Re-infection with COVID-19 is a cause for concern

30th August 2020

Doctors in Hong Kong have reported the first case of an immunocompetent patient who became re-infected with COVID-19, 142 days after the first infection.

The patient, a 33-year old male, became ill in March 2020, presenting with a cough, sore throat, fever and headache and his diagnosis was confirmed by a positive COVID-19 test. The patient was discharged from hospital in April, after two negative COVID-19 tests, 24 hours apart. The patient had travelled to both Spain and the UK and was re-tested upon arrival at Hong Kong airport. During his second infection the patient remained asymptomatic but nevertheless, had a high viral load that gradually declined and he developed antibodies to the virus.

The authors note that this was a definite case of re-infection, rather than a case of prolonged viral shedding which, though rare, has been reported in the literature, in one case up to 104 days. In an analysis of the genetic material of the virus, it was found to have come from a different lineage, that is, it was an altered strain of the virus. In discussing their findings, the authors note that it is possible that the development of herd immunity is unlikely to eliminate COVID-19, although in practice, subsequent infections will be milder that the first.

Although this is the first case to be published, there are recent media reports of at least two other patients in Europe who have become re-infected.

Reference
To KKW et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020; ciaa1275.

Novel syringe technology for injecting subcutaneous biologics

29th August 2020

The development of subcutaneous formulations of biologics is much more convenient for patients, allowing them to self-administer treatment, reducing the need to attend hospital appointments.

However, it is difficult to inject many of these formulations using commercial syringes and needles due to the high viscosity of the solutions.

Now researchers at the Massachusetts Institute of Technology (MIT) engineering department have developed a simple, low-cost device which makes injections much easier. Although subcutaneous injection formulations for biologics are already available, these often employ jet injectors that literally ‘shoot’ the drug through the skin without a needle, but such devices are expensive and can be contaminated from backsplash. Alternatives such as encapsulating drugs prior to injection can clog the needle and EpiPen type syringes are expensive.

The new system involves a syringe with two barrels, one inside the other. The inner barrel delivers the drug whereas the outer barrel provides a thin layer of lubricant that coats the drug as it enters the needle. Because the lubricant passes more easily through the needle, the drug solution experiences less shear stress. In fact, the researchers found that there was a seven-fold reduction in the force required to inject the drug. They also commented on the potential value of the technology for 3D bioprinting of tissues and administration of cell therapies, since in both cases, the treatment can be destroyed by shear damage.

Reference
Jayaprakash V et al. Enhancing the injectability of high concentration drug formulations using core annular flows. Adv Healthc Mater 2020; 24 August https://doi.org/10.1002/adhm.202001022

Honey better than antibiotics for upper respiratory tract infections

According to the results of a new meta-analysis by a team from Oxford University, honey is superior to usual care for the improvement of symptoms related to an upper respiratory tract infection (URTI).

For this new analysis, the researchers identified 14 randomised studies including patients of any age and compared honey with usual care and undertook subgroup analyses where there were differences in the type of usual care. The results were expressed in terms of either the standardised mean differences (SMD) to account for differences in the way in which the same outcome was measured or simply the mean difference (MD).

Compared with usual care, honey improved combined symptom score (MD –3.96, 95% CI –5.42 to –2.51), cough frequency (SMD –0.36 95% CI –0.50 to –0.21) and cough severity (SMD –0.44; 95% CI –0.64 to –0.25). In contrast, subgroup analysis revealed that honey was no more effective than dextromethorphan for combined symptoms but better than diphenhydramine.

An important limitation of the analysis was the variable risk of bias and the broad nature of the interventions measured in studies making an independent evaluation of honey difficult in some of the trials.

Nevertheless, the authors concluded that where clinicians wished to prescribe treatment for an URTI, honey should be considered as a first-line option.

Reference
Abuelgasim H, Albury C, Lee J. Effectiveness of honey for symptomatic relief in upper respiratory tract infections: a systematic review and meta-analysis BMJ Evidence-Based Medicine; 18 August 2020: doi: 10.1136/bmjebm-2020-111336

Is convalescent plasma the answer to COVID-19?

28th August 2020

On 23 August 2020, the Food and Drug Administration (FDA) authorised the use of convalescent plasma as a promising new treatment of hospitalised patients with COVID-19.1

This was granted via the emergency use authorisation procedure, which allows the FDA make use of unapproved medical products or unapproved uses for approved products, in an emergency to diagnose, treat or prevent serious or life-threatening diseases or conditions. In the press release, the FDA reported that their decision was based on a review of the science and data gathered over the last few months. But what exactly is convalescent plasma therapy and how robust is the data for its use as a treatment modality for patients with COVID-19?

History of use
Passive antibody administration therapy involves giving plasma or serum that contains antibodies to a particular infection, to an individual in order to help treat the infection. The concept discovered in 1891 by von Behring who used sheep serum containing antibodies against diphtheria toxin to successfully treat a child with the infection. It was later realised that the transferred plasma was not only able to neutralise the pathogen but also provided immunity against subsequent infection and the technique became known as serum therapy. By the 1930s, serum therapy was widely used to successfully treat a range of infections such as pneumonia and meningococcal meningitis.2 However, the introduction of antibiotics in the 1930’s lead to a decline in the use of serum therapy, largely because chemotherapy with antimicrobials was more effective. Additionally, at the time it was difficult to obtain enough sera from convalescing patients for therapeutic purposes because plasma from one donor can only be used to treat a few patients. Nevertheless, today, antibody therapy is used extensively in medicine but in a highly purified form, for example, monoclonal antibodies.

Convalescent plasma therapy (CP) represents the modern-day equivalent of serum therapy. Patients who have previously been infected with a disease develop circulating antibodies to the pathogen and transferring serum from these individuals to a patient with the specific disease, represents an indirect but effective means through which the recipient becomes immune against the specific pathogen.

Efficacy in viral infections
Despite the development of effective antimicrobial and antiviral agents, CP therapy has emerged periodically over the years, especially during outbreaks of infections for which, at the time, there were no effective drug or vaccines available. For example, CP therapy was used to treat patients with the Spanish influenza pneumonia and an analysis in 2006 that included eight studies with 1703 patients, found that patients receiving the treatment may have experienced a clinically important reduction in the risk for death.3 The value of CP therapy has also been evaluated in the context of viral infections such as the SARS-CoV, avian influenza (H5N1) and the 2009 pandemic caused by H1NI (swine flu). A 2015 analysis included 32 studies of coronavirus infections and severe influenza concluded that CP therapy led to 75% reduction in the odds of mortality among treated patients.4 The use of CP therapy has also explored in the treatment of Ebola virus. The first reported use of CP therapy in Ebola virus emerged in 1976. A researcher who accidentally infected himself with the virus, was treated with CP therapy from an Ebola patient and made a full recovery.5 In another study in Sierra Leone, 69 patients infected with Ebola virus were offered CP therapy or standard treatment which included IV fluids, multivitamins, antipyretics, analgesics, antibiotics, anthelmintics and antimalarial drugs. A total of 44 agreed to CP therapy and although one patient dropped out of the study, 31 recovery and 12 succumbed to the disease, giving a case fatality rate of 27.9%. In contrast, for those receiving standard, the case fatality rate was 44%. The authors calculated an odd ratio for survival from CP therapy of 2.3 (95% Cl 0.8–6.5) and concluded that CP therapy was a promising treatment of Ebola in a resource-poor setting.6 The mechanism of action for CP therapy is not fully understood but thought to be related to the presence of the neutralising antibodies which are raised against several of the S proteins present on the surface of coronaviruses, which are involved in receptor recognition, viral receptor attachment and cell entry.7

Convalescent therapy for COVID-19
The increasing death rate and rapid global spread of COVID-19 has resulted in an urgent need to develop either an effective drug or vaccine against the virus. According to the World Health Organization database, there are 2360 current studies looking at treatments and interventions for COVID-19.8 Given its historical success, interested has centred on the use of CP therapy for COVID-19 and it was first used in five critically ill Chinese patients, refractory to steroid and antiviral therapy. All received CP therapy from five different donors and three were discharged from hospital and two remained stable after 37 days.9 In a US-based study that included 25 patients with severe and/or life-threatening COVID-19, a single transfusion of plasma was well tolerated and after 7 days, 36% of patients (9/25) had an improvement in clinical symptoms, whereas after 14 days, 76% (19/25) had improved or been discharged.10 In an effort to summarise the effectiveness of CP therapy in COVID-19, a living Cochrane review (that is, one that is constantly reviewed) has been established. In the most recent review, researchers identified 20 studies with a total of 5443 participants, of whom, 5211 received convalescent plasma. In assessing the efficacy of the intervention, the outcomes considered included all-cause mortality, time to death and an improvement in clinical symptoms, defined in terms of the need for respiratory support.

The analysis revealed a non-significant impact on all of the reported outcomes. For example, all-cause mortality (risk ratio, RR = 0.89, 95% CI 0.61–1.31), time to death (hazard ratio, HR = 0.74, 95% CI 0.30–0.82) and improvement in clinical symptoms at 14 days (RR = 1.85, 95% CI 0.91–3.77). In their conclusion, the authors noted that it was currently uncertain whether convalescent plasma was beneficial for people admitted to hospital with COVID-19.11

Moreover, the Cochrane review also examined any associated adverse effects, which included allergic events such as anaphylaxis, transfusion-associated dyspnoea and transfusion-related acute lung injury. While the review included a small number of studies, the authored noted that there were 98 ongoing studies including 50 randomised controlled trials.

Conclusions
Until an effective vaccine or drug therapy is developed, there remains an urgent need to find effective alternative treatments for patients with COVID-19. Renewed interest in passive immune therapy in the form of convalescent plasma has shown some promise and has been endorsed by the FDA. While the currently available data are limited, it does suggest some benefit although there remains considerably uncertainty. At the time of the Cochrane review, the authors felt that CP therapy was likely to be of benefit since re-infection with COVID-19 was unlikely although a recent case report of re-infection in a patient casts doubt on this assertion.12 Nevertheless, in the absence of effective treatments, CP therapy may offer hope to some of the patients with more severe disease. As more data emerges from on-going studies, both the value and position of CP therapy in the management of those with COVID-19 infection will become much clearer.

References

1. FDA News release. FDA issues emergency use authorization for convalescent plasma as potential promising COVID–19 treatment, another achievement in Administration’s fight against pandemic.
   www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
2. Casadevall A, Scharff MD. Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis 1995;21(1):150–61.
3. Luke TC et al. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med 2006;145(8):599–609.
4. Mateus ALP et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral aetiology: a systematic review and exploratory meta-analysis J Infect Dis 2015;211(1):80–90.
5. Edmond RT et al. A case of Ebola virus infection Br Med J 1977;2(6086):541–4.
6. Sahr F et al. Evaluation of convalescent whole blood for treatment Ebola virus disease in Freetown, Sierra Leone. J Infect 2017;74(3):302–9.
7. Du L et al. The spike protein of SARS-Cov – a targer for vaccine and therapeutic development. Nat Rev Microbiol 2009;7:226–36.
8. Clinicaltrials.gov. COVID-19 studies.
   https://clinicaltrials.gov/ct2/who_table
9. Shen C et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582.
10. Salazar E et al. Treatment of coronavirus disease 2019 (COVID-19) patients with convalescent plasma Am J Pathol 2020;190:1680–90.
11. Piechotta V et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Sys Rev 2020; issue 7. Art No: CD013600.
12. To KKW et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020; ciaa1275, https://doi.org/10.1093/cid/ciaa1275.

Current social distancing guidance might not be enough

The social distancing guidance is based on outdated science and should reflect the multiple factors that affect transmission risk according to a new review published by researchers at Oxford University.

The notion that either keeping either 1 or 2m apart is sufficient to reduce transmission of the virus, overlooks the physics of respiratory emissions which depends on a number of factors including the viral load of the emitter, duration of exposure and an individual’s susceptibility to infection.

The authors cite evidence from recent studies which have indicated how COVID-19 can persist in airborne samples for up to 16 hours and that breathing out, singing coughing and sneezing generate warm, moist high momentum gas clouds that can extend much further than 2m and up to 8m in a few seconds. The authors offer a guide to how the risk of transmission from an asymptomatic individual varies in different settings and for different exposure times and call for more research to establish solutions to indoor environments at varying levels of occupancy.

Airflow patterns within building are an equally important contributors to the risk of transmission, as evidenced from a Chinese restaurant study in which infection occurred over a distance of 4.6m in the space of an hour without physical contact.

The authors conclude that physical distancing should be viewed as only one aspect of an overall strategy that considers people-air-surface-space management, occupancy levels, air management and appropriate use of masks for a given setting.

Reference
Jones NR et al. Two metres or one: what is the evidence for physical distancing in Covid-19? BMJ 2020;370:m3223 http://dx.doi.org/10.1136/bmj.m3223

Aspirin in the elderly associated with increased risk of metastatic cancer

The use of aspirin in elderly patients appears to increase the risk of incident solid cancers presenting at an advanced stage according to the results of a new study.

Researchers from Monash University, Australia, randomised 19,114 individuals aged 70 years and older, without cardiovascular disease, dementia or physical disability to either enteric coated aspirin 100mg daily or matching placebo and followed them for a median of 4.7 years.

The results showed that during the trial, 1933 (10%) individuals developed a cancer, with prostate, colorectal, breast, melanoma and lung, accounting for over 80% of all solid organ cancers. Use of aspirin was not associated with the risk of developing cancer (hazard ratio, HR = 1.04, 95% CI 0.95–1.14). However, aspirin use was associated with metastatic cancer at diagnosis (HR = 1.19, 95% CI 1–1.43) and with an increased incidence of cancers presenting at stage 4 (HR = 1.22, 95% CI 1.02–1.45). Furthermore, there was an increased progression to death among those taking aspirin, regardless of whether the initial cancer had been localised or metastatic.

The authors concluded that aspirin appeared to increase the risk of cancer evolution in older adults and reported that they are continuing the follow the cohort to examine the impact of aspirin in the longer term.

Reference
McNeal JJ et al. Effect of aspirin on cancer incidence and mortality in older adults. J Natl Cancer 2020; Aug 11: doi.org/10.1093/jnci/djaa114

Greater use of antibiotics increases risk of developing IBD

27th August 2020

According to a new study by a team from Massachusetts General Hospital and the Karolinska Institute, higher exposure to systemic antibiotics may be associated with a greater risk of new-onset inflammatory bowel disease (IBD) and its subtypes.

In this prospective case-controlled study, researcher identified cumulative antibiotic use until one year before matching with 117,827 control, a total of 23,982 individuals at least 16 years of age, with a diagnosis of IBD including ulcerative colitis, Crohn’s disease and unclassified IBD.

The results were analysed using logistic regression and expressed as adjusted odds ratios (aORs). For a diagnosis of IBD in those who had used antibiotics compared to those who had never used antibiotics, the aOR was 1.88 (95% CI, 1.79–1.98), 1.74 (95% CI, 1.64–1.85) for ulcerative colitis and 2.27 (95% CI, 2.06–2.49) for Crohn’s disease. Furthermore, the aORs for each condition increased with increasing courses of antibiotics and in particular, with broad-spectrum agents. In addition, there were similar but attenuated risks when siblings were used as the reference group.

The authors called for longer-term prospective studies to examine the potential mechanisms involved and concluded that if their findings were substantiated, greater emphasis should be placed on antibiotic stewardship to prevent the rise of IBD.

Reference
Nguyen LH et al. Antibiotic use and the development of inflammatory bowel disease: a national case-control study in Sweden. Lancet Gastroenterol 2020; Aug 17: doi.org/10.1016/S2468-1253(20)30267-3

Virtual consultations: the new norm for cardiology services

Virtual consultations are here to stay for cardiology services, according to a new report by the British Cardiovascular Society.

The report notes how in a short space of time, both primary and secondary outpatient care has become largely virtual in response to the COVID-19 pandemic. Moreover, as services begin to re-start, the need for separate COVID-19 positive and COVID-free facilities, will result in a reduction in the productivity of diagnostics such as echocardiography, catheter lab sessions and face-to-face clinics. It is anticipated that cardiology referrals from primary care will now occur electronically via a single triage portal using agreed local protocols for any advice on referrals, investigations and the management of common conditions.

The report also recognises the need to make greater use of the skills of the wider heart team including specialist nurses and pharmacists and cardiac physiologists, in running virtual and face-to-face clinics. The move to a digital platform will enable patients to be prepared in advance, for example, by ensuring that they have relevant information readily available for the consultation, for example, current medication.

The report acknowledges the requirement for face-to-face consultations to examine patients with complex heart needs and how digital technology provides an opportunity for patient education, for example, through webinars from professional societies and patient groups.

The report concludes that these changes will require an investment in IT infrastructure and diagnostic capacity and a recognition that NHS clinical staff will need to organise their time in different ways.

Reference
British Cardiovascular Society. The future of cardiology. www.britishcardiovascularsociety.org/__data/assets/pdf_file/0010/21142/BCS-Future-of-Cardiology-17-Aug-2020.pdf

Bundled transition care in older adults likely to reduce hospital re-admission

The combination of self-management activities, telephone follow-ups and medicine reconciliation are most likely to reduce readmissions to hospital in older patients

This is the conclusion of a meta-analysis from a group of researchers from the Universities of Bradford and Leeds in the UK.

For the analysis, the team looked at studies in which the interventions were either delivered in hospital prior to discharge or within one month of discharge and that included patients 65 years of age and older. The main outcome of interest was a reduction in hospital readmission rates. In total, 24 studies conducted in 12 countries and thus covering a range of public and privately funded healthcare systems and with 17,664 participants were analysed.

When stratified by the intervention component, each of the following were associated with a statistically significant reduction in hospital readmission. Self-management activities (relative risk, RR = 0.81, 95% CI 0.74–0.89), telephone follow-up (RR = 0.84, 95% CI 0.73–0.97) and medication reconciliation (RR = 0.88, 95% CI 0.81–0.96). However, studies were highly heterogenous and it was therefore difficult to attribute the success to individual components within bundles.

Nevertheless, the authors concluded that interventions which included these three components were most likely to be effective although it remained unclear how best to engage with patients or carers in order to provide this support.

Reference
Tomlinson J et al. Successful care transitions for older people: a systematic review and meta-analysis of the effects of interventions that support medication continuity. Age Ageing 2020 Jul 1;49(4):558–69.

Single dose radiotherapy in early breast cancer as effective as standard radiotherapy

26th August 2020

A new study suggests that risk adapted immediate single dose intraoperative radiotherapy (TARGIT-IORT) after lumpectomy has similar long-term local control and survival outcomes compared with conventional radiotherapy.

The study by an international team from 32 centres in 10 countries, randomised 2298 women aged 45 years and over, with invasive ductal carcinoma on a 1:1 basis, to receive either TARGIT-IORT, which was given immediately after lumpectomy or conventional treatment, involving daily fractionated courses of external beam radiotherapy (EBRT), for 3 to 6 weeks. The main outcome of the trial was defined as non-inferiority (of the two procedures) with a margin of 2.5% for the absolute difference between the 5-year local recurrence rates and long-term survival.

At 5 years, the difference in local recurrence between both arms was 1.16% (90% CI 0.32–1.99) and there were 14 fewer deaths in the TARGIT-IORT group. After a median follow-up period of 8.6 years, there were no significant differences in local recurrence-free survival (hazard ratio, HR = 1.13, p = 0.28) between the two arms.

The authors concluded that in eligible patients, TARGIT-IORT was an effective alternative to standard therapy (EBRT) and is associated with an approximately 80% of avoiding a full course of radiotherapy.

Reference
Vaidya JS et al. Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial. BMJ 2020;370:m2836.