-symptomatic transmission occurred 1 – 3 days before the onset of symptoms. However, a criticism of the study is that it was not possible to determine whether a single source was responsible for the initiation of all cases. Despite this limitation, in a secondary analysis of published data, Casey et al8 found that the proportion of pre-symptomatic transmission ranged from 42.8% to 80.6%, although the pooled estimate was 56.4%. In a further review of the duration of infectivity of COVID-19,9 the authors highlighted the difficulty of inferring infectiousness given the heterogeneity of the available evidence. They concluded based on what is currently known, that the median infectious period for asymptomatic individuals is 6.5 – 9.5 days and that the infectious period for pre-symptomatic infection was between 1 and 4 days. They calculated that the mean time from symptom onset to having two negative COVID-19 tests was 13.4 days with a range of 10.9 to 15.8 days. The study including modelling work which implied that patients with more severe infection could be infectious for approximately 4 days longer.
Finally, Byrne et al9 concluded that the highest infectivity (86%) occurred within the first 5 days of symptom onset, but that this could continue for up to 30 days. A further consideration is the evidence that the virus can be detected in faecal swabs of COVID-19 positive patients up to 18 days after the onset of symptoms.10 While this indicates the possibility of oro-faecal transmission of the virus, to date infection through this route has not been reported and thus the significance of this finding remains uncertain.
In summary, the change of government advice on self-isolation is now aligned with guidance from both the US and WHO. While this change is to be welcomed, due to the current uncertainty in the duration of post-symptomatic infectivity, clinicians and patients need to remain cautious to the continued presence of infectivity. Though it seems reasonable to assume that most individuals will much less infective after 10 days there is still uncertainty in this estimate. Furthermore, the current lack of comparative data indicating differences in the period of infectivity between asymptomatic and symptomatic individuals or even if symptom severity prolongs the duration of infectivity, leaves both health professionals and patients with a high degree of uncertainty as to when it might be safe to exit self-isolation. Further research is urgently needed to answer these important, yet unresolved questions.
References
28th July 2020
The efficacy of the allergen powder was established in a randomised, double-blind trial with 496 children (aged 4 to 17 years) of which 372 received the allergen powder, were given a maintenance dose of 300mg/day (after a dose titration phase) for total of 24 weeks.
The primary outcome measure was the proportion of participants who could ingest a challenge dose of 600mg (roughly two peanuts) of peanut protein without dose-limiting symptoms at the trial end. A secondary outcome was the proportion of participants tolerating and 300 and 100mg dose also at the study end. The results showed that 62.7% of those given Palforzia tolerated a dose of 300mg of peanut protein with no more than mild symptoms, compared to 4% in the placebo group. For the secondary outcome, 76.6% and 50.3% tolerated a 300 and 100mg dose respectively compared with 8.1% and 2.4% in the placebo group.
Palforzia must be taken continuously and is indicted for children aged 4-17 years and in those 18 years and over. However, patients still need to practice allergy avoidance and carry an adrenalin injector.
Reference
Peanut allergen powder (Palforzia). JAMA 2020;324(2):192-3.
The olfactory epithelium contains olfactory sensory neurons (OSN), which detect and transmit odours to the brain, sustentacular cells that provide structural support to the OSNs and olfactory stem cells that create new OSNs.
In a yet to be peer-reviewed study, the team focused on two genes, ACE2 and TMPRSS2, which encode for proteins which help COVID-19 gain entry into cells. These genes expressed their respective proteins in the sustentacular and stem cells but not in the OSNs. In other words, primary infection of non-neuronal cells, rather than the OSNs cells may be the main reason why COVID-19 leads to anosmia.
The authors speculated that infection of these supportive cells might lead to inflammation which could impede effective odour transmission or damage to either the sustentacular or stem cells that ultimately affected the structure of the olfactory epithelium and thus smell perception.
While their work is preliminary, it may account for why loss of smell is only temporary in some patients (because the supportive cells recover) or permanent, which has been observed in a subset of patients, due to irreparable damage of the olfactory epithelium.
Reference
Brann DH et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv 2020; July 24: DOI: 10.1126/sciadv.abc5801
The test is based on the same process used for blood group typing (that is, detecting if someone is type A, or blood type O etc) and relies on an agglutination assay.
Red blood cells are coated with peptides from COVID-19 and mixed with a patient’s blood sample. If the patient’s blood contains antibodies to COVID-19, these react with the coated red blood cells and clump together (that is, agglutinate).
The sample is centrifuged and placed on a gel card which contains a separation media and due to its size, the antibody-red blood cell complex cannot pass through the gel card, and the complex becomes visible as a red line which can be easily visualised on the gel cards.
The assay was tested on ten samples of blood, five of which were positive for COVID-19 and the researchers found that the agglutination reaction was absent from samples without the antibodies.
The authors, who have filed for a patent, called to the test to be further evaluated with a larges sample but commented that because the assay is based on a commonly used laboratory process routinely available across the world, it could be easily scaled up and used to quickly assess for the presence of COVID-19 antibodies.
Reference
Alves D et al. Rapid Gel Card Agglutination Assays for Serological Analysis Following SARS-CoV-2 Infection in Humans. ACS sens 2020.
22nd July 2020
This is the conclusion of a new modelling study by a team from Guy’s and St Thomas’ Trust, London.
The team used the English NHS cancer registry and hospital administrative datasets for patients aged 15-84 years of age, diagnosed with breast, colorectal, oesophageal and lung cancer between January 2010 and December 2012 with follow-up dates to December 2015.
They used a route-to-diagnosis framework to estimate the impact of a diagnostic delay over a 12-month period. For instance, patients who would normally be diagnosed through a screening and routine referral pathway were reallocated to a 2-week-wait and emergency pathway.
In the second scenario, they modelled the effect of an 80% reduction in workload via this pathway (which was already observed as a result of the lockdown) and the third scenario assumed an even longer wait time due to the backlog of cases created by the lockdown. The dataset included a total of over 93,500 patients with the four cancers.
Compared with pre-pandemic figures, they estimated up to 9.6% extra breast cancer deaths up to five years after diagnosis. Together with the other cancers, this was projected to result in between 3291 and 3621 additional deaths over 5 years.
The authors concluded that there was an urgent need for policy interventions to manage the backlog in cases and to mitigate the impact of COVID-19 on patients with cancer.
Reference
Maringe C et al. The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based modelling study. Lancet Oncol 2020; July 20.
The study by a group of Chinese researchers gathered data from 129 prospective studies including over 10 million individuals. The results showed that compared to normoglycaemia, the presence of impaired glucose intolerance in the general population was associated with a 13% increased risk of all-cause, a 15% greater risk of composite cardiovascular disease and a 14% increased risk of stroke. However, among patients with existing ACD, the risk of all-cause mortality was 36% and 37% for composite cardiovascular disease. The results also showed that among those with ACD, the mortality risk was 44% higher among Asians compared with non-Asians and that the risk of mortality was further increased among those with higher levels of impaired glucose tolerance.
A limitation of the study recognised by the authors was that they did not identify an association between prediabetes and stroke among those with ACD and therefore concluded that it remains uncertain if the two conditions are related.
The authors suggest that since prediabetes is often asymptomatic, it represents a window of opportunity to prevent the progression to type 2 diabetes and all of its complications.
Reference
Cai X et al. Association between prediabetes and risk of all-cause mortality and cardiovascular disease: updated meta-analysis. BMJ 2020;370:m2297
The team modified a previously unpublished tool developed for planning during the swine influenza pandemic in 2009 but which was updated in 2020 because of the current pandemic. In order to determine the treatment requirements, the tool estimated the likely usage of all classes of drugs normally used in critical care based on the typical length of stay at ICU.
This information was mapped to available stock from the Trust and wholesalers and allowed for more effective procurement planning. The usage information was updated based on real-world data collected from ICU and the model used a traffic light system to identify the availability of individual drugs, that is, green (sufficient stock) to red (insufficient stock).
The authors conclude that the robustness of the model will increase and that it can be further refined based on evolving real-world data. In addition, they discussed how a similar approach could be adopted across a range of therapeutic classes and settings to assist medicine planning and preparedness during any future pandemics.
Reference
Hogg A et al. Informing critical care drug requirements in response to the COVID-19 pandemic Eur J Hosp Pharm 2020; doi:10.1136/ ejhpharm-2020-002368
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