As authors of a recent article demonstrating an increase in Accident and Emergency presentations for acute vaccine reactions following the introduction of the group B meningococcal vaccine (4CMenB) into the UK infant immunisation schedule in 2015 (1), we welcome correspondence from Mukherjee et al emphasising the ongoing risk of invasive meningococcal disease (IMD) in this country.
These data give a local perspective to the national Public Health England surveillance data demonstrating a 50% reduction in group B meningococcal disease following introduction of the 4CMenB vaccine (2). Despite immunisation with 4CMenB being 82.9% effective against group B invasive meningococcal disease in infants, there were still 56 cases in England in the year to March 2017 in under 1 year olds, and a further 119 cases in 1 to 4 year olds (an age group that currently includes both immunised and unimmunised cohorts) (2) (3). In the context of the epidemiology of meningococcal disease in the UK, the benefits of immunisation with 4CMenB to infants clearly outweigh any risks of a transient febrile reaction. The current 4CMenB immunisation campaign is not expected to induce herd immunity, therefore invasive meningococcal bacteria will continue to circulate in the community and unimmunised infants remain at increased risk of invasive meningococcal disease compared to their immunised peers. Parents and clinicians need t...
As authors of a recent article demonstrating an increase in Accident and Emergency presentations for acute vaccine reactions following the introduction of the group B meningococcal vaccine (4CMenB) into the UK infant immunisation schedule in 2015 (1), we welcome correspondence from Mukherjee et al emphasising the ongoing risk of invasive meningococcal disease (IMD) in this country.
These data give a local perspective to the national Public Health England surveillance data demonstrating a 50% reduction in group B meningococcal disease following introduction of the 4CMenB vaccine (2). Despite immunisation with 4CMenB being 82.9% effective against group B invasive meningococcal disease in infants, there were still 56 cases in England in the year to March 2017 in under 1 year olds, and a further 119 cases in 1 to 4 year olds (an age group that currently includes both immunised and unimmunised cohorts) (2) (3). In the context of the epidemiology of meningococcal disease in the UK, the benefits of immunisation with 4CMenB to infants clearly outweigh any risks of a transient febrile reaction. The current 4CMenB immunisation campaign is not expected to induce herd immunity, therefore invasive meningococcal bacteria will continue to circulate in the community and unimmunised infants remain at increased risk of invasive meningococcal disease compared to their immunised peers. Parents and clinicians need to remain aware of the ongoing risks of this disease and benefits of immunisation against this potentially fatal bacterium.
References
1. Nainani V, Galal U, Buttery J, Snape MD. An increase in accident and emergency presentations for adverse events following immunisation after introduction of the group B meningococcal vaccine: an observational study. Arch Dis Child. 2017.
2. Parikh SR, Andrews NJ, Beebeejaun K, Campbell H, Ribeiro S, Ward C, et al. Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study. Lancet. 2016;388(10061):2775-82.
3. Public Health England. Meningococcal disease: laboratory confirmed cases in England. [Online]. Cited 7th September 2017. Available at: https://www.gov.uk/government/publications/meningococcal-disease-laborat...
Dr. Goldwater's review once again reflects a suberb understanding of SIDS and related phenomena. He consistently presents information to his readers in a most interesting and objectively accurate and well-written set of steps, which are typically precise, factual, and to the point. For example, he ends the review by observing as follows:
" If multiple causes were involved, then it would be reasonable to expect a variety of pathological findings. This demonstrably is not the case. There is a fixed pattern to the vast majority of cases. The crux of the argument against broad polycausality of SIDS is the consistent pathological picture (usually in more than 90% of cases) "
" In moving forward, SIDS researchers should be asking the following questions: (1) Does my hypothesis take into account the key pathological findings in SIDS? (2) Is my hypothesis congruent with the key epidemiological risk factors? (3) Does the hypothesis link questions (1) and (2) This review has shown that infection meets these questions appropriately and researchers in this area deserve acknowledgement and funding support. There remain gaps in our knowledge with regard to the infection model, but it is clear that other lines of research are not making the grade ...."
Note that while Dr. Goldwater has provided a formidable case on behalf of supporting and funding infection related SIDS research, and also given that there unquestionably is a relationshi...
Dr. Goldwater's review once again reflects a suberb understanding of SIDS and related phenomena. He consistently presents information to his readers in a most interesting and objectively accurate and well-written set of steps, which are typically precise, factual, and to the point. For example, he ends the review by observing as follows:
" If multiple causes were involved, then it would be reasonable to expect a variety of pathological findings. This demonstrably is not the case. There is a fixed pattern to the vast majority of cases. The crux of the argument against broad polycausality of SIDS is the consistent pathological picture (usually in more than 90% of cases) "
" In moving forward, SIDS researchers should be asking the following questions: (1) Does my hypothesis take into account the key pathological findings in SIDS? (2) Is my hypothesis congruent with the key epidemiological risk factors? (3) Does the hypothesis link questions (1) and (2) This review has shown that infection meets these questions appropriately and researchers in this area deserve acknowledgement and funding support. There remain gaps in our knowledge with regard to the infection model, but it is clear that other lines of research are not making the grade ...."
Note that while Dr. Goldwater has provided a formidable case on behalf of supporting and funding infection related SIDS research, and also given that there unquestionably is a relationship between the two, nevertheless he has not claimed that bacterial and/or viral infective agents are the actual cause of the fatalities.
At present, the foregoing actually comes to down to applying the 'Law of excluded middle'. Either infections are the cause of the SIDs or they are not. If they are, then Dr. Goldwater and other fellow travellers are hopefully treading the royal road to success. If not, and applying what his review clearly implies, then infection has to be a concominant variant. In other words, whatever causes SIDS also is responsible for the presentation of many, if not all of the accompanying pathological 'markers' of the 'syndrome', and with particular reference to infections being the predominant consideration. That aspect would involve the identification of a cause of death which also carries with it the inability to protect the body again infection in 90% of the SIDS cases
In that regard, meriting consideration and available on PubMed is a free PMC article. Entering PMC2647905 will screen up the text.
We thank Dr Neefjes for engaging so thoroughly with our research, which focuses on an important area of care that has a significant impact on parents, children and clinicians. We readily agree that early discussions about end-of-life care might be beneficial in giving parents more time to explore treatment options. Further research could explore whether earlier discussions would be acceptable and of benefit. In our research we found, unsurprisingly, that parents want the best for their children and that clinicians want to do the best for their patients. Reducing the chance for relationships to become ‘adversarial’ is in our view a good aim where possible. It is true that, if parents feel that they are no longer able to defend the best interests of their children, this loss of empowerment may precipitate conflict. However, it was apparent in our research that parents with whom we spoke did not think of their rights of consent in absolute terms. Instead they thought that their rights to consent were complex and not necessarily absolute in that they sometimes amounted to the power to agree to– or disagree with –a narrow range of options (including, in some cases, in relation to decisions to withdraw or withhold treatment). This is not to say that all other parents share this opinion (we lack evidence for such a general empirical claim), but more that the nuance in the way that these parents perceived consent may distinguish parental consent from consent in other populations....
We thank Dr Neefjes for engaging so thoroughly with our research, which focuses on an important area of care that has a significant impact on parents, children and clinicians. We readily agree that early discussions about end-of-life care might be beneficial in giving parents more time to explore treatment options. Further research could explore whether earlier discussions would be acceptable and of benefit. In our research we found, unsurprisingly, that parents want the best for their children and that clinicians want to do the best for their patients. Reducing the chance for relationships to become ‘adversarial’ is in our view a good aim where possible. It is true that, if parents feel that they are no longer able to defend the best interests of their children, this loss of empowerment may precipitate conflict. However, it was apparent in our research that parents with whom we spoke did not think of their rights of consent in absolute terms. Instead they thought that their rights to consent were complex and not necessarily absolute in that they sometimes amounted to the power to agree to– or disagree with –a narrow range of options (including, in some cases, in relation to decisions to withdraw or withhold treatment). This is not to say that all other parents share this opinion (we lack evidence for such a general empirical claim), but more that the nuance in the way that these parents perceived consent may distinguish parental consent from consent in other populations. Ethically, we also see a distinction between the right of a person to consent on their own behalf and their right to consent on another’s behalf. Further, we suggest, there is a serious risk that the interests of children can in some cases be diminished or under-emphasised (for example, in disputes that last many months). The prohibitive costs of legal action, fear of further undermining relationships, and a lack of confidence in the courts may all contribute to a desire not to seek legal judgment. It is because of all these factors, rather than believing it is representative of parental wishes as such, that we suggest parental assent might have the potential to balance competing factors better than parental consent.
Future research is certainly needed given that assent itself is (so far) poorly conceptualised in the wider bioethical literature. In our view, a key attribute of any future development would be to ensure that ‘parental assent’ would not itself precipitate early disputes by undermining trust in the decision-making process. Currently, the vast majority of cases appear to be resolved sensitively, expeditiously and with due regard to the interests of both parents and children. Unfortunately, even where discussions between parents and clinicians are sensitive and take place at an early stage, in a small minority of cases this balance is lost and discussion stalls. While acknowledging the importance of building good relationships with early discussion, in these cases we consider the interests of both parents and children ultimately suffer. We suggest it is vitally important to seek to address– and hopefully avoid –this.
In his recent review “Infection: the neglected paradigm in SIDS research” Goldwater (2017) demonstrated that the infection model is the key pathological finding and the key epidemiological risk factor in SIDS. He reasoned that future research regarding the process how the microbiome shapes the immune system in infancy, will close remaining gaps in the knowledge about these tragic events. The well-known and worldwide similar distribution of age of SIDS-death with a clear peak between the 2nd and 4th month (AAP 2005, 2016) likewise supports this infection hypothesis. In this time slot the battle between microbial colonizing of the dermal and the mucosal tissue, including pathogens as well as microbiome building bacteria (Gensollen 2016) and the proceeding of the infant’s immature to a mature immune system (Basha 2014, Elahi 2013), potentially complicated by viral infections, opens a wide window for an immunological burst. In the neonate with little immunological memory the innate and adaptive immune system (immune cells, cytokines, antibodies, etc.) starts to mature rapidly in the first three months of his life (Basha 2014). Additionally CD71+ erythroid cells, which are enriched in the newborn period and which have actively immunosuppressive and immunomodulatory properties, vanish during the first months, leaving the infant exceedingly susceptible to infections (Elahi 2014).
At the same time the passive protection by transplacentally transferred maternal antibodies, w...
In his recent review “Infection: the neglected paradigm in SIDS research” Goldwater (2017) demonstrated that the infection model is the key pathological finding and the key epidemiological risk factor in SIDS. He reasoned that future research regarding the process how the microbiome shapes the immune system in infancy, will close remaining gaps in the knowledge about these tragic events. The well-known and worldwide similar distribution of age of SIDS-death with a clear peak between the 2nd and 4th month (AAP 2005, 2016) likewise supports this infection hypothesis. In this time slot the battle between microbial colonizing of the dermal and the mucosal tissue, including pathogens as well as microbiome building bacteria (Gensollen 2016) and the proceeding of the infant’s immature to a mature immune system (Basha 2014, Elahi 2013), potentially complicated by viral infections, opens a wide window for an immunological burst. In the neonate with little immunological memory the innate and adaptive immune system (immune cells, cytokines, antibodies, etc.) starts to mature rapidly in the first three months of his life (Basha 2014). Additionally CD71+ erythroid cells, which are enriched in the newborn period and which have actively immunosuppressive and immunomodulatory properties, vanish during the first months, leaving the infant exceedingly susceptible to infections (Elahi 2014).
At the same time the passive protection by transplacentally transferred maternal antibodies, which contribute to early defense against pathogenic organisms, decreases significantly (Waaijenborg 2013).
In consideration of that high complexity and numerous possibilities of interaction between various parts of this immune ontogeny it is comprehensible that, in case of inauspicious conditions, an overwhelming sepsis/septic shock, i.e. SIDS as the maximum credible accident might occur.
Thus, the infection model should not only be considered in further research “solving the tragic enigma of SIDS” (Goldwater 2017) but it also stresses the importance of all infection preventive recommendations, such as breast feeding, infant sleep location and exposures to smoking.
References:
American Academy of Pediatrics Task Force on Sudden Infant Death Syndrome. The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics. 2005 Nov;116(5):1245-55.
TASK FORCE ON SUDDEN INFANT DEATH SYNDROME. SIDS and Other Sleep-Related Infant Deaths: Updated 2016 Recommendations for a Safe Infant Sleeping Environment. Pediatrics. 2016 Nov;138(5). pii: e20162938.
Basha S1, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol. 2014 Sep;10(9):1171-84.
Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, Chaturvedi V, Strong BS, Qualls JE, Steinbrecher KA, Kalfa TA, Shaaban AF, Way SS. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature. 2013 Dec 5;504(7478):158-62.
Elahi S. New insight into an old concept: role of immature erythroid cells in immune pathogenesis of neonatal infection. Front Immunol. 2014 Aug 12;5:376, 1-7.
Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016 Apr 29;352(6285):539-44
Goldwater PN. Infection: the neglected paradigm in SIDS research. Arch Dis Child. 2017 Aug;102(8):767-772.
Waaijenborg S, Hahne SJ, Mollema L, et al. Waning of maternal antibodies against measles, mumps, rubella, and varicella in communities with contrasting vaccination coverage. The Journal of infectious diseases. 2013; 208(1):10–16.
Lemer has very usefully carried out a 5 year review of policy implementation. Policy is only as good as the receivers at the other end and these change frequently along with an ever changing political and economic landscape.Thus the exercise is valuable in not only taking stock but also reminding those in power of an independent review process with recommendations which should transcend governments. Sadly , the focus on funding education of the workforce (recommendations 10-12) do not appear to have been a priority and without this foundation, we will not move ahead sufficiently fast with a child and family friendly service. The Children and Young Persons Outcomes Framework is similarly the result of much work in a previous government and must not be allowed to whither on the vine. Perhaps we should regularly remind policy makers in the current administration of the value of persistence with other such initiatives which have a broad professional consensus and can be dusted off and re-badged as necessary to tempt politicians to move the goal posts a little closer to what is required to optimize child health? Lets see how far we have got in another 5 years.
Is Bexsero® (MenB vaccine) effective in preventing invasive meningococcal disease? Experience of a tertiary hospital in the UK. Novel meningococcus serogroup B vaccine (Bexsero®) was introduced in UK national immunisation programme on 1 September 2015. All babies born from July 2015 were offered the vaccine alongside other routine immunisations and all babies born in May 2015 were offered Bexsero® as a one-off catch-up. Bexsero® is estimated to protect against 73–88% of MenB strains causing invasive meningococcal disease (IMD) in England and Wales1,2. Among the diseases preventable by immunisation, IMD remains a high public profile illness deserving the most rigorous consideration because of its rapid and severe onset, high mortality rate and burden of sequelae. Epidemiological data suggest that infants in the first year of life experience the highest risk of infection peaking at around 5 months and declining thereafter. We continue to observe IMD in the first year of life despite the introduction of Bexsero® in our national immunisation programme (Table 1). This retrospective data was obtained as part of service evaluation at Central Manchester University Hospital Foundation Trust from our microbiology department. We are one of the biggest integrated Children's hospitals in the UK providing a wide range of services for the North West region and have over 220,000 patient visits each year. The epidemiological year starts from July to June, rath...
Is Bexsero® (MenB vaccine) effective in preventing invasive meningococcal disease? Experience of a tertiary hospital in the UK. Novel meningococcus serogroup B vaccine (Bexsero®) was introduced in UK national immunisation programme on 1 September 2015. All babies born from July 2015 were offered the vaccine alongside other routine immunisations and all babies born in May 2015 were offered Bexsero® as a one-off catch-up. Bexsero® is estimated to protect against 73–88% of MenB strains causing invasive meningococcal disease (IMD) in England and Wales1,2. Among the diseases preventable by immunisation, IMD remains a high public profile illness deserving the most rigorous consideration because of its rapid and severe onset, high mortality rate and burden of sequelae. Epidemiological data suggest that infants in the first year of life experience the highest risk of infection peaking at around 5 months and declining thereafter. We continue to observe IMD in the first year of life despite the introduction of Bexsero® in our national immunisation programme (Table 1). This retrospective data was obtained as part of service evaluation at Central Manchester University Hospital Foundation Trust from our microbiology department. We are one of the biggest integrated Children's hospitals in the UK providing a wide range of services for the North West region and have over 220,000 patient visits each year. The epidemiological year starts from July to June, rather than January to December. Most forms of IMD, like many infectious diseases, display seasonal variation and reach a peak during the winter. Looking at epidemiological years means that every winter peak always falls within one year rather than being divided between two consecutive calendar years. ‘Unvaccinated’ cases (Table 1) had all routine vaccinations apart from Bexsero® (before September 2015). The ‘Vaccinated’ group includes those who ‘supposedly’ received Bexsero® (after September 2015). The assumption was made that all patients born from July 2015, received Bexsero®; their vaccination records were not checked. There are uncertainties about how effective it will be in protecting against invasive meningococcal disease3. Good active population-based sentinel surveillance would allow gathering important information also about the capability of the new vaccine to disrupt carrier chain and reach herd immunity.
REFERENCES
1.Frosi G, et al., Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage. Vaccine, 2013.
2.Vogel, U., et al., Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment. Lancet Infect Dis, 2013. 13(5): p. 416-25.
3.Andrews SM, Pollard AJ. A vaccine against serogroup B Neisseria meningitidis: dealing with uncertainty. The Lancet infectious diseases. 2014;14(5): 426–34. doi: 10.1016/S1473-3099(13)70341-4 [PubMed]
The title of the paper and the majority of the introduction imply that the study is about adolescents with CFS/ME. However, the final sentence of the introduction undermines that objective: “As children in our study were not examined by a physician, we have used the term ‘chronic disabling fatigue’ (CDF) rather than CFS/ME to indicate chronic fatigue that is disabling.”
Those children may have had a variety of different diseases that cause prolonged fatigue, yet we are led to believe that a study of their collective conditions can somehow add to the body of literature on a specific disease process. CFS/ME is a highly contentious disease with a great deal of conflicting evidence and hypotheses; answers as to its exact nature and cause are as yet to be determined. By publishing a study of patients who are so poorly defined as to be undefined, Archives of Disease in Childhood has further muddied already murky waters. The addition of this study to the body of literature is not only unhelpful, but is actively detrimental to the pursuit of answers for patients with this highly disabling disease.
How are ADC or the authors able to justify publishing a study that to all appearances is about CFS/ME, yet fails to properly assess if any of the study participants actually have CFS/ME?
We would like to thank the authors of the Pavone paper for their interest in our paper (1,2). We are sorry for not quoting their paper in our study report but do confirm that we were aware of it (2). In our introduction we selected several papers to quote in order to introduce the uncertainty with respect to the need to record 1, 2 or 3 nights of overnight oximetry and the Pavone paper was not one we selected. The Pavone paper claims excellent night to night consistency in oximetry and that only one night of oximetry measurement is necessary while our study did not find this to be the case (2).
While we agree that the Pavone study used a pulsed oximeter with some superior properties (Radical Masimo) compared to that which we used (Nonin 9600) we do not believe that this is one of the most important reasons why our results differ from the Pavone study.
We believe the main reasons for differences between the two papers include;
1] Different primary aims - our study was aimed to determine whether doing 2 or 3 nights oximetry would increase the chances of getting adequate traces to make a report. We therefore included all studies (whether satisfactory or not). In the Pavone study only those with 2 nights each with > 6 hours satisfactory tracing were included and about one third of the children initially identified were therefore excluded. We do not know what then happened to these children – i.e. whether further studies had to be rescheduled. Clearly selec...
We would like to thank the authors of the Pavone paper for their interest in our paper (1,2). We are sorry for not quoting their paper in our study report but do confirm that we were aware of it (2). In our introduction we selected several papers to quote in order to introduce the uncertainty with respect to the need to record 1, 2 or 3 nights of overnight oximetry and the Pavone paper was not one we selected. The Pavone paper claims excellent night to night consistency in oximetry and that only one night of oximetry measurement is necessary while our study did not find this to be the case (2).
While we agree that the Pavone study used a pulsed oximeter with some superior properties (Radical Masimo) compared to that which we used (Nonin 9600) we do not believe that this is one of the most important reasons why our results differ from the Pavone study.
We believe the main reasons for differences between the two papers include;
1] Different primary aims - our study was aimed to determine whether doing 2 or 3 nights oximetry would increase the chances of getting adequate traces to make a report. We therefore included all studies (whether satisfactory or not). In the Pavone study only those with 2 nights each with > 6 hours satisfactory tracing were included and about one third of the children initially identified were therefore excluded. We do not know what then happened to these children – i.e. whether further studies had to be rescheduled. Clearly selecting only those with ‘good’ adequate tracings could improve repeatability. However, as stated in our paper, we did not find this to be the case when we analysed the repeatability for those with 3 adequate nights recording.
2] Pavone in their study excluded children with complex conditions (ie children with neuromuscular, complex or genetic conditions were not included). In our study this group represented close to 50% of those studied (Down Syndrome, Neuromuscular disorders and craniofacial structural problems, neurological disorders). We were especially worried about differential repeatability in children with Down Syndrome when compared with neuromuscular disorders. It is thus quite possible that better correlation will be noted in a specific group of otherwise normal children who also have performed well and allowed 2 nights of ‘good’ recordings to be made.
3] A 3rd and very important difference between our paper and that off Pavone relates to the method of statistical analysis for the continuous variables. We were particularly interested in determining the agreement between measures addressing the question whether one night could be replaced by the value of the second night and what the repeatability was. We used Bland & Altman 95% limits of agreement with plots and the intraclass correlation. In the Pavone paper only Pearson and Spearman correlation coefficients are quoted for relating night 1 with night 2 continuous variables and thus we were unable to estimate how good the agreement between these measures actually was. Bland & Altman have previous shown that two measurements of the same quantity (as occurs in repeated measures) are highly likely to closely correlate and especially so if a wide range of values are included (3). It is now well known that while repeated measures variables may correlate well they often do not agree to the extent that one value could be used to replace another (3). Eye balling the scatter plots (with regression lines) in the Pavone paper would not suggest that agreement was necessarily good. However, this is impossible to determine without seeing the Bland & Altman plots (with 95% limits of agreement) or the scattergrams (night 1 versus night 2) with the line of identity included rather than the regression line.
4] Pavone compared agreement between the two nights McGill Score (MOS) which is used to quantify the severity of Obstructive Sleep Apnoea (OSA). We did not use this as a significant proportion of our children especially those with neuromuscular disease were being studied for sleep disordered breathing with potential hypoventilation rather than detecting OSA. It would not have been appropriate to use the MOS score in this situation.
Unfortunately, for these reasons, we do not find that the Pavone paper provided reassurance that a single nights oximetry is adequate when screening children for the variety of sleep disordered breathing problems that we studied.
Finally, while the mean duration of overnight oximetry in our study was 8.4 hours (8.3 hours in the Pavone study) we included > 4 hours of technically satisfactory trace as adequate as our lower limit of acceptability. We agree that this may differ from the ATS recommendations but we think this is an important point for further discussion – and ask the question: Should we be discarding traces that are of good quality but only of 5.5 hours, 5 hours or even 4 hours duration in this group of children? We do not have the answer as to what is the minimum duration of good quality trace that should be regarded as useable. Instead of using a rather arbitrary value of > 6 hours our team considered that 3 hours was too short but that 5 hours was likely adequate and as a group agreed that if the trace was > 4 hours we would like and want it to be reported. It would be interesting and important to determine whether reporting studies of > 4 hours duration would accurately increase the diagnostic pick up in children who present with possible OSA.
References
1. Night-to-night consistency of at-home nocturnal pulse oximetry testing for obstructive sleep apnea in children. Pavone M, Cutrera R, Verrillo E, Salerno T, Soldini S, Brouillette RT. Pediatr Pulmonol. 2013 Aug;48(8):754-60
2. Night-to-night variation of pulse oximetry in children with sleep-disordered breathing.
Burke RM, Maxwell B, Hunter C, Graham D, O'Donoghue D, Shields MD. Arch Dis Child. 2016 Dec;101(12):1095-1099
3. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307–10
I agree with Dr. Goldwater that an undetected prodromal respiratory infection can suddenly fulminate and cause acute anoxic encephalopathy. In such an instance, there may not be time for visible pulmonary histological pathology to form. Then if a lung culture is not performed or gives sepsis-negative results, the cause may be coded as SIDS rather than an ARI. See Farber S. Fulminating streptococcus infections in infancy as a cause of sudden death. N Engl J Med 211:154-158, 1934 and Mage et al. .Front Neurol. 2016 Aug 23;7:129. doi: 10.3389/fneur.2016.00129. eCollection 2016. PubMed ID 27602017
We thank Professor Wright for her comments, and we welcome the opportunity to provide some clarification and further analysis.
We reported Z-scores rather than percentiles, although some comments on approximate percentiles can be made. Assuming that Z scores of -1.96 and -3 represent approximately the 2.5th and 0.2nd centiles respectively, 36/101 children were below the 2.5th centile, and 17/101 were below the 0.2nd centile for weight. Additionally, our mixed effects model (accounting for multiple measurements) modelling the group trend over time estimated the mean weight Z score at 11 years to be -1.63 (approximately 5th centile).
Despite the overall short stature of the group, 24/101 children had a BMI Z score of less than -1.96. So, by this approach, their weight was low even after taking into account stature. We agree that we cannot infer causality from this observational study, but we believe a proportion of the stunted growth is explained by low weight. We are exploring other measures of malnutrition, such as skin-fold thickness.
Whilst our patient numbers are small, they do give some weight to the argument that PEG feeding halts the progression of malnutrition. We investigated the rate of decline of weight after PEG insertion. In a mixed effects model with a random intercept for individual patients, the rate of wei...
We thank Professor Wright for her comments, and we welcome the opportunity to provide some clarification and further analysis.
We reported Z-scores rather than percentiles, although some comments on approximate percentiles can be made. Assuming that Z scores of -1.96 and -3 represent approximately the 2.5th and 0.2nd centiles respectively, 36/101 children were below the 2.5th centile, and 17/101 were below the 0.2nd centile for weight. Additionally, our mixed effects model (accounting for multiple measurements) modelling the group trend over time estimated the mean weight Z score at 11 years to be -1.63 (approximately 5th centile).
Despite the overall short stature of the group, 24/101 children had a BMI Z score of less than -1.96. So, by this approach, their weight was low even after taking into account stature. We agree that we cannot infer causality from this observational study, but we believe a proportion of the stunted growth is explained by low weight. We are exploring other measures of malnutrition, such as skin-fold thickness.
Whilst our patient numbers are small, they do give some weight to the argument that PEG feeding halts the progression of malnutrition. We investigated the rate of decline of weight after PEG insertion. In a mixed effects model with a random intercept for individual patients, the rate of weight Z score decline was 0.01 units per year, in contrast with 0.1 per year in the un-operated population, although low numbers prevent a meaningful statistical comparison. Given the ultra-rare nature of the disease, a randomised trial is effectively impossible and probably anyway unethical.
The multifactorial aetiology of wasting is unique in A-T. The disease compromises varying components of chronic inflammation, poor feeding ability, and increased calorie consumption due to dystonic and athetoid movements. The prognosis in A-T is truly appalling, and therefore we aim for the best possible quality of life. As well as showing that PEG feeding halts the progression of malnutrition (albeit in small numbers of children as compared to controls) and making feeding safer in the presence of possible aspiration, one consistent theme (not reported in our paper but consistently reported by parents in our clinic and previously published by other groups(1)) is significant caregiver satisfaction and reduction in very lengthy meals times. This has a very significant impact in improving the quality of life of carers and patients.
It is well recognised in other chronic paediatric diseases, such as cystic fibrosis and chronic kidney disease that nutrition is a predictor of overall quality of life. Currently, we have very little to offer patients with A-T in terms of intervention to prevent the development of malignancy or neurological progression, but we believe by extrapolating from other similar patient groups, we can reduce the risk of death from pulmonary failure. Key to this is prevention of wasting.
All long term invasive medical technologies interfere with the human condition of childhood, and we wholeheartedly agree that a PEG is life-changing and should always be carefully considered on an individual basis. However, given the poor weight gain in many A-T children, we believe it is important to discuss whether a PEG would be useful early, and consider placement prior to the respiratory deterioration of the child.
Yours sincerely
Emma Stewart1, Andrew P Prayle2, Alison Tooke1, Sara Pasalodos3, Mohnish Suri3, Andy Bush4,5,6, Jayesh M Bhatt1
Author affiliations:
1 Nottingham Children's Hospital, National Paediatric Ataxia Telangiectasia Clinic, QMC, Nottingham, UK
2 University of Nottingham, School of Clinical Science, Queens Medical Centre, Child Health, Nottingham, UK
3 Nottingham Clinical Genetics Service, National Paediatric Ataxia Telangiectasia Clinic, Clinical Genetics Service, City Hospital Campus, Nottingham, UK
4 Imperial College, London, UK
5 National Heart and Lung Institute, London, UK
6 Royal Brompton & Harefield NHS Foundation Trust, London, UK
1. Lefton-Greif MA, Crawford TO, McGrath-Morrow S, Carson KA, Lederman HM. Safety and caregiver satisfaction with gastrostomy in patients with Ataxia Telangiectasia. Orphanet J Rare Dis. 2011;6:23.
Nainani V, Gulal U, Buttery J, Snape MD
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As authors of a recent article demonstrating an increase in Accident and Emergency presentations for acute vaccine reactions following the introduction of the group B meningococcal vaccine (4CMenB) into the UK infant immunisation schedule in 2015 (1), we welcome correspondence from Mukherjee et al emphasising the ongoing risk of invasive meningococcal disease (IMD) in this country.
These data give a local perspective to the national Public Health England surveillance data demonstrating a 50% reduction in group B meningococcal disease following introduction of the 4CMenB vaccine (2). Despite immunisation with 4CMenB being 82.9% effective against group B invasive meningococcal disease in infants, there were still 56 cases in England in the year to March 2017 in under 1 year olds, and a further 119 cases in 1 to 4 year olds (an age group that currently includes both immunised and unimmunised cohorts) (2) (3). In the context of the epidemiology of meningococcal disease in the UK, the benefits of immunisation with 4CMenB to infants clearly outweigh any risks of a transient febrile reaction. The current 4CMenB immunisation campaign is not expected to induce herd immunity, therefore invasive meningococcal bacteria will continue to circulate in the community and unimmunised infants remain at increased risk of invasive meningococcal disease compared to their immunised peers. Parents and clinicians need t...
Show MoreDr. Goldwater's review once again reflects a suberb understanding of SIDS and related phenomena. He consistently presents information to his readers in a most interesting and objectively accurate and well-written set of steps, which are typically precise, factual, and to the point. For example, he ends the review by observing as follows:
Show More" If multiple causes were involved, then it would be reasonable to expect a variety of pathological findings. This demonstrably is not the case. There is a fixed pattern to the vast majority of cases. The crux of the argument against broad polycausality of SIDS is the consistent pathological picture (usually in more than 90% of cases) "
" In moving forward, SIDS researchers should be asking the following questions: (1) Does my hypothesis take into account the key pathological findings in SIDS? (2) Is my hypothesis congruent with the key epidemiological risk factors? (3) Does the hypothesis link questions (1) and (2) This review has shown that infection meets these questions appropriately and researchers in this area deserve acknowledgement and funding support. There remain gaps in our knowledge with regard to the infection model, but it is clear that other lines of research are not making the grade ...."
Note that while Dr. Goldwater has provided a formidable case on behalf of supporting and funding infection related SIDS research, and also given that there unquestionably is a relationshi...
We thank Dr Neefjes for engaging so thoroughly with our research, which focuses on an important area of care that has a significant impact on parents, children and clinicians. We readily agree that early discussions about end-of-life care might be beneficial in giving parents more time to explore treatment options. Further research could explore whether earlier discussions would be acceptable and of benefit. In our research we found, unsurprisingly, that parents want the best for their children and that clinicians want to do the best for their patients. Reducing the chance for relationships to become ‘adversarial’ is in our view a good aim where possible. It is true that, if parents feel that they are no longer able to defend the best interests of their children, this loss of empowerment may precipitate conflict. However, it was apparent in our research that parents with whom we spoke did not think of their rights of consent in absolute terms. Instead they thought that their rights to consent were complex and not necessarily absolute in that they sometimes amounted to the power to agree to– or disagree with –a narrow range of options (including, in some cases, in relation to decisions to withdraw or withhold treatment). This is not to say that all other parents share this opinion (we lack evidence for such a general empirical claim), but more that the nuance in the way that these parents perceived consent may distinguish parental consent from consent in other populations....
Show MoreIn his recent review “Infection: the neglected paradigm in SIDS research” Goldwater (2017) demonstrated that the infection model is the key pathological finding and the key epidemiological risk factor in SIDS. He reasoned that future research regarding the process how the microbiome shapes the immune system in infancy, will close remaining gaps in the knowledge about these tragic events. The well-known and worldwide similar distribution of age of SIDS-death with a clear peak between the 2nd and 4th month (AAP 2005, 2016) likewise supports this infection hypothesis. In this time slot the battle between microbial colonizing of the dermal and the mucosal tissue, including pathogens as well as microbiome building bacteria (Gensollen 2016) and the proceeding of the infant’s immature to a mature immune system (Basha 2014, Elahi 2013), potentially complicated by viral infections, opens a wide window for an immunological burst. In the neonate with little immunological memory the innate and adaptive immune system (immune cells, cytokines, antibodies, etc.) starts to mature rapidly in the first three months of his life (Basha 2014). Additionally CD71+ erythroid cells, which are enriched in the newborn period and which have actively immunosuppressive and immunomodulatory properties, vanish during the first months, leaving the infant exceedingly susceptible to infections (Elahi 2014).
Show MoreAt the same time the passive protection by transplacentally transferred maternal antibodies, w...
Lemer has very usefully carried out a 5 year review of policy implementation. Policy is only as good as the receivers at the other end and these change frequently along with an ever changing political and economic landscape.Thus the exercise is valuable in not only taking stock but also reminding those in power of an independent review process with recommendations which should transcend governments. Sadly , the focus on funding education of the workforce (recommendations 10-12) do not appear to have been a priority and without this foundation, we will not move ahead sufficiently fast with a child and family friendly service. The Children and Young Persons Outcomes Framework is similarly the result of much work in a previous government and must not be allowed to whither on the vine. Perhaps we should regularly remind policy makers in the current administration of the value of persistence with other such initiatives which have a broad professional consensus and can be dusted off and re-badged as necessary to tempt politicians to move the goal posts a little closer to what is required to optimize child health? Lets see how far we have got in another 5 years.
Is Bexsero® (MenB vaccine) effective in preventing invasive meningococcal disease? Experience of a tertiary hospital in the UK. Novel meningococcus serogroup B vaccine (Bexsero®) was introduced in UK national immunisation programme on 1 September 2015. All babies born from July 2015 were offered the vaccine alongside other routine immunisations and all babies born in May 2015 were offered Bexsero® as a one-off catch-up. Bexsero® is estimated to protect against 73–88% of MenB strains causing invasive meningococcal disease (IMD) in England and Wales1,2. Among the diseases preventable by immunisation, IMD remains a high public profile illness deserving the most rigorous consideration because of its rapid and severe onset, high mortality rate and burden of sequelae. Epidemiological data suggest that infants in the first year of life experience the highest risk of infection peaking at around 5 months and declining thereafter. We continue to observe IMD in the first year of life despite the introduction of Bexsero® in our national immunisation programme (Table 1). This retrospective data was obtained as part of service evaluation at Central Manchester University Hospital Foundation Trust from our microbiology department. We are one of the biggest integrated Children's hospitals in the UK providing a wide range of services for the North West region and have over 220,000 patient visits each year. The epidemiological year starts from July to June, rath...
Show MoreThe title of the paper and the majority of the introduction imply that the study is about adolescents with CFS/ME. However, the final sentence of the introduction undermines that objective: “As children in our study were not examined by a physician, we have used the term ‘chronic disabling fatigue’ (CDF) rather than CFS/ME to indicate chronic fatigue that is disabling.”
Those children may have had a variety of different diseases that cause prolonged fatigue, yet we are led to believe that a study of their collective conditions can somehow add to the body of literature on a specific disease process. CFS/ME is a highly contentious disease with a great deal of conflicting evidence and hypotheses; answers as to its exact nature and cause are as yet to be determined. By publishing a study of patients who are so poorly defined as to be undefined, Archives of Disease in Childhood has further muddied already murky waters. The addition of this study to the body of literature is not only unhelpful, but is actively detrimental to the pursuit of answers for patients with this highly disabling disease.
How are ADC or the authors able to justify publishing a study that to all appearances is about CFS/ME, yet fails to properly assess if any of the study participants actually have CFS/ME?
We would like to thank the authors of the Pavone paper for their interest in our paper (1,2). We are sorry for not quoting their paper in our study report but do confirm that we were aware of it (2). In our introduction we selected several papers to quote in order to introduce the uncertainty with respect to the need to record 1, 2 or 3 nights of overnight oximetry and the Pavone paper was not one we selected. The Pavone paper claims excellent night to night consistency in oximetry and that only one night of oximetry measurement is necessary while our study did not find this to be the case (2).
Show MoreWhile we agree that the Pavone study used a pulsed oximeter with some superior properties (Radical Masimo) compared to that which we used (Nonin 9600) we do not believe that this is one of the most important reasons why our results differ from the Pavone study.
We believe the main reasons for differences between the two papers include;
1] Different primary aims - our study was aimed to determine whether doing 2 or 3 nights oximetry would increase the chances of getting adequate traces to make a report. We therefore included all studies (whether satisfactory or not). In the Pavone study only those with 2 nights each with > 6 hours satisfactory tracing were included and about one third of the children initially identified were therefore excluded. We do not know what then happened to these children – i.e. whether further studies had to be rescheduled. Clearly selec...
I agree with Dr. Goldwater that an undetected prodromal respiratory infection can suddenly fulminate and cause acute anoxic encephalopathy. In such an instance, there may not be time for visible pulmonary histological pathology to form. Then if a lung culture is not performed or gives sepsis-negative results, the cause may be coded as SIDS rather than an ARI. See Farber S. Fulminating streptococcus infections in infancy as a cause of sudden death. N Engl J Med 211:154-158, 1934 and Mage et al. .Front Neurol. 2016 Aug 23;7:129. doi: 10.3389/fneur.2016.00129. eCollection 2016. PubMed ID 27602017
Dear Editor,
We thank Professor Wright for her comments, and we welcome the opportunity to provide some clarification and further analysis.
We reported Z-scores rather than percentiles, although some comments on approximate percentiles can be made. Assuming that Z scores of -1.96 and -3 represent approximately the 2.5th and 0.2nd centiles respectively, 36/101 children were below the 2.5th centile, and 17/101 were below the 0.2nd centile for weight. Additionally, our mixed effects model (accounting for multiple measurements) modelling the group trend over time estimated the mean weight Z score at 11 years to be -1.63 (approximately 5th centile).
Despite the overall short stature of the group, 24/101 children had a BMI Z score of less than -1.96. So, by this approach, their weight was low even after taking into account stature. We agree that we cannot infer causality from this observational study, but we believe a proportion of the stunted growth is explained by low weight. We are exploring other measures of malnutrition, such as skin-fold thickness.
Whilst our patient numbers are small, they do give some weight to the argument that PEG feeding halts the progression of malnutrition. We investigated the rate of decline of weight after PEG insertion. In a mixed effects model with a random intercept for individual patients, the rate of wei...
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