Prior bariatric surgery associated with better outcomes in patients with COVID-19

30th November 2020

Obesity represents a risk factor associated with a worse prognosis in patients with COVID-19. Metabolic surgery for weight reduction leads to improvements in health and wellbeing and could therefore result in a better outcome among those who become infected with COVID-19.

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.

Findings
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.

Reference
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

No increased risk for transmission with COVID-19 mutations

Since the move of COVID-19 from animals to humans has been a relatively recent transition, a potential concern is that the virus has not fully adapted to the human host and may continue to evolve and mutate to become more transmissible.

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.

Findings
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.

Reference
Van Dorp Let al. No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2 Nat Commun 2020;11:5986.

Uncertainty over the efficacy of up-dosing antihistamine in chronic urticaria

27th November 2020

Between 0.5 and 1% of the population experience chronic spontaneous urticaria (CSU) which is characterised by recurrent pruritic wheals and/or angioedema that can persist for up to six weeks.

While the precise cause of CSU remains unclear, contemporary European guidelines advocate the use of second-generation antihistamines as a first-line treatment for the condition. Although these drugs can be effective, for patients in which symptom control remains inadequate, the guidance recommends up-dosing to four times the recommended dose as a second-line treatment option.

This latter commendation is based on expert opinion and for this study, a team from the Allergology Department, Complexo Hospital, A Coruna, Spain, set out to review the available evidence to support this approach. They included studies published in English or Spanish with patients at least 12 years of age with CSU on regular (as opposed to “on-demand”) therapy with a second-generation antihistamine. Other inclusion criteria were that the study should have a single antihistamine (rather than a combination), a placebo arm and using the drug at a higher than recommended dosage.

Findings
In total and after removal of duplicates and exclusions, only 14 articles were analysed in detail including 20 to 439 patients. Six studies focused on fexofenadine (up-dosing to 720 mg), 2 on cetirizine, levocetirizine, rupatadine, desloratadine and 1 trial with either ebastine or bilastine. Furthermore, only 5 of these trials were placebo controlled and all studies lasted between 2 and 8 weeks except for one fexofenadine trial which lasted 16 weeks. A higher dose of fexofenadine produced a dose-dependent significant response and controlled CSU in the majority of patients. Commenting on their findings, the authors noted that of the 14 trials, only 6 were of high quality and that the high level of heterogeneity in sample size, design, duration etc, which made it very difficult to make comparisons. Interestingly, they also note that despite current guideline recommendations, most studies did not find a significant impact on symptom control from up-dosing.

The authors concluded that while up-dosing appears both effective and safe, there is a lack of evidence to support this approach and called for further studies to validate the recommendations in guidelines.

Reference
Iriarte SP T et al. Up-dosing antihistamines inn chronic spontaneous urticaria: efficacy and safety. A systematic review of the literature. J Investig Allergol Clin Immunol 2020 doi: 10.18176/jiaci.0649

Statins reduce cardiac events in adults aged 50-75 after only 2.5 years

24th November 2020

Statins are used for primary prevention in adults aged 40 to 75 years who are at high risk (that is, greater than 7.5% risk of a major adverse cardiac event or MACE) over the next 10 years).

Guidance on the use of statins as a means of reducing this risk recommends that any decisions are made jointly by patients and clinicians, especially given the wide range of cardiovascular risk factors, comorbidity burden and life expectancy of patients within this age range. While the benefits of statin therapy are well established, what remains unclear is the time-frame over which these benefits occur. In other words, how long is the “time to benefit” (TTB) from statins.

In an analysis, researchers from the Division of Geriatrics and Gerontology, University of California, US, conducted a meta-analysis of the major randomised clinical trials to determine the TTB, which served as the primary outcome and which they defined as the time from starting a statin to the first MACE. The team only included trials which had more than 1000 participants, aged at least 55 years and older. Given that the focus was primary prevention, researchers also limited the search to those trials in which less than 15% of participants had pre-existing cardiovascular disease.

Findings

A search of all the major databases, identified 8 randomised trials including 65,383 patients (66.3% male) and with less than 10% of participants having existing cardiovascular disease. The analysis showed how the benefit of statin therapy increased with the duration of the study so that, for example, after 1 year, 0.3 MACEs were prevented for every 100 people treated with statins and this increased to 2.5 MACEs after 5 years. They calculated that 2.5 years were required to prevent 1 MACE for every 100 patients given statins. Thus statin treatment was only likely to benefit patients aged 50 to 75 years where they had a life expectancy of at least 2.5 years. Interestingly, only one statin trial found that therapy reduced overall mortality.

The authors concluded that their results reinforce the importance of individualised statin treatment-related decision making.

Reference
Yourman LC et al. Evaluation of time to benefit of statins for primary prevention of cardiovascular events in adults aged 50 to 75 years. A Meta-analysis. JAMA Intern Med 2020

Taking vitamin C with iron has no effect on haemoglobin levels

20th November 2020

Vitamin C is a dietary constituent which has been shown to promote iron absorption in the duodenum and upper jejunum.

Oral iron is always oxidised to the Fe3+ state, irrespective of how it is taken and requires an acidic environment for adequate absorption. Vitamin C creates a more acidic environment and can prevent the oxidation of iron to the ferric form. However, whether the common practice of advising that vitamin C is taken alongside iron supplements to enhance iron absorption is beneficial has never been tested.

As a result, for this study a team from the Department of Haematology, Huashan Hospital, Shanghai, China, undertook a randomised, open-label trial in adult patients with newly diagnosed iron-deficiency anaemia (IDA). Participants were given 100mg oral iron tablets plus 200mg of vitamin C or 100 mg of iron alone every 8 hours for a total of 3 months and the authors assessed treatment compliance by determining the number of iron and vitamin tablets returned at the end of the study. Included patients had a haemoglobin level less than 13g/dl for men or less than 12g/dl for women. Although treatment continued for 3 months, the primary outcome measure, the change from baseline in haemoglobin levels, was assessed after two weeks. Secondary outcomes included the increase in serum ferritin after 8 weeks and the haemoglobin level after 4 and 8 weeks.

Findings
A total of 440 patients with a mean age of 38.3 years (96.8% women) were randomised and treatment compliance was 98.2%. The mean baseline haemoglobin level was 8.76g/dl in both groups and serum ferritin, 5.89 in the vitamin C group and 6.34 in the iron only group. After two weeks, the change from baseline in haemoglobin levels was 2.00g/dl in the vitamin C group and 1.84g/dl in the iron only group which was not significant. Similarly, the mean change in serum ferritin levels were 35.75ng/ml vs 34.48ng/ml (vitamin C vs iron only). Furthermore, there were no differences in haemoglobin levels after 2, 4, 6 or 8 weeks. The authors concluded that it is unnecessary to add in vitamin C to the iron regime for patients with IDA.

Reference
Li N et al. The efficacy and safety of vitamin D for iron supplementation in adult patients with iron deficiency anaemia: A randomised clinical trial. JAMA Network Open 2020;3(11):e2023644. doi:10.1001/jamanetworkopen.2020.23644 (R

Ticagrelor and aspirin superior to aspirin alone in ischaemic stroke

It is known that only a quarter of patients who experience an ischaemic stroke with a disability will improve over time and are at an increased risk of subsequent death.

Thus any intervention that is able to reduce disability by reducing a subsequent ischaemic stroke is a major objective of immediate therapy. Although the use of aspirin in combination with clopidogrel has been shown to reduce the risk of further stroke and myocardial infarction, to date, evidence for a beneficial effect from adding ticagrelor to aspirin in terms of a reduction in the burden of disability after a stroke is lacking.

In an analysis, researchers from the Department of Neurology and Stroke Center, University of Paris, France, sought to examine whether combing both drugs reduced the 30-day risk of disabling stroke or death. Disability was measured using the modified Rankin Scale (mRS) which ranges from 0 to 6, in which 0-1 represents no disability, 2-5 increasing disability and 6, death. Patients were enrolled if they were 40 years of age and older, with a non-cardioembolic acute ischaemic stroke and a stroke scale score of 5 or less (higher scores indicate more severe stroke). They were randomised to ticagrelor or matching placebo 1:1 and a loading dose of 180mg was given as soon as possible after randomisation, followed by a daily dose of 180mg (90mg twice daily). In addition, all patients received 300 to 325 mg of aspirin on the first day, followed by 75 to 100mg until day 30. The main outcome measure was the time to the occurrence of disabling stroke or death within 30 days, measured by the mRS scale.

Findings
A total of 11,016 patients with a mean age of 68.1 years (42.6% female) were included in the study. A primary end point with a mRS > 1 at day 30 (that is. disabling stroke or death) occurred in 221 (4.0%) of patients taking ticagrelor and in 260 (4.7%) of those taking placebo. This provided a number needed to treat of 133. In other words, treating 133 patients with ticagrelor and aspirin for 30 days, avoided 1 disabling stroke or death at day 30. Furthermore, disability burden (based on the mRS scale) was reduced by 23%.

Reference
Amarenco P et al. Ticagrelor added to aspirin in acute ischemic stroke
or transient ischemic attack in prevention of disabling stroke: A randomized clinical trial. JAMA Neurol doi:10.1001/jamaneurol.2020.4396

Inhaled interferon-beta shows promise as COVID-19 treatment

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

Study adds little to the vitamin D and COVID-19 debate

16th November 2020

During the current pandemic there has been much interest and debate over the potential protective role of vitamin D, especially as the hormone plays an important role in immunity.

It has been speculated that a lack of vitamin D, which is common in the elderly (and who are at increased risk of death), prevents the body from attenuating the pro-inflammatory cytokine response which characterises lung damage. In this latest study, a team from the University Hospital of Marques de Valdecilla, Santander, Spain, conducted a retrospective analysis of patients hospitalised with COVID-19 and compared their vitamin levels with an age-matched control group of patients. Demographic data was collected from hospital records and all included patients had a PCT COVID-19 positive test result to confirm infection. Vitamin deficiency was defined as a serum 25OHD level of < 20ng/ml. As part of the treatment plan, patients received tocilizumab if their PaO2/FIO2 ratio was < 300. The authors defined a composite endpoint of admission to intensive care, requirements for mechanical ventilation or in-hospital mortality and compared this endpoint between the two groups.

Findings
The study included 216 patients of whom 19, were already taking supplementation. The median age was 61 years and 62.4% of participants were male. The mean 25OHD levels in COVID-19 patients were 13.8 (± 7.2ng/ml) compared to 20.9 (± 7.4) ng/ml in control patients (p < 0.0001). Overall, vitamin D deficiency was recorded in 82.2% of those with COVID-19 compared to 47.2% of matched controls. Furthermore, compared to those who were vitamin deficient, vitamin D replete patients had a reduced need for tocilizumab (17% vs 33.1%, p = 0.032), less frequent radiological progressions (14.9% vs 30.2%, p = 0.037), lower intensive care admissions 912.8% vs 26.6%, p = 0.048) and a slightly shorter hospital stay (12 vs 8 days). However, the authors found no correlation between serum 25OHD levels and the composite severity endpoint, with an odds ratio of 1.13 (95% CI 0.27 – 4.77, p = 0.865). Commenting on this finding the authors noted that whether it has a preventative role or even improves prognosis remains to be determined.

Thus, while this study demonstrates lower vitamin D levels among patients with COVID-19, it adds very little to our overall understanding of the role of this vitamin in relation to infection with the virus.

Reference
Hernandez JL et al. Vitamin D status in hospitalised patients with SARS-Cov-2 infection. J Clin Endocrinol Metab 2020 dgaa733. https://doi.org/10.1210/clinem/dgaa733

Latest neutralising antibody accelerates the natural decline in COVID-19 viral load

Animal data on the use of neutralising antibodies against COVID-19 have shown promise with positive results from, for example, REGN-COV2.

Now in an interim analysis of a Phase II trial, a team from the Department of Medicine, Women’s Guild Lung Institute, California, have found that a new and potent, antispike neutralising antibody, LY-CoV555, which has been developed by Eli Lilly and which is derived from convalescent plasma, appears to reduce hospitalisations for those with COVID-19. This was a randomised, double-blind, single-dose trial conducted at 41 centres in the US among patients who tested positive for COVID-19 and presented with mild or moderate symptoms. All received a single intravenous infusion of LY-CoV555 at doses of 700mg, 2800mg and 7000mg or placebo for approximately 1 hour, within 3 days after a positive COVID-19 test. Although patients could receive additional treatments, the current publication only reports on the results for LY-CoV555. The study’s primary outcome was the change in COVID-19 viral load which was measured using the PCR test, from baseline to day 11 (± 4 days) after a positive result and data on viral-related symptoms were collected up to 29 days. Secondary outcomes collected related to safety assessments and symptom burden as reported via a questionnaire and clinical outcomes, which included admission to hospital, a visit to the emergency department of death.

Although a Phase II study, the authors concluded that LY-CoV555 appears to be both safe and effective.

Findings
A total of 452 patients with a median age of 45 years (55.3% female) and including 10.7%, were randomised to either placebo or one of 3 doses of LY-CoV555. Overall, 75.1% had mild disease and the mean viral load (based on the Ct value) was 23.9. By day 11, the mean decrease in viral load across all patients was -3.81, which resulted in an elimination of more than 99.97% of viral RNA. The greatest difference in reduction of viral load compared to placebo occurred among patients receiving the 2800mg dose of LY-CoV555 (-0.53) and this group also had a greatest reduction in viral load after 7 days compared to placebo (-0.45). At day 29, the proportion of patients hospitalised due to COVID-19 was 1.6% in the LY-CoV555 group vs 6.3% among the placebo group and this was similar across the three doses. Furthermore, on days 2 to 6, symptom burden was less among those given LY-CoV555 and there were no deaths or safety concerns.

Reference
Chen P et al. SARS-CoV-2 neutralising antibody LY-COV555 in outpatients with COVID-19. N Engl J Med 2020 DOI: 10.1056/NEJMoa2029849

Persistent fatigue after COVID-19 common and independent of disease severity

Tiredness or fatigue has become a recognised symptom among patients infected with COVID-19, reportedly affecting between 44% and 69% of individuals. Although in the past, chronic fatigue has been documented among patients affected by other coronaviruses, little is known about whether this symptom persists in those who have recovered from COVID-19.

Researchers from the Department of Infectious Diseases, St James’s Hospital, Dublin, Ireland, have examined the prevalence of fatigue using the Chalder Fatigue Scale (CFQ-11) in patients who had recovered from the acute phase of a COVID-19 infection. The CFQ-11 scale asks about symptoms over the past month and assesses both physical and psychological fatigue with a total score greater than 4 meeting the criteria for fatigue. The researchers also measured white blood cell counts, CRP and interleukin-6 and sCD25 to assess if there was a correlation between these markers and fatigue.

Findings
A total of 128 patients with a mean age of 49.5 years (53.9% female) were included in the final analysis and 55.5% of these had been admitted to hospital because of COVID-19 with the remainder seen at an outpatient clinic. The mean baseline CFQ-11 score was 15.8 across the study population with a mean physical score of 11.38 and a mean psychological score of 4.72. Overall, 52.3% of participants met the criteria for persistent fatigue, with a mean CFQ-11 score of 20 at a median 10 weeks after the initial COVID-19 infection. Interestingly, there was no association between the severity of COVID-19 infection and fatigue scores and an analysis of the blood tests did not reveal any association between fatigue scores and IL-6 levels or sCD25. Furthermore, the impact of fatigue had led to almost a third (31%) of participants not having returned to work after 10 weeks.

The authors concluded that their study suggests that COVID-19 creates a huge burden of fatigue which is likely to impair quality of life necessitating management strategies for convalescing patients.

Reference
Townsend L et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS ONE 2020 e0240784. https://doi.org/ 10.1371/journal.pone.0240784