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21st September 2021
The available evidence clearly shows that infection with COVID-19 is disproportionately higher in adults compared with children. Nevertheless, emerging data suggests that in children infection with COVID-19 can induce multisystem inflammatory syndrome and lead to serious illness. While the pandemic has revealed how several clinical factors such as older age, various co-morbidities and ethnicity, are all associated with a higher level of COVID-19 severity, much less is known about which factors lead to more severe disease in children.
This lack of information prompted a group of US researchers from the Division of Hospital Medicine, Monroe Carell Jr, Children’s Hospital, Vanderbilt, Nashville, Tennessee, US, to undertake a retrospective cohort study across 45 US children’s hospitals to assess factors associated with COVID-19 severity in paediatric patients. The researchers included patients as young as 30 days old to 18 years of age, discharged from either an emergency department (ED) or inpatient setting with a primary diagnosis of COVID-19. The researcher collected demographic data and information on the presence of any co-morbidities, particularly those which appeared to result in a worse prognosis among adults. The outcome of interest was COVID-19 severity which was categorised as mild (i.e., ED discharge), moderate (in-patient admission) and severe (intensive care (ICU) admission) and very severe (ICU admission with mechanical ventilation, shock or death). The results were analysed using regression analysis and presented as odds ratios adjusted for various factors including ethnicity and co-morbidities.
The study included 19,976 ED encounters of children with a median age of 6 years (51.2% male) with the most common ethnicities being Hispanic (48.8%) and non-Hispanic White (21.1%). In the majority of cases (79.9%) COVID-19 severity was mild (79.7%) and these individuals were discharged from the ED. However, among the 4063 (20.3%) patients who were hospitalised, the majority had moderate COVID-19 severity (79.3%) with 11.3% classed as severe and 9.4% as very severe. When compared with those who were discharged from the ED, the clinical factors associated with an increased odds of hospitalisation included obesity/type 2 diabetes (adjusted Odds ratio, aOR = 10.4, 95% CI 8.90 – 13.3), asthma (aOR = 1.40, 95% CI 1.3 – 1.60), cardiovascular disease (aOR = 5.0), an immunocompromised condition (aOR = 5.9) and pulmonary disease (aOR = 3.2). Only Black ethnicity impacted on the risk of hospitalisation compared to those of White ethnicity, (aOR = 1.52, 95% CI 1.20 – 1.93). With respect to age, compared to children aged 0 – 4 years, the risk of hospitalisation was lower among those aged 5 – 11 years (aOR = 0.50, 95% CI 0.45 – 56) and 12 – 17 years (aOR = 0.75, 95% CI 0.69 – 0.82). However, once hospitalised, the risk of higher COVID-19 severity increased in both groups: 5 – 11 group (aOR = 2.66) and 12 – 17 years (aOR = 2.09).
The authors concluded that while older children were at a lower risk of hospitalisation with COVID-19, once hospitalised, they appeared to be a higher risk of more severe disease. In addition, as with adults, similar co-morbidities were associated with a greater risk of hospitalisation and higher COVID-19 severity once admitted.
Antoon JW et al. Factors associated with COVID-19 disease severity in US children and adolescents. J Hosp Med 2021
Detection of breast cancer requires that mammography scans are interpreted correctly and thus guidelines on screening require that robust quality control and quality assurance are in place. Although an assessment of performance against standards can be achieved through audits, such audits offer little insight of the diagnostic skills of individual radiologists. The use of on-line self-assessment, using pre-diagnosed mammograms, offers a means of identifying any knowledge gaps and could serve as an important educational tool.
An on-line self-assessment tool was adopted by the Italian Society of Medical Radiology in 2018 as part of a national on-line self-assessment program for interpretation of mammograms and the results have published. The test set was a collection of 24 pathology-confirmed cancers combined with 108 mammograms which were reported on as negative after double reading. All cases were acquired with full-field digital mammography and came from women aged 50 – 69 years, who represent those at average risk of breast cancer. For the assessment, the society determined a pass threshold for sensitivity of 62% (amounting to at least 15/24 cancers correctly identified) and 86% specificity (93/108 negative mammograms correctly identified). The on-line self-assessment was posted on a dedicated website and upon registration, radiologists provided information on demographics such as age, gender, place of work (public or private sector), years of breast imaging experience and a qualitative self-judgement of mammography interpretative skills as “beginner”, “average” and “expert”. As with usual mammography practice, the radiologists were required to submit a dichotomous diagnosis (i.e., positive/negative) for every case. In addition to reporting on the radiologist’s success in the test, the authors employed regression analysis and odds ratios to identify the most important predictor variables for diagnostic accuracy.
A total of 685 radiologists registered for the on-line self-assessment and 49.9% (342) with a mean age of 46 years (69% female), completed test. Among those completing, two-thirds (64%) self-judged their interpretative skills as “average” and respondents had a median of 8 years breast imaging experience although 38.3% reporting having more than 10 years’ experience. Participants reported a median number of 1501 mammographic interpretations per year and the majority (68.7%) worked in the public rather than private sector.
When examining the proportion who successfully completed the assessment, only 28.7% of radiologists (98/342) passed on their first attempt. After an initial failure, 138 of the remaining 244 radiologists, re-took the test of whom, only 35.5% (49/138) passed. In fact, the authors reported that overall, only 44.2% (151/342) of radiologists who completed the on-line self-assessment were successful.
Using regression analysis, a significant association for diagnostic accuracy was found only for the assessment of > 3,000 mammograms per year compared to < 1,000 (Odds ratio, OR = 3.88, 95% CI 1.07 – 14.14, p = 0.04) and working the in public rather than private sector (OR = 1.65). Other variables such as age, self-judged interpretative skills and years of breast imaging experience had no significant effect.
The authors concluded that their study suggested that breast imaging experience does not guarantee diagnostic accuracy in screening reading. They also noted that their on-line self-assessment test could be included as a criterion for the accreditation process of breast units.
Brancato B et al. Mammography self?evaluation online test for screening readers: an Italian Society of Medical Radiology (SIRM) initiative. Eur Radiol 2021
Regular intake of nuts has been associated with a 15% lower risk of cardiovascular disease and a 23% lower risk of cardiovascular mortality. This reduction in risk is probably due to a reduction in low-density cholesterol (LDL-C) levels with one pooled analysis of 25 intervention trials finding that a mean daily intake of 67g of nuts produced a 7.4% mean reduction in LDL-C levels. However, none of the 25 trials lasted longer than 8 weeks and have not examined the effect of nuts on different LDL sub-fractions. In trying to establish the effect of both daily nut consumption and any differences in the effect on low-density lipoprotein levels, a team from the Lipid Clinic, Endocrinology and Nutrition Services, Villarroel, Barcelona, Spain, decided to explore these effects in a randomised trial. The team established the Walnuts and Healthy Aging (WAHA) trial which ran from 2012 to 2014 and was designed to examine the impact of bioactive compounds, such as n-3 fatty acids (found in walnuts) on both cognitive function and retinal health. Free-living participants were randomised to receive 30 – 60g/day of walnuts, which were delivered to the intervention group individuals, or to abstain from the nuts for the two years of the trial. One of the secondary outcomes of the original trial was changes in lipoprotein levels. Together with fasting glucose, lipoprotein levels were were measured at baseline at after 2 years. In addition, given that those eating walnuts were consuming more fat and thus likely to experience weight gain, this was also measured and compared with the baseline reading.
There were 636 participants with a mean age of 69 years (67% female) who completed the two-year trial. The mean baseline LDL-C and triglyceride levels were 117 and 105 mg/dL respectively. Among those taking walnuts, mean total cholesterol levels decreased by 4.4%
(-8.5 mg/dL, 95% CI -11.2 to -5.4), LDL-C by 3.6% (-4.3, 95% CI -6.6 to -1.6) and intermediate-density lipoprotein cholesterol by 16.8% (-1.3, 95% CI -1.50 to -1.0). Interestingly, levels of both triglycerides and high-density lipoprotein levels were unchanged. Weight changes in the walnut group were negligible at 0.06kg (95% CI -0.32 to 0.44). Furthermore, LDL-C reductions were higher for men than women (7.9% vs 2.6%, men vs women). In addition, there were also reductions in total LDL particles and small LDL particle number by 4.3% and 6.1% respectively.
The authors suggest that the reduction is LDL-C cholesterol at 4.3 mg/dL was modest and concluded that daily walnut intake may be useful way to improve cardiovascular risk.
Rajaram S et al. Effects of Walnut Consumption for 2 Years on Lipoprotein Subclasses Among Healthy Elders. Findings From the WAHA Randomized Controlled Trial. Circulation 2021.
In a 2006 European survey of over 46,000 respondents in 15 countries, 19% reported experiencing pain which lasted for at least 6 months. Moreover, a more recent 2019 study in developing countries found a similar incidence (18%) among the general population. However, the impact of chronic pain, i.e., which persists past the normal healing time and lasts or recurs for more than 3 to 6 months, has a much wider impact upon affected individuals, reducing physical functioning, daily activities and mental health. Although opioid drugs have been used for the management of chronic pain, evidence suggests that compared with placebo, there are only small beneficial effects. Consequently, there has been increased interest in the use of alternative pain management strategies, one of which is the use of medical cannabis. In fact, its use as a therapeutic alternative has been recommended in some guidance for chronic pain, especially in cases where other treatments have been ineffective. However, the overall effectiveness of medical cannabis in chronic pain remains unclear with some organisations such as NICE in the UK, advising against the use of cannabis-based medicinal products to manage chronic pain in adults unless as part of a clinical trial.
With uncertainty over the effectiveness of medical cannabis in chronic pain, Canadian researchers led by a team from the Department of Anesthesia, McMaster University, Ontario, Canada, performed a systematic review and meta-analysis to determine the benefits and harms of medical cannabis in patients with chronic pain, including cancer pain. They included randomised controlled trials that enrolled at least 20 patients with chronic pain (defined as lasting longer than 3 months) and who were assigned to any form of medical cannabis and which was compared to placebo with a follow-up period of at least one month. As well as the impact on pain, the team also captured data on physical, emotional and social functioning and sleep quality. They assessment the benefits in terms of change scores from baseline as opposed to end of study results and determined whether use of cannabis achieved the minimally important difference (MID). This represents the smallest amount of improvement in a treatment outcome that patients recognise as important. For example, using a 10 cm visual analogue scale for pain, the MID is approximately 1 cm. The researchers modelled the risk difference (RD) of achieving at least the MID.
A total of 32 trials with 5174 adults in which 29 compared medical cannabis with placebo were included in the analysis. In terms of pain relief, there was moderate certainty evidence from 27 trials that medical cannabis compared to placebo, resulted in a small increase in the proportion of patients experiencing pain relief at or above the MID. This difference was modelled as 10 % (95% CI 5% to 15%). Data from 10 trials suggested a 7% increase in the proportion of patient experiencing at least a 30% reduction in pain with medical cannabis compared to placebo. Similarly, there was a 4% modelled difference in physical functioning and a 6% modelled risk difference for an improvement in sleep quality. However, there was no apparent improvement in emotional or social functioning. With respect to adverse effects, it appeared that medical cannabis gave rise to a 2% risk of transient cognitive impairment, impaired attention (3%) and nausea (5%).
The authors concluded that there was moderate to high certainty evidence of a small to very small increase in the proportion if people with chronic pain who experience an important improvement in their pain. Their results have been summarised in an accompanying rapid recommendation.
20th September 2021
A squamous cell carcinoma on the head or neck is the sixth most common cancer globally, with around 890,000 new cases and 450,000 deaths in 2018. The main form of treatment is curative radiotherapy and in patients with locoregionally advanced cancers, prior scanning with fluorodeoxyglucose positron emission tomography and computed tomography (PET-CT) has been shown to have good diagnostic performance for the detection of regional nodal metastasis. However, where there is a delay between radiotherapy and the initial PET-CT scan, does this impact on radiotherapy planning and might it be necessary to perform a second scan prior to radiotherapy? This was the question posed by researchers from the Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland. The team performed a retrospective analysis of patients with advanced head or neck squamous cell carcinoma and who had received two PET-CT scans prior to radiotherapy, to determine whether the second scan led to any modifications to radiotherapy treatment. The team looked for changes in the primary tumour, lymphatic spread and the presence of distant metastases between the two scans. They categorised any changes as minor if there were modifications to the RT plans such as dose changes and major where treatment moved from curative to palliative or the addition of induction chemotherapy, a switch to surgery or any additional diagnostic work-up that led to postponement or cancellation of treatment.
There were 32 newly diagnosed patients with locoregionally advanced squamous cell cancer with a median age of 64 years (34% female). The median interval between the initial scan for staging assessment and the second scan was 42.5 days. Just over half (53%) of patients had a grade 2 and 41% a grade 3 tumour. Fortunately, a major treatment change occurred in only 1 patient although nodal upstaging occurred in 10% (3/29) of patients. Minor treatment changes were required in 52% (16/31) of patients with new lymph node metastases detected in all 16 patients and in 6 cases, there was evidence of progression of the primary tumour size.
In discussing their findings, the authors noted that despite an initial PET-CT scan to assess tumour staging, a second scan identified the need for minor changes in just over half of all patients. Based on these findings, they called for the potential benefits of a second scan to be further investigated and validated. They also noted that the practice of undertaking a second scan of patients where the delay was more than four weeks has become the established practice at their hospital.
Elicin O et al. Impact of pre-treatment second look 18FDG-PET/CT on stage and treatment changes in head and neck cancer. Clin Trans Radiat Oncol 2021
According to Cancer Research UK, there are around 47,800 new lung cancer cases each year and approximately 35,100 deaths, which equates to 96 deaths every day. Furthermore, Cancer Research UK estimates that 79% of lung cancer cases in the UK are preventable with 72% caused by smoking. With such a high incidence of not only cases, but more importantly, preventable cases, there is an urgent need for effective screening methods, especially among individuals who are deemed at high risk such as smokers. In a 1999 study, a low computed-tomography (CT scan) was shown to greatly improve the likelihood of detecting small, non-calcified nodules and hence lung cancer, at an earlier and hence more curable stage. Moreover, subsequent studies have also demonstrated a reduction in lung cancer mortality among those undergoing a low dose CT scan.
With the value of CT screening already firmly established, a UK-based team have published their own findings of a trial comparing the effect of a low dose CT scan compared to usual care, in high-risk patients. The UK lung cancer screening (UKLS) trial, randomised patients to low dose CT screening or usual care, i.e., with no CT scan and was undertaken at two thoracic hospitals in the UK. Eligible patients, aged 50 to 75 years, were those deemed to be at a high risk of developing lung cancer over the next 5 years defined by a risk score of at least 4.5% based on the Liverpool Lung Project risk model (LLPv2). This model includes several possible risk factors such as gender, age, smoking status, smoking duration, family history of lung cancer. Included patients were then randomised to the intervention group (CT scan) or usual care although given the nature of the intervention, blinding was not possible. The primary outcome was mortality due to lung cancer, defined as a death during the follow-up period where lung cancer was listed as an underlying cause. In an effort to provide further evidence, the researchers also undertook a meta-analysis of other recent trials and included their own data, to get a more robust estimate of the benefits of CT scanning.
A total of 1987 and 1981 individuals were randomised to the CT scan and control arm respectively and followed for a median of 7.3 years. The median age at consent was 68 years (25% female) and among the CT scan group, 38% were current smokers, of whom, 93% had smoked for more than 20 years. During the follow-up period, 76 lung cancers were detected, 30 in the CT scan arm and 46 in the control arm although this difference was not significant (relative risk, RR = 0.65, 96% CI 0.41 – 1.02, p = 0.062). Furthermore, there were no significant differences between the sexes. In addition, there were 512 deaths from any cause and again there was no significant difference between the groups (p = 0.315).
When these results were added to a meta-analysis of 9 randomised, controlled trials, low dose CT scan screening was associated with a 16% relative reduction in lung cancer mortality compared with no screening (RR = 0.84, 95% CI 0.76 – 0.92).
The authors concluded that while their trial had not demonstrated a statistically significant reduction in lung cancer mortality, when their data was combined with other studies, the pooled estimate was significant and provided further support for lung cancer screening via a low dose CT scan.
Field JK et al. Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis. Lancet Regional health Europe 2021
Although a formal diagnosis of COVID-19 is based on a positive PCR test, it can take up to 24 hours before the result is available. Given that COVID-19 is a respiratory infection, clinicians have often turned to chest imaging with lung ultrasound, X-rays and CT scans, to diagnose the infection prior to confirmation from a PCR test. In fact, a Cochrane review has concluded that the use of a lung ultrasound correctly diagnoses COVID-19 in 86.4% of infected patients.
With the potential value of lung ultrasound as a diagnostic aid in COVID-19, an Italian team from the Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy, undertook a prospective, observational study to further examine the value of the imaging modality in those with suspected COVID-19. Patients were those consecutively admitted to the emergency department of a single hospital with suspected COVID-19. Each underwent a standard lung ultrasound examination which included 12 thoracic areas. The team then calculated several different measures with a view to determining whether any of these could be used prognostically for COVID-19. The scores for each thoracic areas were added to calculate a regional lung ultrasound severity score (rLUSS) and a lung ultrasound severity score (LUSS) was calculated by summing all rLUSS values. The number of different ultrasound patterns found in each area defined the regional lung ultrasound heterogeneity score (rLUHS). A regional lung ultrasound severity index (rLUSI) was then calculated as rLUSS/rLUHS for each area. Finally, the team computed a lung ultrasound severity index (LUSI), which was the sum of all the rLUSI scores. The team were interested in whether LUSI, rLUSS or LUHS. The outcomes of interest were a diagnosis of COVID-19 pneumonia and in-hospital mortality and the area under the receiver operating curves (AUROC) analysis was used to determine the relationship between LUSS, LUHS, LUSI and the severity of pneumonia.
The study included 159 patients with a mean age of 64.6 years (66% male) of whom, 49% had respiratory failure upon admission. For each of the three lung ultrasound measures (i.e., LUSS, LUHS and LUSI), in relation to the differentiation of COVID-19 positive and negative cases, LUSI offered the greatest sensitivity and specificity with an AUROC of 0.72 (95% CI 0.64 – 0.78), giving a sensitivity of 63% and a specificity of 75%. With respect to overall in-hospital mortality, again LUSI scores provided the best AUROC, at 0.81 (95% CI 0.73 – 0.86) providing a sensitivity of 90.9% and a specificity of 65.6%. Finally, when considering only COVID-19 patients, LUSI also gave the highest AUROC, 0.76 (95% CI 0.66 – 0.84) with a sensitivity of 63.1% and a specificity of 90%.
The authors concluded that their newly developed lung ultrasound severity index provided the highest accuracy with respect to COVID-19 diagnosis and prognosis. They also added that a further advantage was how the lung ultrasound could be performed in under 10 minutes, allowing LUSI scores to quickly identify patients at a higher risk of both COVID-19 and mortality and called for future studies to understand LUSI’s role for different clinical goals such as monitoring of treatment or progression.
Spampinato MD et al. Lung Ultrasound Severity Index: Development and Usefulness in Patients with Suspected SARS-Cov-2 Pneumonia. A Prospective Study. Ultrasound Med Biol 2021
17th September 2021
The presence of poor metabolic health in conditions such as obesity and type 2 diabetes is known to be associated with worse outcomes in COVID-19. In fact, a higher body mass index has been found to be a causal risk factor for COVID-19 susceptibility and severity. Obesity is influenced by dietary intake but an important factor is the quality of an individual’s diet so that a higher diet quality is associated with a lower risk of obesity. Various measures have been developed to evaluate diet quality and how this can impact on the risk of chronic diseases. One such diet score is the healthful Plant-Based Diet Index (HPBDI) and which has been associated with a lower risk of developing type 2 diabetes. However, the association between diet quality and both the risk and severity of COVID-19 is less clear.
In light of this evidence gap, a team led by researchers from Harvard Medical School, Boston, US, decided to explore the relationship between diet quality and COVID-19. The team used data obtained from a smartphone app used for the COVID-19 Symptom Study to prospectively investigate the association. As well as diet, the team sought to examine how the risk of COVID-19 depends on not only on diet quality but also socioeconomic deprivation. Demographic and clinical data were collected via the smartphone app between March and December 2020, together with self-reported COVID-19 testing and symptoms. Diet quality was obtained using a short-form food frequency questionnaire and participants were asked to report how often on average, they consumed one portion of particular foods in a typical week. Using this information, the team calculated a HPDI score which ranged from 14 (lowest) to 70 (highest) with higher scores reflecting a healthier plant-based diet. Individuals were then categorised as having a low, medium or high HPDI score. The primary outcome was COVID-19 risk based on a predictive, symptom-based algorithm and multivariable Cox models were used to calculate hazard ratios (HR) for COVID-19 risk and severity.
Self-reported diet quality was available for 592,571 app users with a mean age of 56 years (68.2% female), of whom, the vast majority (96%) were of White ethnicity and the mean HPDI score for the whole sample was 50. In fully adjusted models, for individuals with the highest HPDI score compared to the lowest score, the risk of COVID-19 was reduced by 9% (HR = 0.91, 95% CI 0.88 – 0.94, p < 0.001). Furthermore, the risk of severe COVID-19 was also significantly reduced for those with the highest HPDI compared to the lowest HPDI scores (HR = 0.59, 95% CI 0.47 – 0.75, p < 0.001).
When considering socioeconomic deprivation, there was clearly an association between an increased risk of COVID-19 and diet quality. For example, among those living in an area of low deprivation and with a low HPDBI score, the risk of COVID-19 was slightly elevated (HR = 1.08, 95% CI 1.03 – 1.14). However, among those with a low HPBDI scores and living in an area of high deprivation, the risk was much higher (HR = 1.47, 95% CI 1.38 – 1.52). In fact, even among those with a high HPBDI but living in a highly deprived area, the risk of COVID-19 was still elevated (HR = 1.28, 95% CI 1.18 – 1.37, p < 0.001).
The authors concluded that a higher diet quality was associated with a reduced risk of both COVID-19 and severe disease but also that the combination of poor diet and increased socioeconomic deprivation further increased COVID-19 risk.
Merino J et al. Diet quality and risk and severity of COVID-19: a prospective cohort study. Gut 2021
The efficacy of currently available COVID-19 vaccines, such as BNT162b, has been clearly demonstrated in clinical trials. Nevertheless, because vaccines are not 100% effective, there are likely to be individuals who experience a breakthrough COVID-19 infection. However, what is less clear is the extent to which these breakthrough infections result in either emergency care (EC) visits or even hospital admission.
In trying to better understand this question, a team from the Department of Emergency Medicine, Beaumont Hospital, Michigan, US, performed an observational cohort analysis comparing the need for EC among those with confirmed COVID-19 infection. The team compared the outcomes for adult patients who were either unvaccinated (UV), partially vaccinated (PV) or fully vaccinated (FV). For the purposes of the study, FV individuals were defined as those who had a positive COVID-19 test result and symptom onset < 14 days after their second vaccination. The team used electronic health records to confirm COVID-19 infection status and collect demographic and clinical data such as co-morbidities. The primary outcome measure was the rate of emergency care/hospitalisation encounters in those testing positive among the three groups. This was defined as the number of newly presenting hospital-based COVID-19 encounters divided by the state population within each respective vaccination group and expressed as a rate per 100,000 visits. The team also calculated weekly rates of COVID-19 EC encounters for each group. Secondary outcomes included severe disease represented as a composite outcome (intensive care admission, mechanical ventilation or in-hospital death), length of hospital stay.
There was a total of 11,834 EC visits which met the inclusion criteria. Patients had an overall mean age of 53 years (47.2% male) of whom 10,880 (91.9%) were UV, 825 (7%) PV and 129 (1.1%) FV. In terms of the weekly rate of COVID-19 EC encounters, the rate of breakthrough COVID-19 infections among FV individuals was 96% lower compared with the UV group. COVID-19 EC visits peaked at 22.61, 12.88 and 1.29 visits per 100,000 for those who were UV, PV and FV respectively.
The composite secondary outcome of severe disease occurred in 6.8% of the UV, 10.3% of the PV and 12.4% of the FV group. While those who were FV had a lower risk of severe disease compared to the UV group, this difference was not significant (hazard ratio, HR = 0.84, 95% CI 0.52–1.38) and the mean age of those with severe disease was 74.1 years. Among the PV group, the risk was either higher or lower (HR = 1.03, 95% CI 0.78–1.35).
The authors concluded that while breakthrough COVID-19 infections occurred in fully vaccinated individuals, these were rare, accounting for only 1% of all COVID-19-related EC visits. Nevertheless, when admission to hospital was required for those who were fully vaccinated, the risk of severe outcomes was similar to those who were unvaccinated.
Bahl A et al. Vaccination reduces need for emergency care in breakthrough COVID-19 infections: A multicenter cohort study. The Lancet Regional Health Americas 2021
Hereditary angioedema (HAE) is a rare, inherited disorder that presents with unpredictable, recurrent attacks of oedema, leading to a rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. The condition affects around 1 in 50,000 of the population in the UK, which equates to around 1,500 people and the condition often first presents between the ages of 5 and 11 years.
The underlying cause of HAE is a mutation of the SERPING1 gene which codes for a protein, C1 esterase inhibitor (CI IHB), which regulates inflammatory pathways. This mutation can result in either low levels of C1 IHB, which is the most common presentation (type 1), accounting for around 85% of cases, or normal levels of C1 IHB, but with a reduced function (type 2). There is also a third, much rarer type characterised by normal C1 IHB levels but other mutations which also give rise to elevated levels of bradykinin. Irrespective of the underlying cause, reduced functioning of C1 IHB leads to an increased production of the vasoactive peptide, bradykinin which mediates vasodilation in subcutaneous or submucosal tissues.
The aim of treatment is to either reverse or prevent attacks with a view to improving patient’s quality of life. Treatments have been based on prophylactic use of C1 IHB concentrates, some of which have been developed as injectables for self-administration. In contrast, berotralstat, is an oral, once daily inhibitor of plasma kallikrein which is hydrolysed to release bradykinin.
The NICE approval was based on the findings of the randomised phase 3 trial, APex-2, a double-blind, parallel-group study in which patients were randomised 1:1:1, to receive once-daily berotralstat in a dose of 110 mg, 150 mg or placebo. In APex-2, the primary efficacy end point was defined as the rate of investigator-confirmed HAE attacks during the 24-week treatment period. The study found that use of berotralstat led to a significant reduction in attack rate at both 110 mg (1.65 attacks per month, p = .024) and 150 mg (1.31 attacks per month, p < .001) relative to placebo (2.35 attacks per month). An extension of APex-2 was published in June 2021 in which patients originally assigned to placebo were randomised to either 110 mg or 150 mg of berotralstat and followed for 48 weeks. At the study end, mean attack rates for the 150mg group declined from a baseline of 3.06 attacks/month to 1.06 at week 48. Similarly, for the 110mg group, attack rates reduced from a baseline of 2.97 to 1.35 at week 48.
NICE has declared berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema and recommended that the drug can be used under the following circumstances.
In people 12 years and older, only if:
• they have at least 2 attacks per month and
• it is stopped if the number of attacks per month does not reduce by at
least 50% after 3 months.
Source: NICE. Berotralstat for preventing recurrent attacks of
hereditary angioedema, September 2021.