The response to our article was received with interest. Grosse and Lanzieri raise important points in connection with our recent paper , noting concerns that the paper overestimates the financial cost burden associated with congenital cytomegalovirus (cCMV). These points are contingent on our estimate that at least 50% total costs associated with cCMV stemmed from the cost of autism spectrum disorder (ASD) among individuals with cCMV.
First, Grosse and Lanzieri point out that an association between cCMV and ASD has not been conclusively established, citing a systematic review and meta-analysis by Maeyama et al. (2017) . We agree that there is uncertainty over this association and the prevalence estimates used (along with many of the other estimates), and have emphasised throughout our article that (i) the model is limited by the validity of the inputs, and (ii) more research is required to fully understand the epidemiology, aetiology and prognosis of cCMV. Indeed, Maeyama et al. (2017)  report a significant association between cCMV and ASD, but caution that these calculations are seriously limited by the infrequent number of events in the included studies. As we do, they stress the need for further research to clarify this issue.
Second, Grosse and Lanzieri suggest that the prevalence calculation of ASD attributable to cCMV should have been calculated as the proportion of cCMV individuals with ASD minus the proportion of non-cCMV individuals with AS...
Second, Grosse and Lanzieri suggest that the prevalence calculation of ASD attributable to cCMV should have been calculated as the proportion of cCMV individuals with ASD minus the proportion of non-cCMV individuals with ASD. While we understand the criticism of the calculation of ASD prevalence in cCMV, had we calculated the prevalence in the way suggested here (i.e. making assumptions that the underlying level of ASD in the cCMV population not attributable to the virus would match that observed in the non-cCMV population, and that this should be removed from our estimates) we would be treating ASD differently to the other impairments reported. For all impairments, the estimated number of children with cCMV affected by that impairment was used, not accounting for the level of diagnosis in the general population. We appreciate that where data are robust, the suggested approach would be advisable, but given the scarcity of prevalence studies for some impairments and level of variation in prevalence estimates for others, we sought to simplify assumptions as far as possible.
While our study aimed to estimate the financial burden of cCMV to the UK, we acknowledge, and indeed state in the discussion, that there is a lack of robust evidence for use as inputs into such an analysis. On the basis of the estimates we have imputed from the available data, we believe the true cost of cCMV is likely to be substantial. Our paper emphasises the need for further and more detailed research into both the costs and impairments associated with cCMV to allow greater accuracy in the calculation of cost estimates.
 Retzler J, Hex N, Bartlett C, et al. Economic cost of congenital CMV in the UK. Arch Dis Child 2018 doi: 10.1136/archdischild-2018-316010 [published Online First: 2018/11/26]
 Maeyama K, Tomioka K, Nagase H, et al. Congenital cytomegalovirus infection in children with autism spectrum disorder: systematic review and meta-analysis. J Autism Dev Disord 2018;48(5):1483-91. doi: 10.1007/s10803-017-3412-x [published Online First: 2017/12/01]
We thank Dr. Garstang and Dr. Debelle for their comments on our article in ADC (1).
We are pleased that the correspondents support our finding of a strong association between chronic conditions and respiratory tract Infection mortality in children which, though well-recognised by clinicians, has not previously been quantified.
The correspondents rightly highlight that our analyses concentrate only on unexpected deaths after age 2 months. We chose this definition because these early deaths are more prone to linkage error and more importantly, tend to be related to maternal health during pregnancy and delivery, preterm birth, intrapartum events and congenital anomalies, and therefore may not be avoidable through improved care after postnatal discharge.
As our paper highlights, an indication of whether a death was expected or not on a death certificate or in hospital records is necessary in order to assess whether a death was avoidable or amenable to healthcare intervention. A classification of whether a death was expected or unexpected could also be notified to Child Death Overview Panels and other agencies by those completing the death certificates. This would be helpful to Child Death Overview Panels in their deliberations as well as feeding into the collation of mortality statistics.
1. 1. Verfürden ML, Gilbert R, Sebire N, Hardelid P. Arch Dis Child 2018;103:1125–1131.
I was very pleased to read this letter on involving children and young people (CYP) which is so important.
RheumMates (https://www.facebook.com/groups/rheumates/) is a group which was already set up together with young people with rheumatological conditions (based on the highly successful NeoMates model, which provides parent peer support for neonatal unit parents) for this purpose.
This came about after we presented NeoMates at the Royal College of Paediatrics and Child Health annual conference at the same time that an inspirational young person presented her work on setting up Raiise (https://raiise.co.uk) to improve care and provide support for young people with "invisible illnesses".
It is a place where CYP can chat to each other safely, knowing that everyone in the group has a common link.
It is also a source of expert knowledge and information.
To complement it, we also set up RheumMatesParents where parents can also chat, gaining the peer support that the NeoMates parents have had for many years.
I wonder if these could in some way be combined to help improve peer support and patient engagement?
Thank you for your attention to this research. Firstly, this systematic review showed that LOS was decreased in the HFNC group comparing with SOT group in low-income and middle-income countries. As you mentioned in the letter that even in high-income countries, it’s not realistic to treat all bronchiolitis patients with HFNC during RSV peaks. The inconsistent result of LOS in different countries may be caused by the level of medical practice in different areas because the LOS in low-income and middle-income countries was significantly longer than in high-income countries. So the clinical heterogeneity suggested that the level of medical practice was also important for bronchiolitis. Secondly, two studies showed that patients with treatment failures in SOT group could be treated with HFNC in the wards. This meta-analysis showed that there was a significant increase in the incidence of treatment failure in HFNC group compared with nCPAP group (RR 1.61, 95% CI 1.06 to 2.42, p=0.02). Therefore, we need more research to explore which choice (HFNC or nCPAP) is better for patients with treatment failures in standard oxygen supplementation.
Retzler et al. report estimates of the economic cost of congenital cytomegalovirus (cCMV) in the United Kingdom.1 The projected costs of autism spectrum disorder (ASD) among persons with cCMV accounted for at least 50% of the total costs attributed to cCMV. However, an association between cCMV and ASD has not been conclusively established,2 and, in their analysis, Retzler et al. did not take into account the cost of ASD among children without cCMV.
Retzler et al. used published ASD prevalence estimates from a Dutch study of >30,000 children screened for cCMV at 6 years of age using stored dried blood specimens, of whom 133 were CMV-positive. Of 26 children classified with symptomatic cCMV, 2 (7.7%) had ASD, as did 2/107 (1.9%) with asymptomatic cCMV.3 Retzler et al. assumed 11% of children with cCMV are symptomatic, which implies a weighted average ASD prevalence of 2.5% among children with cCMV. Five of 274 (1.8%) matched children without cCMV in the Dutch study also had ASD. If ASD were causally associated with cCMV, which has not been shown, the cost of ASD attributable to cCMV would be the cost difference of ASD among children with and without cCMV. Therefore, the projected cost of cCMV has been overestimated. Moreover, if the reported association of cCMV with ASD turns out to be non-causal, the total cost of cCMV could be half that estimated by Retzler et al.
1. Retzler J, Hex N, Bartlett C, et al. Economic cost of congenital CMV...
1. Retzler J, Hex N, Bartlett C, et al. Economic cost of congenital CMV in the UK. Arch Dis Child 2018 doi: 10.1136/archdischild-2018-316010 [published Online First: 2018/11/26]
2. Maeyama K, Tomioka K, Nagase H, et al. Congenital cytomegalovirus infection in children with autism spectrum disorder: systematic review and meta-analysis. J Autism Dev Disord 2018;48(5):1483-91. doi: 10.1007/s10803-017-3412-x [published Online First: 2017/12/01]
3. Korndewal MJ, Oudesluys-Murphy AM, Kroes ACM, et al. Long-term impairment attributable to congenital cytomegalovirus infection: a retrospective cohort study. Dev Med Child Neurol 2017;59(12):1261-68. doi: 10.1111/dmcn.13556 [published Online First: 2017/10/11]
I would like to add to the article ‘What dose of aspirin should be used in the initial treatment of Kawasaki disease?’ by Luke Guo Yang Ho and Nigel Curtis (Archives, 2017, 102, 1180-1182). Fifteen months have passed since this article concluded that low-dose aspirin is not inferior to higher doses in reducing the risk of coronary artery abnormalities in acute Kawasaki disease. Since then, it is worth considering what and if anything has changed in the field. A recent study not included in the review is a retrospective cohort study by Huang et al1 (2018), where 910 patients followed up for 2 years, which showed that there was no significant difference between 3 groups in terms of anti-inflammation or prevention of coronary artery abnormalities. This paper concluded that the role of aspirin in the treatment of the acute phase of Kawasaki disease should be questioned, as a definite benefit has not been shown. Therefore, in concordance with the conclusion of the review, this rapid response poses that current data remains unchanged with regards to the role and effects of administration of higher doses of aspirin on coronary outcome in acute Kawasaki disease. In the absence of evidence to support higher doses in prevention of coronary artery abnormalities, low-dose aspirin (3–5 mg/kg) may be the safest, most rational approach until better evidence becomes available.
There are currently three prospective randomised control trials in process to continue this inv...
There are currently three prospective randomised control trials in process to continue this investigation2-4, it would be interesting to review this on their completion.
1. Huang, X. et al. Is aspirin necessary in the acute phase of Kawasaki disease? J. Paediatr. Child Health 54, 661–664 (2018).
2. NCT02951234. A Multi-center, Randomized to Compare the Efficacy of IVIG Alone and IVIG Plus High-dose Aspirin in Kawasaki Disease. Https://clinicaltrials.gov/show/nct02951234 doi:10.1002/CENTRAL/CN-01559692
3. NCT02359643. Multi-center Prospective Randomized Control Trail of High Dose Aspirin in Acute Stage of Kawasaki Disease. Https://clinicaltrials.gov/show/nct02359643 (2015). doi:10.1002/CENTRAL/CN-01582768
4. Kuo, H.-C., Guo, M. M.-H., Lo, M.-H., Hsieh, K.-S. & Huang, Y.-H. Effectiveness of intravenous immunoglobulin alone and intravenous immunoglobulin combined with high-dose aspirin in the acute stage of Kawasaki disease: study protocol for a randomized controlled trial. BMC Pediatr. 18, 200 (2018).
Hayley Pillai Johnson (Medical Student, Cambridge University, Cambridge)
Authors (full names and academics degrees)
• Laura Moreno-Galarraga1 MD PhD
• Miguel Ángel Martínez-González2 MD PhD MPH
• Diego Mauricio Peñafiel Freire3 MD
• Elsie M Taveras4 MD MPH
1) Department of Pediatrics, Complejo Hospitalario de Navarra. IdisNa; Instituto de Investigación Sanitaria de Navarra, Health Research Institute of Navarra, Pamplona, Spain.
2) Department of Preventive Medicine and Public Health, University of Navarra Pamplona, Spain. Dpt. Nutrition, Harvard TH Chan School of Public Health, Boston, MA. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
3) Department of Pediatrics, Complejo Hospitalario de Navarra, Pamplona, Spain
4) Division of General Academic Pediatrics, Massachusetts General Hospital for Children, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
We have read the article about myths, milk and mucus, and we couldn’t agree more.1 We have observed the prevalence of the same myth and the same concern that many parents are limiting their child’s consumption of dairy products or replacing milk with vegetable drinks, despite the current recommendations.2
We conducted a study in 169 school-age children in Spain and we did not find any association between dairy products consumption (milk, cheese or yo...
We conducted a study in 169 school-age children in Spain and we did not find any association between dairy products consumption (milk, cheese or yoghurt) and respiratory diseases (OR=0.85 95%CI (0.44-1.64))3. Additionally studies conducted in various populations have not found evidence that this association exists1 and some studies even indicate that cow-milk consumption in early life is a protector factor against asthma4. In infant nutrition several scientific societies, as the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), maintain few indications for soy-based formula, and state that in healthy infants they have no nutritional advantages over cow's milk protein formulae, but their utilization rates keeps increasing.5
The question then remains: Why does the myth persist despite the evidence? Authors claim in their article: "Milk-mucus myth needs to be rebutted firmly by healthcare workers".1 But, how?
The perpetuation of this myth might be related to some commercial interests, that have been rigourously addressed by some investigators.6,7 We think that paediatricians should reinforce the current WHO recommendations on paediatric feeding, and specifically inform parents about this unsupported belief and the current scientific evidence. We think that the time has come to find a common ground on this issue; there probably is no need to conduct new clinical studies to discard this myth, but to defend the scientific truth. In the same way as policies to avoid formula milk advertisements that may compromise breast-feeding were implanted, we need now policies to defend the harmlessness of dairy products regarding respiratory problems.1,3,4 It is important to transmit to the general population that avoiding dairy products is not useful to prevent respiratory illnesses, and that vegetables drinks are not “kinds of milk”, that they do not have the same nutritional or health benefits, and that they are not better substitutes of milk during childhood.
Health myths are remarkably persistent. But, if the myth that milk is related to mucus or respiratory pathology has been unfounded by scientific evidence, we believe our next step should be to transmit evidence-based information to the population and to combat false advertising and fake information spreading on social media.
1. Balfour-Lynn IM, Milk, mucus and myths. Arch Dis Child. 2019 Jan;104(1):91-93.
2. World Health Organization Global Strategy for Infant and Young Child Feeding. Geneva: World Health Organization; WHO nutrition publications. 2003. http://www.who.int/nutrition/publications/infantfeeding
3. Peñafiel Freire DM, Martín Calvo N, García Blanco L, et al. Association of dairy consumption with respiratory infections. Myth or reality?. Rev Pediatr Aten Primaria. 2018;20(1):45-52.
4. Lumia M, Takkinen HM, Luukkainen P, et al. Food consumption and risk of childhood asthma. Pediatr Allergy Immunol. 2015; 26(8): 789-96.
5. Agostoni C, Axelsson I, Goulet O, et al. Soy protein infant formulae and follow-on formulae: a commentary by the ESPGHAN Committee on Nutrition. JPediatr Gastroenterol Nutr. (2006) 42:352–61.
6. Nestle M.Corporate funding of food and nutrition research: science or marketing? JAMA Intern Med. 2016;176(1):13-14.
7. Lesser LI, Ebbeling CB, Goozner M, Wypij D, Ludwig DS. Relationship between funding source and conclusion among nutrition-related scientific articles. PLoS Med. 2007 Jan;4(1):e5.
We thank Drs Bok et al. for their comments on our recent editorial about the use of palivizumab in children with Down syndrome (DS). However, most of their arguments are not pertinent to DS. First, they describe the general incidence of respiratory syncytial virus (RSV) in children aged <5years. Second, they discuss the efficacy of palivizumab based on the IMpact trial  that did not include children with DS. We provided concrete evidence from  metanalyses conducted in 1.1 million children with DS, that the risk of RSV-related hospitalisation (RSVH) is 6.1–8.7- fold higher than children without DS.1 Drs Bok et al. also fail to appreciate that the overall relative risk of RSVH without palivizumab, is 5.5-fold (95% CI 3.97 to 7.7) higher based on robust, high quality evidence. In our previous study we also reported that for every 1000 children with DS with RSV there will be 200 more (95% CI,131-297) hospitalisations compared with 1000 children without DS with RSV (RR, 5.53; 95% CI,3.97-7.73; high GRADE). Moreover, Drs Bok et al. have extrapolated the number needed to treat (NNT) with prophylaxis to prevent one RSVH in children with DS using sub-optimal data. In a prospective case-control, cohort study conducted in the Netherlands and Canada, the estimated NNT in children with DS, adjusted for confounding variables, is 12 and not 20. This number also aligns with the report from the CARESS registry  and compares favourably with the NNT of 16 for preter...
We thank Drs Bok et al. for their comments on our recent editorial about the use of palivizumab in children with Down syndrome (DS). However, most of their arguments are not pertinent to DS. First, they describe the general incidence of respiratory syncytial virus (RSV) in children aged <5years. Second, they discuss the efficacy of palivizumab based on the IMpact trial  that did not include children with DS. We provided concrete evidence from  metanalyses conducted in 1.1 million children with DS, that the risk of RSV-related hospitalisation (RSVH) is 6.1–8.7- fold higher than children without DS.1 Drs Bok et al. also fail to appreciate that the overall relative risk of RSVH without palivizumab, is 5.5-fold (95% CI 3.97 to 7.7) higher based on robust, high quality evidence. In our previous study we also reported that for every 1000 children with DS with RSV there will be 200 more (95% CI,131-297) hospitalisations compared with 1000 children without DS with RSV (RR, 5.53; 95% CI,3.97-7.73; high GRADE). Moreover, Drs Bok et al. have extrapolated the number needed to treat (NNT) with prophylaxis to prevent one RSVH in children with DS using sub-optimal data. In a prospective case-control, cohort study conducted in the Netherlands and Canada, the estimated NNT in children with DS, adjusted for confounding variables, is 12 and not 20. This number also aligns with the report from the CARESS registry  and compares favourably with the NNT of 16 for preterms <35 weeks gestation without bronchopulmonary dysplasia, 20 for children with bronchopulmonary dysplasia and 23 for those with congenital heart disease, based on randomised trials.
Last, regarding costs, Drs Bok et al. also fall short in their attempt to reconcile that palivizumab is not cost-effective in children with DS using data derived from preterm infants, which unfortunately has little relevance. In our editorial and original report, we emphasised that a well-conducted cost-utility analysis of RSV prophylaxis in children with DS that measures RSV-related disease burden on both the quality and quantity of life.is still lacking. What we do know from solid evidence is that the burden of illness associated with RSVH in children with DS and those without congenital heart disease compared to children without DS is significant,, and is steadily increasing with concurrent healthcare expenditure. Our editorial provides concrete information about the risks of RSVH in all children with DS while indicating that the real-world use of prophylaxis in this population is of greater benefit versus harm, and that non-intervention has significant clinical, healthcare costs and socioeconomic implications, the latter of which is often overlooked., After systematically weighing the pros and cons, we re-affirm that the time is right to consider RSV prophylaxis for all children with DS aged < 2 years, since the opposing data provided by Dr Bok et al. is at best hypothetical. However, we do agree that the adoption of a global policy for RSV prophylaxis in all children with DS must be balanced in each country against available funding, overall costs for RSVH and incurred short and long-term morbidity.
1 Paes B, Mitra S. Palivizumab for children with Down syndrome: is the time right for a universal recommendation? Arch Dis Child doi:10.1136/archdischild-2018-316408.
2 The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk children. Pediatrics 1998; 102:531-7.
3 Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol 2011; 64:407-15.
4 Mitra S, El Azrak M, McCord H et al. Hospitalization for respiratory syncytial virus in children with Down syndrome less than 2 years of age: A systematic review and meta-analysis. J Pediatr. 2018; 203:92-100.e3.
5 Yi H, Lanctôt KL, Bont L, Bloemers BL, et al. Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. Pediatrics 2014; 133:1031-7.
6 Paes B, Mitchell I, Yi H, et al. Hospitalization for respiratory syncytial virus illness in Down syndrome following prophylaxis with palivizumab. Pediatr Infect Dis J 2014; 33:e29-33.
7 Doucette A, Jiang X, Fryzek J, et al. Trends in respiratory syncytial virus and bronchiolitis hospitalization rates in high-risk infants in a United States nationally representative database, 1997-2012. PLoS One 2016; 11: e0152208.
8 Martínez-Valverde S, Salinas-Escudero G, García-Delgado C et al. Out-of-pocket expenditures and care time for children with Down Syndrome: A single-hospital study in Mexico City. PLoS One 2019;14:e0208076.
We thank Dr Nadeem, for highlighting that the clinical features of drowsiness and infant focal seizures in our case report indicates that early treatment for viral/herpes encephalitis was an imperative.
We would like to reassure Dr Nadeem that our infant did indeed receive a combination of early intravenous antiviral treatment (acyclovir) and antibiotics (cefotaxime and amoxicillin) and this was continued until final viral/bacterial PCR and CSF culture results were obtained. The use of acyclovir and amoxicillin was omitted from the original report due to word count limitations.
Viral PCR tested was negative for a range of viruses including herpes simplex (HSV). Although PCR assay is an important diagnostic modality for viral encephalitis HSV, we would add that due to focal seizures, our infant case received investigations and treatment as per national (1) and local guidelines: immediate brain CT imaging was performed to exclude neurosurgical conditions, and a later cranial MRI scan did not show selective damage to the mesial temporal lobe structures or the hippocampus. In addition, an early electroencephalogram (EEG) was normal. The EEG severity and the presence of epileptic seizures at the initial presentation would be significant indicators for predicting the 6-month clinical outcome in patients with HSE.
The seriousness of HSV CNS infections suggests that clinicians maintain a high index of suspicion to initiate evaluation under s...
The seriousness of HSV CNS infections suggests that clinicians maintain a high index of suspicion to initiate evaluation under suitable circumstances. We are grateful to the Editors for now publishing Dr Nadeem’s response to our letter to highlight this to our readers.
(1) Meningitis Research Foundation (MRF). Management of Bacterial Meningitis in infants <3 months (Neonatal Algorithm) [PDF]. London, United Kingdom: Meningitis Research Foundation (MRF); 2017 [updated Nov 2017]. Available from: https://www.meningitis.org/getmedia/75ce0638-a815-4154-b504-b18c462320c8....
We thank Dr Cliona M Ni Bhrolchain for her interest in our paper and her comments. With the exceptions of newborn hearing and blood spot screening, there is unacceptably wide variation at local level and a lack of commitment at national level in implementation and monitoring of preventive child health programmes. We suggest that this is just one manifestation of a wider problem - the serious inadequacy of NHS investment in leadership, education and training, both in general practice and in the specialties. Morale is low and there are chronic shortages of staff with the relevant skills, when medicine is changing and public expectations rising faster than ever before.
David Hall and David Sowden (affiliations as on our original paper)