This most welcome paper by Verity et al relates the important longstanding work that the PIND Study produces and which all paediatricians should most strongly continue to support.[1]
However, it is important for readers to understand that the PIND Study itself cannot in many cases be expected to be the full story when a child is referred to them.
Indeed the relationship between the referring paediatrician and the PIND Study group can very helpfully continue long after the patient's death when new investigative technologies can finally provide a definitive diagnosis, so long as the appropriate samples have been appropriately taken. In this area, I have found guidance from the PIND Study can be very helpful.
We in Northampton have always referred where appropriate to the PIND Study not only because we highly esteem its work, but also because it remains the only practical means of systemic surveillance of vCJD and other neurodegenerative conditions in the UK. Where inspite of every endeavour a diagnosis has not been found while the patient was alive, we in Northampton have continued to keep the PIND Study in the loop while working internationally with other groups to find an answer.
For one such example, we have had children 2 brothers both referred to the PIND study in the early 2000's with a then undiagnosed condition. Both boys, having had post mortems and DNA storage and working with Professor Baas in the Netherlands were found to hav...
This most welcome paper by Verity et al relates the important longstanding work that the PIND Study produces and which all paediatricians should most strongly continue to support.[1]
However, it is important for readers to understand that the PIND Study itself cannot in many cases be expected to be the full story when a child is referred to them.
Indeed the relationship between the referring paediatrician and the PIND Study group can very helpfully continue long after the patient's death when new investigative technologies can finally provide a definitive diagnosis, so long as the appropriate samples have been appropriately taken. In this area, I have found guidance from the PIND Study can be very helpful.
We in Northampton have always referred where appropriate to the PIND Study not only because we highly esteem its work, but also because it remains the only practical means of systemic surveillance of vCJD and other neurodegenerative conditions in the UK. Where inspite of every endeavour a diagnosis has not been found while the patient was alive, we in Northampton have continued to keep the PIND Study in the loop while working internationally with other groups to find an answer.
For one such example, we have had children 2 brothers both referred to the PIND study in the early 2000's with a then undiagnosed condition. Both boys, having had post mortems and DNA storage and working with Professor Baas in the Netherlands were found to have EXOSC3 mutation in 2012 (8 and 2 years after their deaths respectively). [1]
Being part of a team which maybe many years after that child's death that uncovers the cause, giving that family a reason and specifically a diagnostic test, can give great comfort and closure for all involved in that child's care. Readers of this article will be well aware that medically managing such children can present severe challenges, which even under the best possible care can lead to terrible physical and emotional suffering.
It is for paediatricians and child health professionals to continue to work with the PIND Study.It cannot be expected to shoulder the entire weight for this process. Coincidentally, the very same issue of the Archives has another article emphasising making research central to good paediatric practice.[3] I could not agree more.
References
1] Verity C, Winstone AM, Will R, et al. Surveillance for variant CJD: should more children with neurodegenerative diseases have autopsies?. Archives of Disease in Childhood 2019;104:360-365.
2] Eggens V.R.C., Barth P.G., Niermeijer J. F., Berg J.N., Darin N., Dixit A., Flus J., Foulds N., Hortobágyi T., Jacques T., King M.D., Makrythanasis P., Máté A., O'Rourke D., Price S., Williams A.N., Wilson L.,Suri M., Sztriha L., Dijns-de Wissel M.B., van Meegen M.T., van Ruissen F., Aronica E., Troost D., Majoie C.B.L.M., Marquering H.A.,Poll-Thé B-T, Baas F. EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations Orphanet Journal of Rare Diseases 2014 9:23. doi:10.1186/1750-1172-9-23.
3] Davies HT, Phillips B, Preston J, et al. Making research central to good paediatric practice. Archives of Disease in Childhood 2019;104:385-388.
In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year...
In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year. For DS patients <5 years these numbers are even worse: 594 injections are given to prevent 1 clinical admission, as the NNT in this DS age group is about 100. In our opinion the potential harm of palivizumab treatment does not outweigh the harm of one prevented hospital admission.
What about the financial burden? For the DS newborns <2 years in The Netherlands the costs to prevent one hospitalization will be about Euro 76.200 (20 * 6 * Euro 635); for DS children < 5 years these costs to prevent one admission rise to Euro 630.000 (100 * 6 * Euro 1,050). Recent studies from various countries, including The Netherlands, have evaluated the cost effectiveness of palivizumab prophylaxis for RSV infections in risk groups (5,6). These studies concluded that palivizumab prophylaxis is not cost effective with a probable exception for patients with a strongly increased risk (not DS).
Conclusion. We do not agree with the authors to treat all DS children with palivizumab. Palivizumab should only be given in well proven risk populations. We do agree with the authors that a randomized controlled trial (RCT) to prove the efficacy, safety and (cost)effectiveness of palivizumab prevention is needed in DS children.
In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year. For DS patients <5 years these numbers are even worse: 594 injections are given to prevent 1 clinical admission, as the NNT in this DS age group is about 100. In our opinion the potential harm of palivizumab treatment does not outweigh the harm of one prevented hospital admission.
What about the financial burden? For the DS newborns <2 years in The Netherlands the costs to prevent one hospitalization will be about Euro 76.200 (20 * 6 * Euro 635); for DS children < 5 years these costs to prevent one admission rise to Euro 630.000 (100 * 6 * Euro 1,050). Recent studies from various countries, including The Netherlands, have evaluated the cost effectiveness of palivizumab prophylaxis for RSV infections in risk groups (5,6). These studies concluded that palivizumab prophylaxis is not cost effective with a probable exception for patients with a strongly increased risk (not DS).
Conclusion. We do not agree with the authors to treat all DS children with palivizumab. Palivizumab should only be given in well proven risk populations. We do agree with the authors that a randomized controlled trial (RCT) to prove the efficacy, safety and (cost)effectiveness of palivizumab prevention is needed in DS children.
References.
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. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009; 360: 588-98.
3. Hall CB, Weinberg GA, Blumkin AK, et al. Respiratoy syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics 2013; 132: e341-8.
4. The Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531-7.
5. Olchanski N, Hansen RN, et al. Palivizumab prophylaxis for respiratory syncytial virus: examining the evidence around value. Open Forum Infectious Diseases OFID 2018. Doi: 10.1093/ofid/ofy031.
6. Blanken MO, Frederix GW, et al. Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants. Eur J Pediatr 2018; 177: 133-44 Doi.org/10.1007/s00431-017-3046-1.
We thank Drs Bok et al. for their comments on our recent editorial about the use of palivizumab in children with Down syndrome (DS).[1] 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 [2] that did not include children with DS. We provided concrete evidence from [3] 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.[3] 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).[4] 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.[5] This number also aligns with the report from the CARESS registry [6] 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).[1] 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 [2] that did not include children with DS. We provided concrete evidence from [3] 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.[3] 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).[4] 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.[5] This number also aligns with the report from the CARESS registry [6] 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[1] and original report,[4] 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,[1],[4] and is steadily increasing with concurrent healthcare expenditure.[7] 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.[1],[8] 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.
References
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.
The results of the British Paediatric Surveillance Unit survey show that aspirin in Kawasaki disease (KD) is used in the UK and Ireland at a medium dose of 30-50 mg/kg/day in the acute phase of the disease (1). The guidelines of the American Heart Association (AHA) of 2017 do not give a clear indication on what dose of aspirin should be used in the acute phase of KD, stating that "there are no data to suggest that one dose of aspirin is superior to the other" (3).
However, a recent review of the evidence of literature on the use of aspirin in KD (3), clearly shows that, in conjunction with intravenous immunoglobulin, low-dose ASA (3-5 mg/kg/day) in acute KD is not inferior to high-dose ASA (80-100 mg/kg/day) for reducing the risk of coronary artery (CA) abnormalities, duration of fever, responsiveness to IVIG and time of hospitalization (3). These results supports using low-dose (3-5 mg/kg/day) aspirin in the acute phase of KD (3,4). These studies did not consider the concomitant use of steroid therapy, of which the guidelines of AHA do not define a standardized use (2).
The question of which dose of ASA is used in the acute phase is relevant considering that aspirin treatment exposes a risk of gastrointestinal bleeding, hepatotoxicity and neurosensory hearing impairment and Reye syndrome, and that this effect is strictly dose dependent and related to duration of therapy (3).
We believe that the time has come to reconsider and update the guideli...
The results of the British Paediatric Surveillance Unit survey show that aspirin in Kawasaki disease (KD) is used in the UK and Ireland at a medium dose of 30-50 mg/kg/day in the acute phase of the disease (1). The guidelines of the American Heart Association (AHA) of 2017 do not give a clear indication on what dose of aspirin should be used in the acute phase of KD, stating that "there are no data to suggest that one dose of aspirin is superior to the other" (3).
However, a recent review of the evidence of literature on the use of aspirin in KD (3), clearly shows that, in conjunction with intravenous immunoglobulin, low-dose ASA (3-5 mg/kg/day) in acute KD is not inferior to high-dose ASA (80-100 mg/kg/day) for reducing the risk of coronary artery (CA) abnormalities, duration of fever, responsiveness to IVIG and time of hospitalization (3). These results supports using low-dose (3-5 mg/kg/day) aspirin in the acute phase of KD (3,4). These studies did not consider the concomitant use of steroid therapy, of which the guidelines of AHA do not define a standardized use (2).
The question of which dose of ASA is used in the acute phase is relevant considering that aspirin treatment exposes a risk of gastrointestinal bleeding, hepatotoxicity and neurosensory hearing impairment and Reye syndrome, and that this effect is strictly dose dependent and related to duration of therapy (3).
We believe that the time has come to reconsider and update the guidelines on the KD on two important therapeutic aspects: 1) the dose of aspirin to be used; 2) the early use of corticosteroid therapy, as suggested by the authors of this important surveillance study (1).
References
1. Tulloh RMR, Mayon-White R, Harnden A, et al. Kawasaki disease: a prospective population survey in the UK and Ireland from 2013 to 2015. Arch Dis Child. 2018 Aug 13. pii:archdischild-2018-315087. doi: 10.1136/archdischild-2018-315087. [Epub ahead of print]
2. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-e999.
3. Ho LGY, Curtis N. What dose of aspirin should be used in the initial treatment of Kawasaki disease? Arch Dis Child. 2017;102(12):1180-1182
4. Dallaire F, Fortier-Morissette Z, Blais S, et al. Aspirin Dose and Prevention of Coronary Abnormalities in Kawasaki Disease. Pediatrics 2017;139:e20170098.
Federico Marchetti, Lorenzo Mambelli
Department of Paediatrics,
Santa Maria delle Croci Hospital,
48121 Ravenna, Italy
e mail: federico.marchetti@auslromagna.it
We thank Professor Marchetti for his comments on our article in ADC (1). He raises two important questions we wish to comment on.
Regarding which dose of aspirin to use, we are also interested in the suggestion that anti-aggregant doses of aspirin might be a preferred option for the acute inflammatory phase of Kawasaki disease (KD). It is indeed possible that future guidance may recommend low dose aspirin (3-5 mg/kg/day) at all stages of KD, as suggested by the retrospective data referred to by Professor Marchetti (2). Whilst we acknowledge the potential merits of such an approach, particularly in relation to avoidance of toxicity, there has never been a prospective controlled clinical trial to support this and therefore no high-level evidence on which to base firm guidance. Two other practical considerations are worthy of highlighting in relation to aspirin. Firstly, nonsteroidal anti-inflammatory drugs such as ibuprofen, which antagonize platelet inhibition induced by aspirin (3), should be avoided in patients with KD receiving anti-aggregant doses of aspirin. Secondly, although the risk of low dose aspirin (3-5 mg/kg) in being associated with Reye syndrome is unknown, usual advice is to discontinue in the event of inter-current infection.
Regarding the use of corticosteroids for primary treatment of KD, we have been strong advocates of this for several years, as reflected in previously published guidance (4, 5). This is now brought into...
We thank Professor Marchetti for his comments on our article in ADC (1). He raises two important questions we wish to comment on.
Regarding which dose of aspirin to use, we are also interested in the suggestion that anti-aggregant doses of aspirin might be a preferred option for the acute inflammatory phase of Kawasaki disease (KD). It is indeed possible that future guidance may recommend low dose aspirin (3-5 mg/kg/day) at all stages of KD, as suggested by the retrospective data referred to by Professor Marchetti (2). Whilst we acknowledge the potential merits of such an approach, particularly in relation to avoidance of toxicity, there has never been a prospective controlled clinical trial to support this and therefore no high-level evidence on which to base firm guidance. Two other practical considerations are worthy of highlighting in relation to aspirin. Firstly, nonsteroidal anti-inflammatory drugs such as ibuprofen, which antagonize platelet inhibition induced by aspirin (3), should be avoided in patients with KD receiving anti-aggregant doses of aspirin. Secondly, although the risk of low dose aspirin (3-5 mg/kg) in being associated with Reye syndrome is unknown, usual advice is to discontinue in the event of inter-current infection.
Regarding the use of corticosteroids for primary treatment of KD, we have been strong advocates of this for several years, as reflected in previously published guidance (4, 5). This is now brought into sharp focus in the light of emerging data from several countries regarding poor coronary artery outcomes despite Intravenous immunoglobulin (IVIG) (1, 6-9). Indeed, the use of corticosteroids as primary adjunctive treatment of patients with severe KD has an increasingly compelling evidence-base. Despite that and UK guidance that was published halfway during the BPSU survey (5), our study demonstrates that UK paediatricians are not yet widely using corticosteroids for the treatment of KD (1). The soon-to-be published European SHARE (single hub access for rheumatology in Europe) guidance hopefully will improve that situation for high risk cases, but there clearly remains significant equipoise over the use of corticosteroids as adjunctive therapy for unselected cases of KD. Thus, at the time of writing we are currently setting up a major international clinical trial of corticosteroids as adjunctive treatment for unselected KD cases in the UK and Europe, KDCAAP (the Kawasaki Disease Coronary Artery Aneurysm Prevention trial). It is possible that the added potent anti-inflammatory effect of adjunctive corticosteroids for the primary treatment of KD will obviate the need for any further discussion about anti-inflammatory doses of aspirin. We hope that the UK and European paediatric community will recruit patients to this important clinical trial to resolve this issue once and for all.
Professor Robert Tulloh, Bristol Royal Hospital for Children, Bristol, UK
Professor Paul Brogan, Great Ormond Street Hospital, London, UK
1. Tulloh RMR, Mayon-White R, Harnden A, Ramanan AV, Tizard EJ, Shingadia D, Michie CA, Lynn RM, Levin M, Franklin OD, Craggs P, Davidson S, Stirzaker R, Danson M, Brogan PA. Kawasaki disease: a prospective population survey in the UK and Ireland from 2013 to 2015. Archives of Disease in Childhood. 2018.
2. Ho LGY, Curtis N. What dose of aspirin should be used in the initial treatment of Kawasaki disease? Archives of Disease in Childhood. 2017;102(12):1180-2.
3. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345(25):1809-17.
4. Brogan PA, Bose A, Burgner D, Shingadia D, Tulloh R, Michie C, Klein N, Booy R, Levin M, Dillon MJ. Kawasaki disease: an evidence based approach to diagnosis, treatment, and proposals for future research. Arch Dis Child. 2002;86(4):286-90.
5. Eleftheriou D, Levin M, Shingadia D, Tulloh R, Klein NJ, Brogan PA. Management of Kawasaki disease. Arch Dis Child. 2014;99(1):74-83.
6. Mossberg M, Segelmark M, Kahn R, Englund M, Mohammad AJ. Epidemiology of primary systemic vasculitis in children: a population-based study from southern Sweden. Scand J Rheumatol. 2018;47(4):295-302.
7. Lyskina G, Bockeria O, Shirinsky O, Torbyak A, Leontieva A, Gagarina N, Satyukova A, Kostina J, Vinogradova O. Cardiovascular outcomes following Kawasaki disease in Moscow, Russia: A single center experience. Global cardiology science & practice. 2017;2017(3):e201723.
8. Jakob A, Whelan J, Kordecki M, Berner R, Stiller B, Arnold R, von KR, Neumann E, Roubinis N, Robert M, Grohmann J, Hohn R, Hufnagel M. Kawasaki Disease in Germany: A Prospective, Population-based Study Adjusted for Underreporting. Pediatr Infect Dis J. 2016;35(2):129-34.
9. Friedman KG, Gauvreau K, Hamaoka-Okamoto A, Tang A, Berry E, Tremoulet AH, Mahavadi VS, Baker A, deFerranti SD, Fulton DR, Burns JC, Newburger JW. Coronary Artery Aneurysms in Kawasaki Disease: Risk Factors for Progressive Disease and Adverse Cardiac Events in the US Population. Journal of the American Heart Association. 2016;5(9).
I refer to the paper published by Palmer et al in Archives Diseases Childhood March 20181 that states the recommendation to avoid tramadol when breastfeeding and the contraindication to its use in children (including neonates) is inappropriate in their view. 1
I disagree with the authors that tramadol is a safe for babies of breastfeeding mothers. Their conclusion, in my opinion, is premature and not adequately evidence-based. While they acknowledge, the US Food and Drug Administration (FDA) reported cases, they ignore the serious warnings by both Manufacturer and FDA about administering tramadol to children and breast-feeding mothers. There is increasing concern that narcotics used for treating pain in breastfeeding mothers may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the FDA and the American College of Obstetricians and Gynecologists (ACOG) advocate against the use of codeine and tramadol in women who are breastfeeding because their babies may suffer adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5 Patient safety should be foremost in our minds in making any recommendations that are contrary to Manufacturer, FDA, and AAP recommendations. It would be difficult to justify use of tramadol in a breastfeeding mother in the event of litigation arising from adverse effects of tramadol in the baby...
I refer to the paper published by Palmer et al in Archives Diseases Childhood March 20181 that states the recommendation to avoid tramadol when breastfeeding and the contraindication to its use in children (including neonates) is inappropriate in their view. 1
I disagree with the authors that tramadol is a safe for babies of breastfeeding mothers. Their conclusion, in my opinion, is premature and not adequately evidence-based. While they acknowledge, the US Food and Drug Administration (FDA) reported cases, they ignore the serious warnings by both Manufacturer and FDA about administering tramadol to children and breast-feeding mothers. There is increasing concern that narcotics used for treating pain in breastfeeding mothers may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the FDA and the American College of Obstetricians and Gynecologists (ACOG) advocate against the use of codeine and tramadol in women who are breastfeeding because their babies may suffer adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5 Patient safety should be foremost in our minds in making any recommendations that are contrary to Manufacturer, FDA, and AAP recommendations. It would be difficult to justify use of tramadol in a breastfeeding mother in the event of litigation arising from adverse effects of tramadol in the baby, when safer alternatives are available.
MANUFACTURER WARNING
In March 2008, Janssen Ortho, the manufacturer of tramadol (ULTRAM®) stated that the effects of tramadol on growth and functional maturation of child, and safety in infants and newborn has not been studied and it is not recommended for use in the pediatric population. It issued the following information concerning tramadol:
• LABOR AND DELIVERY
1. ULTRAM® should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn.
2. Tramadol crosses the placenta. The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.
• NURSING MOTHERS
ULTRAM® is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours, post-dose was 100μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
• PEDIATRIC USE
The safety and efficacy of ULTRAM® in patients under 16 years of age have not been established. The use of ULTRAM® in the pediatric population is not recommended. 6
FDA WARNINGS
1. In 2013, FDA placed restrictions on its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.7
2. FDA reviewed adverse event reports submitted to it from January 1969 to May 2015, and identified 64 cases of serious breathing problems, including 24 deaths, with codeine-containing medicines in children younger than 18 years. As this included only reports submitted to FDA, there may be additional cases about which FDA is unaware. FDA also identified nine cases of serious breathing problems, including three deaths, with the use of tramadol in children younger than 18 years from January 1969 to March 2016. Most of the serious side-effects with both codeine and tramadol occurred in children younger than 12 years, and some cases occurred after a single dose of the medicine.8
3. On July1, 2015, FDA issued warning about the potential risks of using codeine cough-and-cold medicines in children on July 1, 2015,4 and in September 21, 2015, FDA issued warning on the risks of using the pain medicine tramadol in children aged 17 and younger issued on September 21, 2015. 9
4. On 1-11-2018, the FDA restricted the use of codeine and tramadol medicines in children as these medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children. FDA warned against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants. 10
5. Use of tramadol during pregnancy could make the baby dependent on the drug and cause Life-threatening withdrawal effects that may necessitate medical treatment for several weeks. 11
Additional concerns relating to the use of tramadol are suicidal thoughts and suicide attempts have emerged. In the article: Tramadol and Suicide attempt - from FDA reports, dated November 8, 2018, suicide attempt is found among people who take Tramadol, especially female, 40-49 old, who have been taking the drug for < 1 month. In the study based on reports of 102,114 people who have side effects when taking Tramadol from FDA, and is updated regularly. 102,114 people reported side effects when taking Tramadol. Among them, 765 people (0.75%) have attempted suicide. Suicide attempts are reported in children from the age of 10 years.12
In the light of the above data, there does not appear to be adequate evidence to support Palmer et al.’s contention that both Manufacturer and FDA recommendation to avoid use of tramadol when breastfeeding and contraindication to its use in children (including neonates) should be ignored.1 The AAP, the FDA, and the ACOG recommend against the use of codeine and tramadol in women who are breastfeeding because their newborns may have adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5
Practice of medicine should be evidence-based. Patient safety comes foremost. Safer alternatives to tramadol are available. Acetaminophen and/or ibuprofen is recommended for pain management in women who are breastfeeding. If narcotic treatment is considered necessary, the lowest effective dose of morphine for the shortest time possible could be prescribed. 2
REFERENCE
1. Greta M Palmer, Brian J Anderson, David K Linscott, Michael J Paech, Karel Allegaert. Tramadol, breast feeding and safety in the newborn. (http://dx.doi.org/10.1136/archdischild-2017-313786).
2. Robert L. Barbieri. Editorial. Stop using codeine, oxycodone, hydrocodone, tramadol, and aspirin in women who are breast-feeding. OBG Manag. 2017 October;29(10):8-10,12. https://www.mdedge.com/obgyn/article/148018/obstetrics/stop-using-codein....
3. Sachs HC; Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796–e809.
4. US Food and Drug Administration. FDA Drug Safety Communication. FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring, MD: US Food and Drug Administration. https://www.fda.gov/Drugs/DrugSafety/ucm118113.htm. Published April 2017.
5. Practice advisory on codeine and tramadol for breast feeding women. American College of Obstetricians and Gynecologists website. https://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-A.... Published April 27, 2017.
6. ULTRAM® (tramadol hydrochloride) Tablets. Full Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033...
7. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. (2-20-2013). https://www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf - accessed February 16, 2019.
8. FDA Drug Safety Communication: FDA evaluating the potential risks of using codeine cough-and-cold medicines in children. https://www.fda.gov/Drugs/DrugSafety/ucm453125.htm
9. FDA Drug Safety Communication: FDA evaluating the risks of using the pain medicine tramadol in children aged 17 and younger. https://www.fda.gov/Drugs/DrugSafety/ucm462991.htm (9-21-2015).
10. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm (1-11-2018)
11. Kaci Durbin. (Updated 29-12-2018) Tramadol. https://www.drugs.com/tramadol.html
12. Tramadol and Suicide attempt - from FDA reports. http://www.ehealthme.com/ds/tramadol/suicide-attempt/
Conflict of Interest
None declared
Professor Dr. Davendralingam Sinniah
Dear Professor Davendralingam Sinniah Paediatrician
In response to your letter. We agree with you patient safety comes first in all age groups.
1. Tramadol is not a full agonist opioid. The issue that we have highlighted with tramadol (and codeine) is when the patient is a CYP2D6 ultrametaboliser there is potential for serious adverse events. The CYP2D6 issue is not at play for the alternative pure opioid agonists oxycodone and morphine (the latter as you suggested). However all these agents have potentially serious adverse effects, including sedation, respiratory depression (in therapeutic doses) and fatality (usually in excessive dosing or at risk patients).
2. We agree with you that the simple non-opioid analgesics (paracetamol and NSAIDs when not contraindicated) are preferred. We are advocating for tramadol when stronger analgesia is required as a 3rd line alternative to the pure opioid agonists. We each work in tertiary centres where tramadol is used: one a women’s hospital where it is used perioperatively post caesarean and vaginal delivery; and the others where is is used off label in children of all ages (including infants).
3. There are few data concerning respiratory depression and tramadol in neonates. However concentrations in breast fed neonates are low and not expected to cause respiratory depression after usual doses.
4. Please point to evidence in the literature that tramadol administered to women who are breastfeeding cause...
Dear Professor Davendralingam Sinniah Paediatrician
In response to your letter. We agree with you patient safety comes first in all age groups.
1. Tramadol is not a full agonist opioid. The issue that we have highlighted with tramadol (and codeine) is when the patient is a CYP2D6 ultrametaboliser there is potential for serious adverse events. The CYP2D6 issue is not at play for the alternative pure opioid agonists oxycodone and morphine (the latter as you suggested). However all these agents have potentially serious adverse effects, including sedation, respiratory depression (in therapeutic doses) and fatality (usually in excessive dosing or at risk patients).
2. We agree with you that the simple non-opioid analgesics (paracetamol and NSAIDs when not contraindicated) are preferred. We are advocating for tramadol when stronger analgesia is required as a 3rd line alternative to the pure opioid agonists. We each work in tertiary centres where tramadol is used: one a women’s hospital where it is used perioperatively post caesarean and vaginal delivery; and the others where is is used off label in children of all ages (including infants).
3. There are few data concerning respiratory depression and tramadol in neonates. However concentrations in breast fed neonates are low and not expected to cause respiratory depression after usual doses.
4. Please point to evidence in the literature that tramadol administered to women who are breastfeeding causes adverse neonatal effects such as excessive sleepiness, difficulty breathing, and fatal breathing problems. Patient safety is always foremost in our minds but we could find little evidence of these adverse effects. Further we present pharmacokinetic evidence as to why that is unlikely
5. You present warnings, not evidence, concerning these complications, like the FDA, AAP and ACOGs conservative and reactive stance. We acknowledge your concerns. Please note that our editorial was a consequence of these warnings that we felt were unjustified. That was the point of the review.
We wish to advocate for pain relief in postpartum mothers who have moderate to severe pain and require analgesic escalation beyond the acetaminophen and nsNSAID. The emphasis from a safety perspective, as you have suggested, is that opioid agonists and tramadol should be prescribed at the lowest effective dose and for the shortest time possible. Sensible advice should be provided to all patients receiving opioid and tramadol scripts at discharge including breastfeeding mothers.
Greta M Palmer1, Brian J Anderson2, David K Linscott3, Michael J Paech4,5, Karel Allegaert6,7
affiliations as per primary article
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.
References
1. Retzler J, Hex N, Bartlett C, et al. Economic cost of congenital CMV...
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.
References
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]
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.
The response to our article was received with interest. Grosse and Lanzieri raise important points in connection with our recent paper [1], 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) [2]. 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) [2] 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...
The response to our article was received with interest. Grosse and Lanzieri raise important points in connection with our recent paper [1], 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) [2]. 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) [2] 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 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.
[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]
This most welcome paper by Verity et al relates the important longstanding work that the PIND Study produces and which all paediatricians should most strongly continue to support.[1]
However, it is important for readers to understand that the PIND Study itself cannot in many cases be expected to be the full story when a child is referred to them.
Indeed the relationship between the referring paediatrician and the PIND Study group can very helpfully continue long after the patient's death when new investigative technologies can finally provide a definitive diagnosis, so long as the appropriate samples have been appropriately taken. In this area, I have found guidance from the PIND Study can be very helpful.
We in Northampton have always referred where appropriate to the PIND Study not only because we highly esteem its work, but also because it remains the only practical means of systemic surveillance of vCJD and other neurodegenerative conditions in the UK. Where inspite of every endeavour a diagnosis has not been found while the patient was alive, we in Northampton have continued to keep the PIND Study in the loop while working internationally with other groups to find an answer.
For one such example, we have had children 2 brothers both referred to the PIND study in the early 2000's with a then undiagnosed condition. Both boys, having had post mortems and DNA storage and working with Professor Baas in the Netherlands were found to hav...
Show MoreIn their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
Show MoreFor the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year...
We thank Drs Bok et al. for their comments on our recent editorial about the use of palivizumab in children with Down syndrome (DS).[1] 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 [2] that did not include children with DS. We provided concrete evidence from [3] 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.[3] 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).[4] 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.[5] This number also aligns with the report from the CARESS registry [6] and compares favourably with the NNT of 16 for preter...
Show MoreThe results of the British Paediatric Surveillance Unit survey show that aspirin in Kawasaki disease (KD) is used in the UK and Ireland at a medium dose of 30-50 mg/kg/day in the acute phase of the disease (1). The guidelines of the American Heart Association (AHA) of 2017 do not give a clear indication on what dose of aspirin should be used in the acute phase of KD, stating that "there are no data to suggest that one dose of aspirin is superior to the other" (3).
Show MoreHowever, a recent review of the evidence of literature on the use of aspirin in KD (3), clearly shows that, in conjunction with intravenous immunoglobulin, low-dose ASA (3-5 mg/kg/day) in acute KD is not inferior to high-dose ASA (80-100 mg/kg/day) for reducing the risk of coronary artery (CA) abnormalities, duration of fever, responsiveness to IVIG and time of hospitalization (3). These results supports using low-dose (3-5 mg/kg/day) aspirin in the acute phase of KD (3,4). These studies did not consider the concomitant use of steroid therapy, of which the guidelines of AHA do not define a standardized use (2).
The question of which dose of ASA is used in the acute phase is relevant considering that aspirin treatment exposes a risk of gastrointestinal bleeding, hepatotoxicity and neurosensory hearing impairment and Reye syndrome, and that this effect is strictly dose dependent and related to duration of therapy (3).
We believe that the time has come to reconsider and update the guideli...
Dear Sir
We thank Professor Marchetti for his comments on our article in ADC (1). He raises two important questions we wish to comment on.
Regarding which dose of aspirin to use, we are also interested in the suggestion that anti-aggregant doses of aspirin might be a preferred option for the acute inflammatory phase of Kawasaki disease (KD). It is indeed possible that future guidance may recommend low dose aspirin (3-5 mg/kg/day) at all stages of KD, as suggested by the retrospective data referred to by Professor Marchetti (2). Whilst we acknowledge the potential merits of such an approach, particularly in relation to avoidance of toxicity, there has never been a prospective controlled clinical trial to support this and therefore no high-level evidence on which to base firm guidance. Two other practical considerations are worthy of highlighting in relation to aspirin. Firstly, nonsteroidal anti-inflammatory drugs such as ibuprofen, which antagonize platelet inhibition induced by aspirin (3), should be avoided in patients with KD receiving anti-aggregant doses of aspirin. Secondly, although the risk of low dose aspirin (3-5 mg/kg) in being associated with Reye syndrome is unknown, usual advice is to discontinue in the event of inter-current infection.
Regarding the use of corticosteroids for primary treatment of KD, we have been strong advocates of this for several years, as reflected in previously published guidance (4, 5). This is now brought into...
Show MoreI refer to the paper published by Palmer et al in Archives Diseases Childhood March 20181 that states the recommendation to avoid tramadol when breastfeeding and the contraindication to its use in children (including neonates) is inappropriate in their view. 1
Show MoreI disagree with the authors that tramadol is a safe for babies of breastfeeding mothers. Their conclusion, in my opinion, is premature and not adequately evidence-based. While they acknowledge, the US Food and Drug Administration (FDA) reported cases, they ignore the serious warnings by both Manufacturer and FDA about administering tramadol to children and breast-feeding mothers. There is increasing concern that narcotics used for treating pain in breastfeeding mothers may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the FDA and the American College of Obstetricians and Gynecologists (ACOG) advocate against the use of codeine and tramadol in women who are breastfeeding because their babies may suffer adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5 Patient safety should be foremost in our minds in making any recommendations that are contrary to Manufacturer, FDA, and AAP recommendations. It would be difficult to justify use of tramadol in a breastfeeding mother in the event of litigation arising from adverse effects of tramadol in the baby...
Dear Professor Davendralingam Sinniah Paediatrician
Show MoreIn response to your letter. We agree with you patient safety comes first in all age groups.
1. Tramadol is not a full agonist opioid. The issue that we have highlighted with tramadol (and codeine) is when the patient is a CYP2D6 ultrametaboliser there is potential for serious adverse events. The CYP2D6 issue is not at play for the alternative pure opioid agonists oxycodone and morphine (the latter as you suggested). However all these agents have potentially serious adverse effects, including sedation, respiratory depression (in therapeutic doses) and fatality (usually in excessive dosing or at risk patients).
2. We agree with you that the simple non-opioid analgesics (paracetamol and NSAIDs when not contraindicated) are preferred. We are advocating for tramadol when stronger analgesia is required as a 3rd line alternative to the pure opioid agonists. We each work in tertiary centres where tramadol is used: one a women’s hospital where it is used perioperatively post caesarean and vaginal delivery; and the others where is is used off label in children of all ages (including infants).
3. There are few data concerning respiratory depression and tramadol in neonates. However concentrations in breast fed neonates are low and not expected to cause respiratory depression after usual doses.
4. Please point to evidence in the literature that tramadol administered to women who are breastfeeding cause...
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.
References
Show More1. Retzler J, Hex N, Bartlett C, et al. Economic cost of congenital CMV...
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.
The response to our article was received with interest. Grosse and Lanzieri raise important points in connection with our recent paper [1], 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) [2]. 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) [2] 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...
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