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9th June 2021
The clinical symptoms of Crohn’s disease (CD) are similar in adults and children although there is evidence that cases of paediatric CD are on the rise, with one study estimating that the highest incidence, at 23 per 100,000 person-years occurred in Europe. Endoscopic evidence of mucosal healing is a valuable therapeutic goal that decreases the risk of disease relapse although little is known about the association between mucosal healing and therapeutic levels of biological treatments such as adalimumab. This prompted a team from the Department of Paediatrics, Samsung Medical Centre, Korea, to examine the relationship between therapeutic drug monitoring of adalimumab and mucosal healing and clinical remission in paediatric patients with CD. The team prospectively recruited paediatric patients with CD receiving adalimumab maintenance therapy and who underwent routine endoscopic evaluation of mucosal healing and therapeutic drug monitoring. Monitoring assessments were made at 4 months and then at years 1, 2 and 3.
In total, 31 children with a mean age of 14.8 years (74% male) were included in the analysis. After 1 year of treatment, 26 (83.9%) had achieved clinical remission and 17 (54.8%) had complete mucosal healing. The mean adalimumab trough levels were higher in patients who had achieved remission compared to those with active disease (7.6 mcg/ml vs 5.1 mcg/ml, remission vs active disease). Similarly, trough levels of adalimumab were significantly higher in those who achieved mucosal healing after 1 year (14.2 mcg/ml vs 7.8mcg/ml, mucosal healing vs non-healed, p = 0.03). Although only 23 children were evaluated after 3 years, adalimumab trough levels remained above 10 mcg/ml and a similar proportion of children maintained mucosal healing (64.3%) and clinical remission (92.9%). Using receiver operating curves, authors calculated that the optimal cut-off adalimumab trough levels to achieve mucosal healing was 8.18 mcg/ml.
In discussing their findings, the authors commented on the results demonstrated that mucosal healing rates increased when adalimumab was used over the longer term and that the drug maintained its efficacy. They concluded that there was merit in using therapeutic drug monitoring to guide proactive optimisation of drug levels to achieve the goal of mucosal healing.
Kim MJ et al. Therapeutic Drug Monitoring of Adalimumab During Long-term Follow-up in Paediatric Patients with Crohn Disease. JPGN 2021;72:870-6.
3rd June 2021
Data have suggested that the risks of adverse outcomes among children infected with COVID-19 are far less than those of adults. Moreover, the classic COVID-19 symptoms such as cough and fever has been found to occur in only half of children infected with the virus. With the reopening of schools and the subsequent increased risk of community transmission, a team from the Division of Cardiovascular Disease, University of Alabama, Alabama, US, investigated the clinical characteristics of children infected with COVID-19 using information derived from a multi-centre healthcare network electronic health database. The authors included paediatric patients with a positive PCR test, aged < 18 years and stratified the population based on their age and ethnicity. Information was also included on past medical history and if hospitalised, whether individuals required mechanical ventilation or other forms of critical care. The PCR positive individuals were propensity matched on sex and ethnicity.
The retrospective analysis included 12,306 children, 672 (5.5%) of whom were hospitalised with a mean age of 9 years (51% male). Interestingly, only 25.1% of the sample had at least one of the classic COVID-19 symptoms (i.e., fever, cough or shortness of breath). The range of symptoms observed included respiratory symptoms (16.5%) such as cough or dyspnoea, gastrointestinal symptoms (13.9%) e.g., nausea, vomiting, skin rashes (8.1%) non-specific symptoms (18.8%) including fever, malaise, myalgia or disturbances of taste and smell. Among those hospitalised, 17.6% required critical care and 4.1% mechanical ventilation and there were fewer than 10 deaths. The risk of hospitalisation was higher in non-Hispanic black children compared with those of white ethnicity (relative risk, RR = 1.97 95% CI 1.49 – 2.61).
The authors described how they had observed a wide range of non-specific clinical symptoms and that only a quarter of those with a positive PCR test actually had the classic COVID-19 symptoms. They suggested that this warranted a need for increased vigilance among healthcare professionals when seeing school-aged children who might be infected with the virus. They concluded that while children can develop severe illness after infection with COVID-19, fortunately this is uncommon.
Parcha V et al. A retrospective cohort study of 12,306 pediatric COVID?19 patients in the United States. Sci Rep 2021
27th April 2021
The parasite Plasmodium falciparum (P. falciparum) is responsible for malaria and which is a leading cause of both morbidity and mortality across the globe. RTS,S, brand name Mosquirix, is the only vaccine available to treat malaria and was approved by the EMA in 2015. Sporozoites are the form of the parasite that enter the body and Mosquirix contains part of the P. falciparum circumsporozoite protein (CSP) and leads to the generation of anti-circumsporozoite antibodies. However, in children, the vaccine efficacy is only 56% whereas the World Health Organization’s strategic goal is for a malaria vaccine to have an efficacy of 75%. This led researchers from the Jenner Institute, University of Oxford to undertake a double-blind, randomised, controlled trial using a vaccine named R21, which is a novel pre-erythrocytic candidate that also targets part of the CSP. The vaccine combines R21 with Matrix-M (MM), an adjuvant which increases immunogenicity. The team recruited children aged 5–17 months in the catchment area of Nanoro, Burkina Faso (West Africa) and which represents a high area of malaria transmission, especially between June and November. All children were randomised to one of three groups; group 1 received a lower dose of MM (i.e., 5 mcg R21/25mcg MM); group 2, a higher dose of MM (5 mcg R21/50mcg MM); and a control group (group 3) who received a control vaccine (rabies). Three doses were administered at 4-week intervals prior to the main malaria season (early May to August) and all participants received a fourth booster dose 12 months after their third vaccination. The primary outcome assessed was protective efficacy from 14 days after the third vaccination to 6 months and clinical malaria was defined in terms of an axillary temperature greater than 37.5 degrees centigrade and a P. falciparum density of greater than 5000 parasites/micro-litre.
A total of 450 children were included in the trial with a mean age of 11.6 months and 222 female participants. Moreover, there were 186 cases of clinical malaria, 43 in group 1, 38 in group 2 and 105 in group 3 (control). Using a Cox regression model which compared group 1 to 3, vaccine efficacy was 74% (95% CI 63 – 82, p < 0.001) and between group 2 and 3, the efficacy was 77% (95% CI 67 – 84, p < 0.0001). Efficacy was also assessed after 12 months at which point, the efficacy was 71% (group 1 vs group 3) and 77% (group 2 vs group 3). The authors calculated that the number of cases averted by the group 1 regime over 12 months would be a rate reduction of 1393 cases per 1000 children years.
The authors observed, however, that antibody levels in groups 1 and 2 decreased over the 12-month period but were boosted back to the levels achieved after the third dose, 28 days after the 4th dose.
Although this is the first study to report on the vaccine, the trial is continuing for a second malaria season to determine the durability of this high level of vaccine efficacy.
Datoo MS et al. High efficacy of a low dose candidate malaria vaccine, R21 in adjuvant Matrix-MTM, with seasonal administration to children in Burkina Faso. Lancet 2021
7th December 2020
A consistent finding of infection with COVID-19 is that the virus is less severe in children, most of whom are asymptomatic, with a mild fever, cough and changes in taste or smell. Whether or not children are less likely to become infected is an ongoing debate but overall, only between 1 and 2% of cases involve children, suggesting that as a group, children are less likely to become infected, even when exposed to similar viral loads.
In a review of all the currently available evidence, a team from the Faculty of Science and Medicine, University of Fribourg, Switzerland, have examined the various potential physiological differences between adults and children and how these might account for the variation in rates of infection.
While there are still no definite answers, the authors suggest that infection of endothelial cells, leading to vasculitis and the formation of microthrombi, is more problematic in adults, especially in the presence of comorbidities such as hypertension and diabetes, both of which affect endothelial cell functioning. While children are less likely to have comorbidities and are therefore at lower risk, immunosuppressed children or those with cancer, do not appear to be at any higher risk from COVID-19. Another possible protector is that children have a stronger innate immune and adaptive immune system with higher number of natural killer cells and both B and T cells, whereas ageing is associated with immunosenescence, i.e., a gradual decline of both immune systems. Other proposed differences which might be protective in children are higher levels of melatonin and the microbiota in the nasopharynx in children which is more heavily colonised in children compared with adults.
The authors conclude that with the exception of the endothelial/clotting function disparities, none of the currently proposed hypotheses are able to account for the differences in susceptibility to infection between adults and children.
Zimmerman P, Curtis N. Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections. Arch Dis Child 2020 doi:10.1136/archdischild-2020-320338