The above question has been asked as a follow up to a number of research findings. For example, it is known that NEC is one of the main causes of severe neonatal thrombocytopaenia, and while there is little correlation between severity of thrombocytopaenia and major bleeding episodes, neonates with NEC-related thrombocytopaenia have twice the number of bleeding episodes than those with non-NEC thrombocytopaenia. In the UK a prospective observational study showed that NEC and gestational age were the strongest predictors of an increased number of bleeding events.  Based on these results many neonates with NEC-related thrombocytopaenia are treated with platelet transfusions in an attempt to diminish the occurrence or severity of bleeding. Paradoxically it has also been shown that the number of platelet transfusions in neonates with NEC correlates with morbidity such as short bowel syndrome, which led investigators to question whether platelet-derived bioactive substances might actually be playing a role. In a recent publication from the Boston Children’s Hospital, researchers took the latter question further by studying leuko-reduced apheresis-derived platelets for transfusion. Their particular interests were in the relationship between frequency of transfusions to neonates with NEC, and also in the relationship between platelet storage time and levels of cytokines PF4 (Platelet Factor 4) and Neuropeptide Y (NPY) in the supernatant. The latter in particular is a potent vasoconstrictor and is responsible for regional splanchnic vasoconstriction during stress. It is synthesized in megakaryocytes and stored in platelets, with increased levels found under various stress conditions. Other actions include enhancement of neutrophil adhesion to endothelial cells, histamine release from mast cells, macrophage adhesion and superoxide production. The NPY and PF4 studies were laboratory-based, while for the clinical element the researchers performed a secondary analysis of a cohort study that investigated transfusion-related transmission of cytomegalovirus. Inclusion criteria were essentially birthweight of ≤1500g and postnatal age of <5days. Illness severity was assessed by means of the SNAP-II score. Forty-four of 598 neonates developed NEC (≥Bell Stage 2). Mean birthweight was 820g and mean gestational age 26.6 weeks.  The platelet transfusion rate (transfusions/time) among NEC infants who died was significantly higher than that of infants with NEC who survived (30.3% vs. 6.0%: p=0.006). Multivariate analysis that adjusted for severity of illness at NEC onset also showed a relationship between mortality and transfusion rate.  The researchers also showed significant increases in both NPY and PF4 over the first few days of storage. These results are not considered to be conclusive but certainly draw attention to the question of whether platelet transfusions are benign in the setting of NEC, and in particular to the ‘age’ of platelets that are being transfused. The authors also cite a study (Platelets for Neonatal Transfusion – Study 2) which showed that neonates transfused at a higher level of circulating platelets had a significantly higher risk of death or major bleeding than those transfused at a lower threshold. As such they recommend that if platelets are to be transfused to neonates with NEC the threshold for transfusion should be 25x10⁹/l.

Read more:

Transfusion 2018; doi:10.1111/trf.15112

New Engl J Med 2018; doi:10.1056/NEJMoa1807320

J Perinatol 2005;25:173-7

The general figure for incidence of profound sensorineural hearing loss (SNHL) is given as 1/1000 live births per year, a figure that is said to be increasing as a result of preterm birth, hypoxic injury and intrauterine infections. Where affordable, cochlear implantation (CI) is increasingly regarded as the standard of care and primary treatment for profound SNHL, globally aiding >100 000 patients per year.  Furthermore, once profound bilateral SNHL has been diagnosed, it is highly recommended that CI is performed before the verbal learning phase. Preoperative MRI is regarded as a routinely-performed investigation to evaluate the status of the inner ear and cochlear nerve, but is also done to screen for any associated CNS disorder. In this regard some 20% of paediatric CI candidates are incidentally detected to have a CNS abnormality, and within the latter group approximately 70% have white matter lesions (WML).  The few studies to date that have attempted to relate CI outcome to presence, absence and/or severity of WML have yielded varying results, ranging from adverse effects of WML to no effects whatsoever after CI and auditory and speech rehabilitation. To gain further insight into the issue, Chinese researchers from Guangzhou performed an elegant study on 35 CI patients with WML and 35 without, evaluating MRIs, auditory and speech performance, auditory event-related potentials, topographic maps and electroencephalographic source imaging. Children with a history of SNHL due to medication, trauma, otitis etc were excluded. Mean age at CI was 2yrs11mths. White matter lesions were graded as mild, moderate or severe according to the Scheltens scale. All children were assessed 6, 12 and 24 months after CI. Results showed that in general the WML group showed signs of short-term auditory and speech problems. Auditory performance improved after at least 12 months of rehabilitation to the level of the group without WML, but speech performance still fell behind that of controls, suggesting that speech rehabilitation speed was not synchronized with auditory recovery.  After stratification according to severity of WML it was clear that the severe WML subjects were affected to a greater extent than the others, while mild WML results were closer to those of subjects without WML. An interesting finding from the EEG source imaging was that post-CI in the normal and non-WML groups the active auditory area was located in the supratemporal lobe, whereas in those with moderate or severe WML the activated area post CI was located in a non-dominant zone close to the auditory area e.g. the inferior frontal or inferior temporal lobe. These results speak to functional plasticity and/or migration post-CI.   The authors conclude from the full range of results that auditory performance relies on perceptual processing after sound inputs, while speech performance was more widely related to signal analysis, information integration and feedback on the basis of intact processing systems and neural networks. No doubt additional studies and longer follow-up are required, but importantly the researchers allude to more rehabilitation being required in those with WML, rather than simply stating that WML is a contraindication to CI.

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Develop Med Child Neurol 2018; doi:10.1111/dccn.14128

Int J Pediatr Otorhinolaryngol 2011; 75: 925-30

Hear Res 2008; 238: 110-7

Most doctors working in emergency rooms/casualty departments and neonatal units who assess febrile neonates and infants of a few weeks of age would likely agree that a ‘septic work-up’ is very common in order to exclude significant underlying infection. Also common is the low rate of positive results, and related to that is the high rate of admission of such infants for treatment. Several scoring systems have been devised over the years to guide clinicians, one being the Rochester Criteria which were developed two decades ago and were recently studied in 8 high-ranking children’s hospitals in the USA. The potential value of a predictive scoring system is illustrated by the numbers provided by the authors: only 85 of 5011 infants aged ≤60 days who underwent blood culture testing in the 8 emergency departments during the 2-year study period had culture-positive bacteraemia, and only 10 of 3381 infants who had lumbar punctures had culture-positive bacterial meningitis. While invasive bacterial infections are far less common than urinary tract infections in febrile infants of this age, they are associated with high rates of morbidity and mortality. Affected infants are consequently subjected to a balancing of the risk of multiple (mostly negative) tests vs. missing an infection as a result of conservative treatment such as ‘watchful expectancy.’ The authors reviewed detailed records of 89 febrile infants of ≤60 days of age (the 85 with positive blood cultures plus 4 with positive CSF and negative blood cultures) and retrospectively applied the Rochester Criteria which predict low risk of bacterial infection if all of the following are satisfied: ≥37 weeks gestation; previously healthy and appearing to be well; no obvious source of infection on examination; peripheral white blood cell count of 5000-15000/μl; band/staff cell count of ≤1500/μl; ≤10 white cells on urine microscopy.  Among these infants the sensitivity of the Rochester Criteria was 92.7% (95%CI 84.9 – 96.6%), but if broken down for neonates of up to 28 days vs. infants of 29-60 days the sensitivities were lower for the neonates at 91.7% (CI 80.5 – 96.7%) vs. 94.1% for the older group (CI 80.9 – 98.4%). Six of the 89 were classified as low risk i.e. the criteria yielded a false-negative result. Statistically the screening test performs quite well, but clinicians may well regard this risk of non-treatment as too high. On the other hand, the case for a screening test becomes stronger if one sees this result in the context of the large number of negative tests in the ~8000 infants who were subjected to blood and CSF culture investigations. Perhaps an answer is for clinicians to add a tool such as the Rochester Criteria to their clinical assessment, prospectively assign a score as they plan and implement treatment, at a future point review the performance of the score, and if it performs well incorporate it in the management plan.

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Pediatr Emerg Care; 2019; 35: 22-7

Evid Rep Technol Assess; 2012; 1: 297

JAMA 2004; 291: 1203-12

Ultrasound has become a widely-used and appropriate non-irradiating modality for diagnosis of a range of conditions in children, adolescents and adults. Previous summaries in this series have noted the value of US in the diagnosis and/or management of undescended testes (1414), hip dysplasia (1806), osteomyelitis (1317) and dehydration (1602). The latter is an example of point-of-care ultrasound, abbreviated to POCUS which has almost become a sub-discipline and an integral part of emergency medicine practice. Its use in emergency paediatrics has been demonstrated for conditions including appendicitis, intussusception, pyloric stenosis, cardiac evaluation in the acutely ill patient and identification of skull fractures in a patient with a head injury. The modality has also been studied in the context of bronchiolitis, and recent work from Turkey has contributed to the literature. The prospective study was carried out in the emergency department of a high-volume teaching hospital in Trabzon. Acute bronchiolitis was diagnosed in 317 children during the 2-year study period of which 77 were randomly entered into the study. Mean age was 7.4 months and 42 were admitted into the hospital (1 into the ICU). Children with underlying problems such as cystic fibrosis, immune suppression, cardiac disease or bronchopulmonary dysplasia were excluded from enrolment. Two paediatricians and a skilled ultrasonographer assessed all subjects, the clinicians assessing according to parameters such as nutritional and dehydration status and the ability to feed, as well as the previously-described modified Bronchiolitis Severity Score (mBSS). The ultrasonographer assessed according to the Bronchiolitis Ultrasound Score (BUS) described by Basile et al. According to these scores patients were categorised as normal or suffering from mild, moderate or severe bronchiolitis. Need for hospitalisation was determined by one or both clinicians. The actual objective of the study was to assess the ability of the BUS to predict hospitalization. In that regard BUS performed as one of the most important predictors of admission, independent of age, gender, clinical score, poor feeding and oxygen therapy. However it appears from the study that the clinical factors contributing to the paediatricians’ assessment would likely prevail in determining admission. For example in a <1year-old nutritionally-compromised and dehydrated infant a ‘mild’ BUS score would likely be irrelevant. Nevertheless some interesting findings emerge from the study such as lung ultrasound being compatible with a clinical diagnosis of bronchiolitis in 97% of the subjects studied, whereas findings compatible with acute bronchiolitis were present on chest X-ray in only 42 of the 77 subjects. This ‘failure’ of X-rays has been observed by others, resulting in the publication of clinical guidelines stating that current evidence does not support routine radiography in children with bronchiolitis. However ‘routine radiography’ prevails in many emergency departments and therefore studies such as the one covered here may be used to promote skills development and the use of lung ultrasound as a safer and more accurate alternative for the diagnosis of acute bronchiolitis.

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Pediatr Emer Care 2018; Ozkaya AK, Yilmaz HL, Kendir OT et al

Crit Ultrasound J 2016; 8: 16.

Curr Opin Pediatr 2014; 26: 265-71

Continuing the theme of non-invasive screening and monitoring of conditions prevalent in paediatric practice, another unusual/unique modality is EBT for management of asthma. Measurement is now possible by means of a user-friendly device that is advertised online for $200 to $300. Various studies have demonstrated that in asthma EBT is related to the degree of airway inflammation. It increases in uncontrolled asthma and decreases in response to anti-inflammatory treatment, is significantly higher in patients with severe asthma compared to those with mild to moderate asthma, and it reflects changes in airway inflammation in children with virus-induced asthma exacerbations. However a number of contradictory studies refute these results, finding that there is no relationship between EBT and measures of asthma or control. Thus further studies are needed to standardize the method of EBT measurement, and to evaluate the usefulness of this biomarker in asthma diagnosis and monitoring in children. In order to understand the rationale for this modality it is useful to note that as asthma is a chronic airway inflammatory disease, assessing airway inflammation is important. Since this cannot be directly measured, non‐invasive monitoring for airway inflammation may assist in the early recognition of asthma, assessment of its severity, and patients’ response to treatment, especially during disease exacerbations. Exhaled markers of airway inflammation have become important in the management of childhood asthma e.g. exhaled nitric oxide, and albumin, C‐reactive protein, and cytokines in exhaled breath condensate have been extensively studied. Inflammation is a protective response characterized by several classic signs, one of which is heat. However it appears that to measure EBT accurately one must ensure that results are not influenced by factors such as elevated ambient temperature, recent ingestion of a meal, presence of an underlying fever or recent bout of exercise. Despite a reasonable body of literature, it appears that data are limited in terms of longitudinal changes in EBT relative to the asthma status. This has recently been addressed by researchers from Korea who studied EBT during and after an asthma attack (defined as worsening of asthma requiring either systemic corticosteroids or hospitalisation). Thirty-eight asthmatics aged between 5 and 18 years were studied, with EBT measured by means of the X-halo breath thermometer. Additional studies included spirometry (PEFR, FEV₁), methacholine challenge, fractional exhaled nitric oxide, IgE levels, viral studies and sputum for eosinophilic airway inflammation. The above were measured during hospitalisation and again at 1 week and 1 month after discharge.  The EBT was higher on admission than at 1 week after discharge, and correlated with increased PEFR over time. The extent to which these findings add to the value of EBT measurement is questionable since other measures such as peak flow are not subject to the vagaries of EBT, are as user friendly as the EBT device, and are considerably cheaper.

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Pediatr Pulmonol 2019 doi; 10.1002/ppul.24225

J Asthma 2017; 54: 699-705

J Breath Res 2017; 11: 034001

Some practitioners would argue that the restricted age span of paediatric and adolescent medicine (i.e. birth to 16-18 years) is a blessing, while others are haunted by the question of how many of their patients fared after being handed over to doctors caring for adults. In some cases e.g. management of congenital heart disease, transfer to specialised transitional clinics is an orderly process, while in others there is simply ‘referral to the adult clinic.’ Long-term management of childhood epilepsy is a case in point and many caregivers, whether nurses, general practitioners or specialists, will at some time have been confronted by parents wanting to know what will happen in the long term to their child who has been labelled as epileptic. Will s/he have seizures forever, will it be possible to drive a car, for how long will medicines be required? Providing some answers to such questions is an article from Sweden covering 195 children enrolled in a study between 1962 and 1964 and followed up for 50 years. While the study numbers are fairly small and there were some differences between sub-groups in terms of year of “seizure debut” prior to enrolment, the results are pertinent to the discussion.  Most were cared for by paediatric neurologists and were seen regularly. Epilepsy was confirmed after a second unprovoked seizure and all were evaluated by means of physical, social, neurological and psychometric examination and classification of seizure type. Overall cerebral palsy was found in 10% and intellectual disability in 12% (obviously with some overlap between the two). In a 12 year follow up 6% of the cohort had died and 64% had remission of seizures (defined as 5 years seizure free). Poor prognostic factors for remission were neuro-deficits, frequent seizures and more than one seizure type. Sixty-percent were still taking anticonvulsant drugs although only 38% were classified as having active epilepsy. After 50 years 25% of the original study group of 195 had died and data were available for 138 (94% of survivors). Only 7 deaths were before 20 years of age (most with intellectual disability and neurological abnormality) and in those who died later, several were epilepsy-related or sudden unexpected death. At older ages mortality was also related to ‘somatic conditions.’ Mean age at follow up was 61.9 years (mean age at diagnosis 6.1 years). The best long-term prognosis for seizure freedom was in children with no intellectual or neurological impairment. Generalised epilepsy (vs. focal) was associated with fewer relapses and less ongoing medication. The most-recently diagnosed of the three sub-groups had the best outcomes with 90% being seizure free. However while only 10% still had seizures, 22% of the sub-group still used anticonvulsants, mostly phenobarbital and phenytoin. The latter findings no doubt relate to the unwillingness of patients (and doctors?) to ‘risk’ a seizure by stopping the medication, particularly one that they know. No doubt drug levels would be helpful in such cases and would likely be sub-therapeutic in at least some. Overall the results demonstrate what we already know i.e. the more-complex the seizures the poorer the prognosis, but one can reassure patients that in those with generalised seizures, normal intelligence and neurological examination the prognosis is excellent.

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Epilepsia 2019;1-12

Brain 2013; 136: 3187-99

New Engl J Med 2010; 363: 2522-9

The previous summary in this series alluded to the ‘loss’ of patients by paediatric caregivers once the child or adolescent had progressed to care in adult disciplines. Other patients often lost to follow up by pediatricians are those who require paediatric surgery. While relatively uncommon in public hospital practice in South Africa, adenotonsillectomy is a common procedure in the private sector. Figures in the USA are given as >600 000 procedures per annum for children and adolescents under 15 years of age.  It is also stated that post-tonsillectomy haemorrhage (PTH) is a well-documented complication, and with a reported incidence of 1-5% it is one of the commonest sources of postoperative morbidity in children.  In a retrospective analysis of 2565 cases over a period of 5 years, researchers from Louisville, Kentucky identified 173 patients who required readmission post-operatively. The initial sample included patients aged between 2 and 12 years who were admitted for adenotonsillectomy (i.e. excluded tonsillectomy alone or in combination with other procedures).  Indications for the procedure were obstructive sleep apnoea (OSA), tonsillar hypertrophy or asymmetry and OSA-tonsillitis. Data collected included demographics, BMI, indication for the procedure, surgical technique (e.g. sharp dissection or harmonic blade), method of removal (intracapsular vs. subcapsular), pain medication, whether readmitted, and if so, reason for readmission. The overall readmission rate was 6.7% with almost one-third (53 of the 173 patients) readmitted for PTH. Predictors of readmission were reviewed in two ways i.e. those readmitted for PTH vs. other reasons for readmission, and those readmitted for PTH vs. the total group of adenotonsillectomy patients. In multivariate analysis of the former, age (between ±8 and ±13 years) and BMI z-score >2 were significant, while for the latter analysis only the BMI was significant. Others have also found overweight/obesity to be a risk factor for PTH. While factors such as longer anaesthesia and operative time for the primary procedure, as well as an increased number of perioperative complications have been reported in obese vs non-obese patients undergoing adenotonsillectomy, the reason for the PTH is not actually clear. However what appears to be clear is that the readmission rate for PTH is not insignificant at up to 5%, and one should be vigilant in the older and particularly in the obese patients.

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Int J Pediatr Otolaryngol 2019; 117: 143-7

Pediatr Surg Int 2017; 33: 1167-75

Paediatr Anaesth 2012; 22: 1171-8

Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, increasing as more children are successfully resuscitated at lower birthweight and gestational age. Worldwide it is estimated that each year 184 700 new cases of blindness are attributable to ROP.  Aetiologically ROP is considered to be multifactorial, inter alia involving oxygen supplementation, nutrition, prematurity, low birth weight, sepsis, glucose imbalance, and blood product transfusion. (Excessive) oxygen supplementation is linked to hyperoxia-induced retinovascular growth attenuation caused by diffusion of oxygen from the choriocapillaris, a highly vascularized layer of unfenestrated blood vessels beneath the retina, to peripheral areas of undeveloped retina. This leads to retinovascular growth attenuation and vaso-obliteration. This ‘hyperoxic ischemia’ creates wide expanses of subsequent hypoxic retina that induces pathologic angiogenesis in response to acute overexpression of cytokines from the avascular areas. Clinical trials have previously compared ‘static/continuous’ oxygen saturations of 85-92% to continuous exposure to 91-95%. Results summarised in a meta-analysis concluded that the lower vs higher oxygen saturations increased the risk of death and necrotizing enterocolitis by at least 3.0%, without a significant impact on disability including blindness. However  in this meta-analysis low oxygen saturations were maintained until at least 36 weeks, 2 to 4 weeks longer than in a biphasic approach previously adopted by multiple nurseries that employed saturation targets of 85-92% until either 32 or 34weeks, and then increased to >95% beyond the cutpoint.  In light of the reported increased risk of mortality at lower oxygen saturations, many/most neonatologists recommend ‘static’ and higher saturations. To assess whether such an approach is in the best interests of very low birthweight infants, researchers from Cleveland USA compared ophthalmic outcomes and mortality within the recommended static protocol (91-95%) to outcomes in neonates treated with the historical biphasic approach (85-92% at <34 weeks and > 95% beyond that gestational age). The primary outcome measure was type 1 ROP. Secondary outcomes compared infant mortality and incidence of any ROP. Inclusion criteria were infants born earlier than 31 weeks and/or weighing less than 1500 g. The data collection was done 41months prior to and 42 months after the change in institutional oxygen saturation targets. The total study sample included 562 neonates, mean birthweight 1151g and mean gestational age 29 weeks. There were 260 subjects in the earlier biphasic group and 302 in the subsequent static group. Strict oxygen targeting was maintained as much as possible, with alarms set at 1% greater than and less than the target oxygen saturation ranges. Of note is that the later group appeared to be clinically better off than the early group: more received prenatal steroids, more were resuscitated with room air, more treated with CPAP, fewer diagnosed with respiratory distress syndrome, and less PDA. Despite these apparent advantages there was decreased incidence and severity of ROP with the biphasic approach, without an increase in mortality. These results demonstrate the following: the apparent sensitivity of the developing retina to very small ‘timing’ differences, the possible risk of changes to NICU policies based on meta-analyses that might not take the full picture into account, and the need for further studies into ROP and mortality outcomes when the biphasic approach is followed.

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JAMA Ophthalmol 2019, doi:10.1001/jamaophthalmol.2018.7021

JAMA 2018; 319: 2190-2201

Pediatrics 2003; 111: 339-345

South Africa is aware of the effects of non-communicable diseases and conditions on its people and its economy. The metabolic syndrome manifesting as obesity, hypertension, diabetes and coronary artery disease features prominently, with evidence emerging that it is not only adults in middle age and beyond who are at risk.  Questions may be asked about whether the country is active enough in tackling the problem of adolescent obesity, and as such it is appropriate that we pay attention to what is happening elsewhere. Summaries 1623, 1708 and 1728 in this series address issues ranging from complications of adolescent obesity and diabetes to drastic interventions such as bariatric surgery. Adding to the literature is a recent study from Brazil in which 172 obese adolescents between 16 and 19 years of age were treated by a multidisciplinary team for 12 months. The programme was intensive, involving a monthly visit to the endocrinologist and three supervised two-hour sessions per week. The latter sessions combined physical exercise, physiotherapy, nutritional advice and psychotherapy.  Adherence to the programme was impressive with 181 volunteers being recruited and 172 completing the programme. Follow-up included 24 anthropometric (e.g. waist circumference, BMI, lean body and fat mass) and biochemical measures (e.g. visceral fat, leptin, glucose, insulin, measures of insulin resistance, lipogram and liver enzymes). Liver enzymes were of particular importance because of previous observations that the entity of non-alcoholic fatty liver disease (NAFLD) occurred in 40% of 16-19 year-old obese adolescent boys and 60% of girls. Overall the aim of the study was to study visceral adipose tissue loss resulting from the programme and seek associations with insulin resistance and levels of leptin (a potent biomarker of energy balance and inflammatory processes related to obesity, and plays a role in development of NAFLD and atherosclerosis). Visceral adipose tissue was measured by a specialist in imaging diagnostics (ultrasound) and difference assessed between baseline and 1-year later. Participants were subsequently divided into three groups based on terciles of visceral fat reduction (1^st tercile - high: >1.8cm; 2^nd – moderate: 0.79 – 1.8cm; 3^rd – low: <0.79cm).   Positive effects of the programme on body composition were observed in all three groups, although mean BMI after one year was still in the obese range. Not surprisingly, visceral fatness was directly related to insulin resistance, and the greater the loss of visceral fat over the year the greater the reduction in insulin resistance. The magnitude of visceral fat loss was also related to leptin levels. While the high group showed changes in 20 of the 24 measured variables, the low group showed changes in only 9 of the 24.  However from analysis of the available results it is possible/likely that the latter group differed from the others in that subjects weighed significantly less than the others but had similar BMIs and less visceral fat at baseline. As such their ability to respond to the programme in terms of fat reduction, insulin resistance and leptin release may well have been different.

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Diabetes Vasc Dis Res 2019; doi; 10.1177/1479164118825343  

Int J Endocrinol 2013; 2013: 541032

Dig Liver Dis 2008; 40: 132-9

It is possible, maybe even likely that readers of this series of summaries will not even be aware of the existence of AIS or its contribution to physical and psychological morbidity in paediatric/adolescent practice. Once again it is an example of pathology that often escapes the notice of paediatricians because if/when the problem is identified it is referred to the likes of physiotherapists and/or orthopaedic surgeons.  Worldwide incidence of AIS is given 0.5 to ~5% of girls aged between 10 and 16-17 years, and it is recommended that countries should be aware of overall rate and possible differences between ethnic and other groups. For example a 2006 Masters dissertation from the University of Johannesburg identified a risk of around 2%, with coloured girls being at greater risk than other groups. Potentially this means that in a girls-only school with 2 or 3 classes covering grades 8-12 (i.e. 10-15 classes overall) and 20-30 girls in each class i.e. 200-450 girls overall, more than 20 girls would be found to have various degrees of AIS. This statistic makes a strong case for routine examination of girls at secondary school level, specifically including examination of the spine. A recent article from Nanjing, China gives some insight into the magnitude of the problem and one of the dilemmas facing caregivers, viz. whether to proceed to early corrective surgery vs. proceeding with a trial of conservative bracing. The study focused specifically on patients with high degrees of scoliosis i.e. >40^o. Some 3283 patients (boys and girls) diagnosed with AIS between 2005 and 2016 and for whom brace treatment was prescribed were reviewed. This figure equates to around 200 eligible for bracing each year, or 4 per week at a single centre, and would exclude girls diagnosed with milder degrees of AIS who are subjected to observation only. Within the group of 3283 a subset of 90 was analysed. Included were those with an initial curve of 40-50^o, skeletal maturity according to Risser staging (which is based on ossification and fusion of the iliac apophysis), no treatment prior to diagnosis, >90% compliance with the bracing protocol, and a minimum of 1-year follow up. Data collected on all included age, gender, menarche, BMI, curve pattern (i.e. major thoracic or other), initial curve correction/curve progression and skeletal maturity. Endpoint for bracing was achievement of skeletal maturity with curve well controlled, or curve progression beyond 50^o and surgery recommended. At final follow up the curve was considered to have progressed if magnitude was >5^o vs. baseline, improved if <5 and stable if within 5^o.  The study group included 14 boys and 76 girls, in keeping with usual rates for the genders.  Even within this high-risk group there was a response to bracing in 37.8%, while 13.3% were stable. However 48.9% progressed significantly beyond 50^o and became eligible for surgery. Intergroup comparison showed those who progressed were younger, showed less in the way of initial correction, and had predominantly a thoracic pattern. Logistic regression showed that lower initial correction (<10%) and lower skeletal maturity according to the Risser stage were at greater risk of progression. Essentially this is saying that if a younger, less mature patient has a high degree of curvature and responds poorly to bracing than s/he is likely to continue to ‘curve’ as s/he goes into puberty. The message is also that one should not continue to subject such patients to futile bracing, which itself is often/usually a traumatic and potentially isolating event for an adolescent. Various braces are in use around the world, some flexible and others rigid, and while the flexible may be more appealing, less obtrusive and more likely to be accepted by patients, the data are not conclusive as to whether results are different.

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World Neurosurg 2019; doi:10.1016/j.wneu.2019.03.008

J Back Musculoskelet Rehabil 2019;32: 101-9

Masters dissertation: https://core.ac.uk/download/pdf/54186429.pdf

Big data is one of the buzzwords of the 21^st century. Social media platforms are in the spotlight for using and abusing client data, while at the other extreme researchers clamour for large scale ethically-collected data, ideally from multicentre and multinational collaborations. On occasions where our researchers are active in a particular field and are members of a formal multinational collaboration, it is not unusual to find that the country contributes significantly to the dataset. One such example is the African Surgical Outcomes Study (ASOS) which recently published results of a 7-day prospective observational cohort study into maternal and neonatal outcomes after caesarean delivery, which is one of the Bellweather procedures of the Lancet Commission on Global Surgery. South African participating institutions mainly included academic departments of anaesthesiology/critical care and/or surgery, with only one university department of obstetrics and gynaecology being listed. The country provided data covering 44 of the 183 participating hospitals and around 40% of the almost 3700 patients included in the analysis. Overall 80% of the hospitals were state-funded and 13% were privately-funded; 46% were university-affiliated, and almost half were central or specialised hospitals. Given South Africa’s substantial contribution to the dataset and the latter three statistics, one might expect to see a reassuring set of results. On the contrary, the authors found that the maternal mortality after caesarean delivery in this African study was 5.43 per 1000 operations and neonatal mortality was 44/1000 births. African mothers are therefore at least 50 times more likely to die after caesarean delivery than mothers in high-income countries, and neonatal mortality is double the global average. Obstetric haemorrhage and anaesthesia complications contributed significantly to the maternal mortality. There is evidence that too few caesarean sections are done, but also that the procedure is dangerous with almost 25% of all anaesthetics being administered by non-physician anaesthesia providers. More disturbing is the authors’ statement that the results are probably an under-estimate of the magnitude of the problem. No doubt specialists in both the private and academic sectors in South Africa would take issue with the results and carefully interrogate data relating to their specific practices, but of importance here is that this research focuses on but one aspect of maternal and neonatal mortality. On a far more positive note, when looking at the overall picture of obstetric care, recent results published by associates and members of the South African Committee on Confidential Enquiries into Maternal Deaths show a 29.3% reduction in the number of maternal deaths in a before-and-after study of the effects of the skills-and-drills emergency obstetric care (EmOC) training programme, specifically introduced into 12 healthcare districts which were considered to be ‘most-in-need’ on the basis of poor health outcomes.

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Lancet Glob Health 2019; 7: e513-22

S Afr Med J; 2019; 109: 241-4

JAMA 2015; 314: 2263-70

After many years of research and public health initiatives there is little that is not known about the effects of smoking during pregnancy and beyond on the offspring. Adding to the body of knowledge is a recent article from Scotland in which almost 700 000 singletons born between 1997 and 2009 were followed up until 2012. Smoking status at maternity booking was studied in relation to pregnancy outcomes and children’s hospital admissions and death during the first 5 years of life. Twenty-three percent of mothers admitted to smoking during the pregnancy, a figure higher than other studies but could be even higher because status was recorded as unknown in 12%.  Statistical models were adjusted for maternal age, socioeconomic status, infant feeding, country of birth, sex, birth order and delivery mode. Maternal smoking significantly increased the risk of preterm birth (Odds Ratio 1.41) and being small for gestational age (OR 2.67). Smoking also increased the risk of hospital admission for acute respiratory infection (Hazard Ratio 1.29), with HRs for admission for bronchiolitis under 1 year of 1.43 and asthma at 1-5 years of 1.29. Maternal smoking increased the risk of neonatal mortality (Odds Ratio 1.32) and also post-neonatal mortality (OR 2.18). The postnatal outcomes could well have been influenced by maternal smoking beyond the pregnancy, but this was not specifically addressed. As such the results are presented as relating only to smoking during the pregnancy, which is questionable. Perhaps more important at this time is a need to focus on significant changes in smoking behaviour, specifically the advent of e-cigarettes and popularity of vaping, but also the widespread liberalisation of access to cannabis and the inclusion of cannabis in vaping products. At this time there are many proponents of both vaping and cannabis being safe for human consumption. Hopefully advocates of maternal and foetal health will continue to play a role in protecting their patients, at least until we have data on the consequences. In a literature review of 40 articles it was shown that up to 15% of pregnant women ‘vape’ but others have shown that at least double that number both vape and smoke. The amount of nicotine consumed through vaping is at least comparable to that consumed by cigarette smokers. At this stage most of the data are derived from animal studies but there is concern about effects on the foetal immune system, neural development and lung and cardiac function. Research is also being conducted into ‘secondary vaping’ of the aerosol emitted by the devices. This aerosol also contains nicotine, along with ultrafine particles at higher concentration than in cigarette smoke, and low levels of toxins that are known to be carcinogenic. Based on an animal study there is also the possibility of teratogenicity with development of craniofacial defects.

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BMJ Open 2019; 9: e023213

Obstetr Gynecol Surv 2018; 73: 544-8

Tob Control 2014; 23: 133-9.

On the basis of clinical observations, studies in animals and humans, systematic reviews and meta-analyses, neonatologists have considered the extent to which extremely-low-birthweight neonates with respiratory insufficiency require immediate assistance via positive airway pressure. The European Resuscitation Council guidelines recommend up to 5 inflation breaths of 2-3 seconds if a newborn is apnoeic or gasping, but the International Liaison Committee on Resuscitation concluded some years back that more data are required. Enter the SAIL trial (Sustained Aeration for Infant Lungs) which involved 18 NICUs in 9 countries in North America, Europe and Australasia between 2014 and 2017. The study evaluated the hypothesis that sustained inflations in extremely preterm infants, compared with standard intermittent positive pressure ventilation, would reduce the risk of death or BPD at 36 weeks postmenstrual age. Infants between 23+0/7 and 26+6/7 weeks were enrolled if they required positive pressure resuscitation at birth because of inadequate respiratory effort or heart rate below 100bpm. Continuous pressure of 5-7cm H₂O was applied first and if response was inadequate the infants were randomised to sustained inflation of 15 seconds at 20cm H₂O, and subsequent inflation of 15 seconds at 25cm H₂O if required (by mask or nasopharyngeal tube) vs. standard resuscitation with intermittent positive pressure ventilation and  positive end-expiratory pressure. Any further respiratory support was according to standard guidelines for intubation and subsequent extubation. The primary outcomes were death or BPD at 36 weeks corrected age, while participants were also assessed for an extensive range of secondary outcomes including surfactant administration, postnatal steroids, duration of respiratory support, pneumothorax and/or other air leaks, intraventricular haemorrhage, necrotising enterocolitis, patent ductus arteriosus, length of stay and retinopathy. The trial was completed by 426 infants (mean gestational age ~25 weeks and mean birthweight ~730g); 215 were subjected to sustained inflation and 211 had standard care. Primary outcomes of death and BPD showed no difference between the groups, and for 27 of the secondary efficacy outcomes assessed at 36 weeks corrected age only one showed a significant difference viz. rate of early death (within the first 2 days of life). The latter was not attributable to factors such as pneumothorax or IVH, and as such was not explained. The trial was stopped early as a result of the lack of benefit shown by the intervention and the increased early death rate, and the authors concluded that the use of ventilation with sustained inflations in extremely premature infants cannot be supported, although early termination of the trial limited definitive conclusions. This study highlights both the beauty and the frustration of well-designed fairly large scale multicentre studies. While the hypothesis was sound and the methodology and statistical analysis sophisticated, at the end one is left with questions rather than answers. For example were inflations with 20-25cm H₂O excessive for such tiny neonates and should they perhaps have been lower, maybe at 15-18cm H₂O and for 10 instead of 15 seconds? Do the same conclusions apply to infants born at 27 to 30 weeks? Once again the need is for more research. If nothing else the results call into question the routine application of sustained inflation for infants born at less than 30 weeks.

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JAMA 2019; 321: 1165-75

Cochrane database Syst Rev 2017; 7: CD004953

Eur J Med Res 2010; 15: 493-503

Whether assessing the significance of apnoea in adults with sleep apnoea or preterm infants with apnoea of prematurity, investigators rely on factors such as duration of the apnoea, frequency, associated hypoxaemia and changes in heart rate. A clinical study in 24-36 week infants based only on accurate recording of clinically significant cardiopulmonary events (CSCPEs) which were defined as 20 secs of no breathing or 10 secs of no breathing concurrent with either heart rate of <80/min or O₂ desaturation to below 85%, revealed that accurate recording reduced the frequency of diagnosis of apnoea of prematurity, as well as the use of caffeine and home monitoring after discharge. Measurement may be based on clinical observations combined with information derived from monitoring modalities ranging from oximetry to complex polysomnography. Recent developments combine some of the latter factors into various indices. For adult patients clinicians speak of the hypoxia burden index (HBI), which reflects the degree and duration of oxygen desaturation and may have value in predicting cardiovascular disease in the subjects. Application of the HBI to preterm infants has shown a greater burden in infants with severe intracranial haemorrhage than in those without, but it is not clear which is cause and which the effect. Researchers from New Zealand have recently published results of studies that make use of another index, the desaturation index (DSI), also making the point that ‘apnoea of prematurity’ is increasingly being referred to as intermittent hypoxia (IH) in order to describe brief episodic drops in oxygen saturation after short apnoea events. The DSI measures events per hour ≥ a defined percentage change in saturation level, with the authors focusing on the DSI 3% and DSI 4% which reflect the number of times per hour that the saturation decreased by ≥3 and ≥4% respectively, and also the DSI 4%>10s which combines the desaturation with duration. Prior research showed that these indices correlated with obstructive and central apnoea indices derived from polysomnography. The New Zealand study objective was to gain greater insight into these indices in preterm (defined as <32 weeks) and near-term (32-37 weeks) infants clinically assessed to be fit for discharge home. Using appropriate oximeters and software, 38 subjects were studied for 24 hours prior to discharge. There is no suggestion of adverse outcomes in the month following discharge but formal follow up was only reported for 9 of 12 infants born at <32 weeks. Median event rates for DSI 3% were 83/hr for preterm infants and 73/hr for the near-term; DSI 4% were 64/hr and 49/hr for the two groups, and DSI 4%>10sec 7.7/hr and 12.7/hr respectively. One month later DSI 3% was down to 41.5/hr, DSI 4% 25.5/hr and DSI 4%>10sec down to 5.2/hr. the importance here is that in infants considered to be fit for discharge there may be high numbers of 3-4% desaturation events that represent normality, possibly periodic breathing. However, recognising that the DSI 4% and DSI 4%>10sec groups would also include infants who desaturated to a greater extent, perhaps those with higher event rates should be more carefully monitored.

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Pediatr Pulmonol 2019; doi 10.1002/ppul/24276

J Perinatol 2019; 39: 48-53

J Perinatol 2017; 37: 88-90

Doctors caring for small children frequently face the dilemma of whether or not a child with a persistent or recurrent cough has asthma and if so, whether atopy is an issue.  Skin tests may assist with the latter, but in small children spirometry to measure bronchial hyper-reactivity (BHR) after a challenge with a bronchoconstrictor is difficult.  A procedure that appears to have enjoyed more popularity in the past is a bronchial challenge with AMP and measurement of the response by means of auscultation, desaturation on oximetry, and development of tachypnoea.  This challenge test is known as AMP-PCW, with the latter representing the point at which the administered concentration of AMP induces a wheeze. Bronchial hyper-responsiveness is a characteristic feature of asthma and an integral element of asthma definition.  Adenosine 5’ monophosphate is considered a trigger for smooth muscle contraction in asthmatics, mainly by indirect stimulation of IgE-dependent inflammatory mediators, and by activation of purinergic receptors expressed on mast cells and afferent nerve endings.  The AMP challenge has been shown to be more sensitive than the exercise challenge test, and more specific than the methacholine challenge for the diagnosis of asthma, and also has a high positive predictive value in terms of asthma recurrence.  In atopic subjects the AMP challenge induces wheeze, desaturation and tachypnoea at significantly lower AMP concentrations than in non-atopic patients, a difference not seen with a methacholine challenge. This confirms the superiority of the AMP test as a reflection of airway inflammation. The use of AMP-PCW surfaced recently in an article from Israel which covered 54 children aged between 2 and 8 years who had been referred to the medical centre between 2006 and 2012 for assessment of recurrent respiratory symptoms suspected to be asthmatic in origin. Thirty-five tested positive on AMP-PCW and 19 showed no response. The test involved administration of a nebulised solution of AMP via a face mask using airflow of 5l/min for 2 minutes. Concentrations of AMP were sequentially doubled from 0.39mg/ml up to 200mg/ml or until the endpoint, which was defined as one or more of the following: wheeze over trachea or chest; oxygen saturation drop of at least 5% from baseline for 30 seconds; an increase in respiratory rate of ≥50% from baseline.  Severity was graded as mild if endpoint was reached at concentration >100mg/ml, and severe at concentrations below 12.5mg/ml. Severity of BHR was positively associated with the number of severe exacerbations over the subsequent 3 years, while none of the children with a negative AMP-PCW had asthma exacerbations during the follow up. The test thus facilitates the diagnosis of asthma, is able to predict exacerbations and also aids in the tailoring of dosage of medications.               

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Pediatr Pulmonol 2019; doi 10.1002/ppul.24337

Allergy Asthma Immunol Res 2012; 4: 341-5

Pediatr Allergy Immunol 2011; 22: e101-6

Previous studies have linked CKD to low birthweight (LBW) to CKD during childhood; linked born small-for-gestational-age to end stage renal disease (ESRD) at up to 38 years; linked LBW to ESRD at up to 42 years; and linked LBW or preterm birth to CKD at up to 15 years of age. As such a recent Swedish study does not provide entirely new evidence but is based on >4million lives and apparently for the first time breaks the population down according to gestational age at birth. Once again it is shown what can be achieved when researchers have access to large national databases covering pregnancy, the neonatal period and subsequent life epochs in both hospital and out-patient settings. The particular point made by the researchers in terms of the relationship between gestational age and CKD is that preterm birth interrupts development and maturation of kidneys during a critical growth period. During the third trimester more than 60% of nephrons are formed, so interruption of this process can result in lower nephron numbers and a high percentage of abnormal glomeruli. An additional factor, particularly in the sickest and smallest neonates, is exposure to potentially nephrotoxic drugs.  Possible consequences include glomerular hyperfiltration, sodium retention, further loss of nephrons and progressive kidney disease due to secondary focal segmental glomerulosclerosis. Extracted data for the analysis included foetal gender and growth, birth order and family history. Maternal characteristics included age, education level, BMI, smoking history, diabetes, pre-eclampsia and other hypertensive disorders. Only singleton births were studied. Subjects with congenital abnormalities were included in the dataset. Specific categories explored were <27wks (extremely preterm); 28-33wks (very preterm); 34-36wks (late preterm); 37-38wks (early term); and 39-41wks (full term) which was the reference group. Summary estimates for preterm birth involved the combination of the first three groups (i.e. <37wks).  The diagnosis of CKD was recorded in 4305 of 4 186 615 subjects i.e. incidence of 0.1%. Skewing the data to some extent is the fact that the database included at least 300 subjects diagnosed with acute renal failure in the neonatal period, and 116 subjects on record as having congenital abnormalities, however overall there was a significant inverse relationship between gestational age and development of CKD. Preterm birth as defined above was associated with a twofold increase in risk from birth until mid-adulthood, and extreme preterm birth with a threefold increase when compared to full term neonates. An increased risk was also observed in those born at early term. The association between preterm birth and CKD was strongest at ages 0-9 years but was significant through to 43 years.  While the authors make a strong case for vigilance, monitoring and preventive actions in infants born preterm and at early term, this must be balanced against the incidence. Even the group at highest risk i.e. those born extremely preterm, only had an incidence rate of 13.3 per 100 000 person years, but one should nevertheless not lose sight of the message and the association between CKD and low gestation.

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BMJ 2019; 365:1346

Pediatr Nephrol 2016; 31; 2213-22

J Am Board Fam Med 2015;28: 121-3

A 2017/2018 review published by the SA Childhood Asthma Working Group (SACAWG) concluded that that asthma in children remains a common condition, affecting 10-20% between the ages of 6 and 14 years and showing an increasing prevalence in both urban and rural areas. Adding to the problem is that many asthmatics lack a formal diagnosis and thus access to treatment. Figures from the USA are in accordance with the local figures, showing prevalence of 9.6% in 2009 with the highest rates among the poor. In 2016 about 8.3 million American children aged <18 years were affected and ~54% experienced an exacerbation. The condition results in absenteeism from school and parental absenteeism from work. USA figures from 2008 showed an overall loss of 10.5 million school days, while parents missed 14.2 million work days. This translated to an annual productivity loss of $3.8bn. Despite broad distribution of treatment guidelines, >50% of children with asthma still have poorly-controlled disease. This leads to poor quality of life (QOL), increased exacerbation risk and frequent utilisation of acute healthcare resources.  Two recently-published studies, one from Missouri, the other from Utah, showed the benefits of specific interventions. The Missouri study focused on neighbourhoods with high asthma and poverty rates, and provided care via a school-based clinic. Paediatric nurse practitioners ran the programme in collaboration with specialists in allergy/pulmonology. Children were reached in their community school while parental communication was telephonic. Care was provided at no cost and involved a monthly visit to each of 12 schools. Patients were referred by the school nurse or parents and enrolled over a 3-year study period. The programme involved asthma education sessions using age-appropriate material, assessment of asthma control, review of inhaler//spacer technique and a focused physical examination which included spirometry. Each visit was followed by written communication to the child’s primary care doctor, parent and school nurse. Changes in healthcare utilisation, absenteeism, staff and student education, inhaler technique and parental satisfaction were measured. The programme recruited 1076 participants aged between 5 and 15 years and results showed reductions in absenteeism, hospitalisations and visits to an emergency department. Staff and student asthma knowledge improved, as did inhaler technique and parental satisfaction.  In contrast the Utah study focused on a predominantly white, affluent population and made use of the web-based electronic –Asthma Tracker (e-AT), a self-monitoring application for children with asthma (https://asthmatracker.utah.edu/public/index.php) which was developed by the researchers with input from parents, and introduced into 11 general paediatric ambulatory clinics. Each clinic had the capacity to accommodate enrolment, and provided a physician champion and care coordinator dedicated to using the e-AT. Participants with persistent asthma aged between 2 and 17 years were enrolled between January 2014 and December 2015 and followed up for 1 year. Adherence of the 327 enrolees was 65%. Results showed significantly improved QOL and asthma control as well as fewer hospitalisations, emergency department visits, and school and work days missed by children and parents respectively. These programmes offer exciting options for treatment of childhood asthma, whether in deprived or advantaged communities.

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Allergy Asthma Proc 2019; 40: 154-61

Pediatrics 2019; doi:10.1542/peds.2018-1711   

S Afr Med J 2018; 108: 537-9       

The estimated global prevalence of CP is 2.1/1000 live births but it is accepted that the figure is higher in low and middle income countries (LMICs).  A study from rural communities in Bangladesh showed the prevalence to be 3.4/1000 live births. This could be even higher given that access to healthcare, diagnostics and record-keeping are often less than optimal. A South African review reported a rate possibly as high as 10%. Most studies that relate to life expectancy and causes of death in CP children are from high-income countries with most children surviving into adulthood. Those who die prematurely are more likely to have suffered from more severe types of CP (e.g. spastic quadriplegia vs. diplegia), had more in the way of associated impairments (intellectual, visual, epilepsy) and had a history of respiratory infections or other chronic disease. The group of researchers involved in the abovementioned Bangladesh study embarked on another study with the objective of estimating mortality rates and causes of death in rural CP children, as well as predictors of death. The cornerstones of the study were enrolment of 726 children with CP aged up to 18 years and the comprehensive recording of clinical history and examination onto the Bangladesh Cerebral Palsy Register (BCPR). The BCPR was established in 2015 as the first population-based CP register in an LMIC. Subjects were enrolled between January 2015 and December 2016 and were followed for a median period of 2 years (interquartile range 11 months). Thirty-one children died and 46 were lost to follow-up. Mean age at registration on the BCPR was 6.3 years and mean age at death for the 31 who died was 7.6 years. The following factors were found to correlate with likelihood of death: age <5 years at enrolment; type/severity of CP; poorer functioning on the GMFCS (Gross Motor Function Classification System); swallowing difficulties; associated impairments (intellectual, visual, hearing, epilepsy); and severe undernutrition.  Immediate causes of death obtained on the basis of the ‘verbal autopsy’ were infections (meningitis, pneumonia, gastroenteritis), with undernutrition playing a significant role. The crude mortality rate was 19.5 per 1000 person years and the authors make the point that this could be lowered because the causes of death are largely amenable to intervention and thus preventable.  This article raises a number of issues, the first being that the mortality rate in these rural children with CP was likely higher: 40 children were lost to follow up and it is probable that at least some of them had died. Secondly, this study enrolled children with existing CP at a mean age of 6.3 years and showed that children under 5 had the lowest chance of survival. This introduces the likelihood that some/many children had already died and did not make it onto the database. Then there is the harsh reality of the ‘consequences’ of introducing measures to prolong the lives of the worst-affected CP sufferers. In an impoverished rural area prolonging the life of the more severe CPs with associated impairments, epilepsy, swallowing difficulties and severe undernutrition may not be ideal for either the child or the parents. South African health workers dedicated to rural children with CP face these issues on a regular basis. Simultaneously they are faced with the challenge of supporting the lesser-affected children who are far more responsive to interventions ranging from assistive devices to special schooling. Sadly health, transport and educational services are lacking or absent in our rural areas and many children have little hope of reaching their full potential.

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Dev Med Child Neurol 2019; doi: 10.1111/dmcn.14256

Semin Pediatr Neurol 2014 21: 30-35

PLoS Med 2006; 3:e18   

An interesting anomaly in intensive care of preterm neonates is the difference between attention given to pre- and/or intrapartum HRV vs. HRV once the neonate has been admitted to the NICU. Patterns detected on cardiotocography (CTG) that caused alarm in the labour ward and might even have led to emergency operative delivery, are often or even usually given less attention once the neonate has been delivered. This applies even if the same pathophysiological factors such as hypoxia, ischaemia, sepsis and acidosis are in play.  Given that one is dealing with the same infant and there is no logical basis for treating the ‘early newborn’ differently from the foetus, the question is whether we should be paying more attention to postnatal continuous heart rate monitoring and variability. Turns out that various researchers have indeed been looking at different clinical situations, and found that continuous HRV may be an important monitoring parameter. One example is late onset neonatal sepsis. Here several studies have shown a good correlation between clinical indicators such as CRP elevation/positive blood cultures and loss of variability, often with frequent bradycardias.  As such, there are recommendations that neonatal monitoring systems that are similar to CTG and permit longer-term observations may provide early warning and alert clinicians to impending sepsis.  A different study into HRV has shown that there is reduced variability in babies born vaginally vs. after caesarean section, while another has shown a greater risk of failed extubation in preterm neonates with reduced HRV vs. those with normal variability. A simplistic proposal for causation in one of the sepsis studies was that neonates incubating an infection may have impaired sleep-wake cycles, a neonatal equivalent of pre-sepsis fatigue shown in adults. However, more-likely underlying mechanisms include autonomic instability and parasympathetic inhibition, a role for development/maturity on the latter (i.e. less autonomic sensitivity in more-mature neonates), and a role for cytokines and their effects on signal transduction. The latter may impact on the autonomic nervous system with TNF-α, IL-1β and IL-6 capable of blunting heart rate responses. In the situation of sepsis there may also be reduction of HRV by endotoxins. Several monitoring systems provide the option of continuous monitoring; NICU’s should perhaps consider adding this modality to their armamentaria.

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Early Hum Develop 2019; 134: 31-3

J Perinatal Med 2019; 47: 252-7

IEEE Transact Biomed Eng 2006; 53: 126-131  

Since the introduction of artificial surfactant in the 1980s the improved figures for survival of even the tiniest and most-preterm infants have been accompanied by developments and enhancements in the field of respiratory support. Ventilators are purpose-built, pressure support ranges from CPAP to oscillation and fully-assisted mechanical ventilation. Meanwhile equipment-infant interfaces have been the subject of great interest. If and when respiratory intervention is indicated, the goal is to do as much as possible to avoid sustained intubation and positive pressure ventilation. CPAP is the modality of choice, whether as ‘step-up’ as part of neonatal resuscitation (see summary 1913) or ‘step-down’ as part of weaning from mechanical ventilation. Equipment-infant interfaces have evolved from long-pronged cannulae to devices with short prong,s and more-recently to nasal masks. Techniques have evolved from treatment via NCPAP to one using HHHFNC (heated humidified high-flow nasal cannula). The latter two have been studied and HHHFNC is gaining support around the world as it is equal to NCPAP in terms of respiratory safety and efficiency, but is less invasive and causes less trauma because of its lower nasal prong –nares ratio (N-N ratio). A recent systematic review and meta-analysis evaluated studies that compared nasal prongs and nasal masks for both step-up and step-down management of VLBW and ELBW neonates requiring NCPAP. For the primary outcomes it was shown that the mask was superior and decreased the rate of NCPAP failure within 72 hours of initiation (RR 0.72), and also that there was less in the way of nasal injury (RR0.71). In a sub-group analysis of preterm infants specifically requiring step-up NCPAP after resuscitation at birth, the mask decreased the need for subsequent surfactant administration (RR 0.78) and also reduced the risk of subsequent moderate-severe BPD  (RR 0.47). Secondary outcomes such as pneumothorax, retinopathy, IVH and mortality were not different. Relevant to these interventions is a study that measured the resistance of various NCPAP devices and showed that masks have the lowest resistance when compared to prongs. Also shown was that there are significant inter-product differences. One should therefore be alert to the fact that a high-resistance device might reflect a desired level of CPAP proximal to the baby but have an inadequate pressure beyond the nares.

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Neonatology 2019; doi; 10.1159/000496462

Arch Dis Child Fetal Neonatal Ed 2018;0:F1-5

Pediatr and Neonatol 2017; 58: 295-302 

An excellent review article has drawn attention to the need to expand recognition of foetal alcohol syndrome (FAS) to also include foetal alcohol spectrum disorder (FASD). In terms of global prevalence, FASD at 0.77% is similar to autism spectrum disorder at 0.6%, but there is general agreement that FASD is underdiagnosed because of social stigma, concealment of maternal alcohol consumption, diagnostic complexity, reliance on facial features and characteristics that overlap with those of other conditions. There is variation in the prevalence of FASD above the 0.77% by country. Saudi Arabia is around 0.01%, Europe and America range from 2-5% while South Africa tops the list at 11.1%. Because manifestations persist into adulthood the public health burden of FASD is significant and can include lifelong physical and cognitive disability, psychiatric and medical comorbidity, diminished productivity, homelessness and incarceration. Several other important issues are raised in the review apart from the statement that after 40 years of animal and human research, no safe level of prenatal alcohol exposure has been established. The FASD includes FAS, partial FASD and alcohol-related neurodevelopmental disorder, although categorization is made difficult by the lack of a uniform diagnostic and classification system across four domains: magnitude of prenatal exposure, growth impairment, dysmorphic facial features and neurodevelopmental abnormalities.  Classical craniofacial dysmorphology of FAS included short palpebral fissures, smooth philtrum and thin upper lip but in FASD the list has been considerably expanded to include features such as railroad-track ears, ptosis and anteverted nares. In this regard automated tools that can be accessed online are being developed. Three-dimensional imaging, increasingly possible with smartphones, can already distinguish between controls and children with prenatal exposure by recognizing subtle facial features (97% specificity for FAS and 90% for partial FAS). In the brain, alcohol produces a variety of processing abnormalities involving sensory perception and cognition. Odour and taste, vision and hearing can all be affected. In adults with FASD the ‘pleasantness’ of alcohol odours has been shown to be proportional to the magnitude of prenatal exposure, possibly exposing them to an increased risk of alcohol use disorder.  Cognitive disorders can be present even without the physical abnormalities of FASD (so-called alcohol-related neurodevelopmental disorder). Neurological deficits may range from fine motor deficits to increased step-width and gait abnormality and to ataxia. In a retrospective review of 425 individuals with FASD, epilepsy was found in 5.9% vs. 0.5% in the general population, possibly related to malformations of cortical development such as heterotopia or polymicrogyria. Other brain characteristics of FASD such as hypoplasia of the corpus callosum and cavum septum pellucidum have been described. However MRI is not regarded as being sufficiently sensitive to detect the abnormalities responsible for the functional impairments in communication networks. No specific drug treatment is available for FASD, but an emerging approach is targeted nutritional supplementation during key developmental periods e.g. pre- or postnatal choline supplementation which appeared to improve recognition and sequential memory. Targeted educational interventions might also improve patient outcomes.

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Lancet Neurol 2019; http://dx.doi.org/10.1016/S1474-4422(19)30150-4

Alcohol Clin Exp Res 2018; 42: 1327-41

Birth Defects Res 2018; 110: 1335-42

Both ADEM (Acute Disseminated Encephalomyelitis) and anti-NMDAR (Anti-N-Methyl D-Aspartate Receptor) encephalitis are included under the broad umbrella of autoimmune encephalitis, but demyelination is a prominent feature of the former. Some have shown the antibodies in different categories: directed against intracellular antigens (producing limbic encephalitis), synaptic antigens (e.g. NMDA, GABA or Dopamine receptors), and ion channel (aquaporin 4) or cell-surface proteins e.g. Myelin Oligodendrocyte Glycoprotein (MOG) which has been shown to be associated with ADEM but also with other demyelinating syndromes. Most cases of ADEM occur in children (mostly <10 years of age) with some up to age 20, but cases have been described in patients up to 80 years of age. Often preceded by an acute systemic infection or vaccination, it is characterized by encephalopathy and other neurological signs such as cranial nerve palsies, ataxia, hemiparesis, myelopathy or optic neuritis. CSF typically shows mild pleiocytosis, while oligoclonal bands are uncommon. Brain MRI shows multiple large abnormalities in various parts of the brain and spinal cord. Where the association with MOG has been studied, in children the association is strongest for ADEM while in adults the majority of cases have neuromyelitis optica. In general ADEM is regarded as occurring more commonly than anti-NMDAR encephalitis, although there appears to be agreement that the latter is underdiagnosed or unrecognized. There are several notable differences between anti-NMDAR encephalitis presentation in adults vs. children. In the latter it is often preceded by a flu-like illness and neurological symptoms (seizures, movement disorders, speech disturbance) are more likely than psychiatric symptoms. Most children will develop memory disturbances, behavioural changes, sleep-wake cycle disturbances and dysautonomias. Movement disorders are also frequent, while some might show autistic regression and opsoclonus or myoclonus. In contrast to adults the association with malignancy is rare. The main differential diagnoses are viral, toxic or metabolic encephalopathies and recently-describes genetic causes of movement disorder.  Brain MRI may differentiate from other aetiologies, especially viral, but may often be normal or only show non-specific changes. CSF white cells are often only mildly elevated, while oligoclonal bands are positive in a proportion of cases. The diagnosis is confirmed if antibodies to the GluN1 subunit of NMDAR are present. EEG assists in differentiating between movement disorders and seizures. The basis of treatment for both ADEM and anti-NMDAR encephalitis is immunotherapy involving immunoglobulins, corticosteroids and plasma exchange.  Children may be affected by encephalitis resulting from antibodies to neuronal surface targets other than NMDAR, but cases are too limited to draw definite conclusions in terms of differences between adults and children.

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Neurol Sci 2019 https://doi.org/10.1007/s10072-019-03930-3

Dev Med Child Neurol 2018; 60: 958-62

Lancet Neurol 2016; 15: 391-404   

Previous summaries in this series have drawn attention to the gut biome and the associations and/or consequences of an altered biome (see 1624, 1733, 1835).  An altered biome may produce disease, but interventions targeted at altering a ‘dysbiotic’ biome, for example by using pre- or probiotics, may also be beneficial. In a recent journal article a group from Canada reported on the outcome of a randomized controlled study of children and adolescents with Type 1 diabetes (T1D) who were treated with placebo or a prebiotic for 12 weeks and followed up for changes related to insulin activity. In the context of diabetes the key appears to be biome-related effects on intestinal permeability and metabolic regulation. Animal studies have shown that a dysbiotic gut biome generates high levels of lipopolysaccharide (LPS), which leads to mucosal inflammation, loss of tight junction integrity between epithelial cells and increased permeability. The LPS crosses into the circulation resulting in endotoxaemia, systemic inflammation, insulin resistance and poor glycaemic control. Human studies have shown that the biome of T1D subjects differs from that of healthy individuals, and that intestinal barrier function and permeability are impaired, resulting in a ‘leaky gut’. In animal studies, interventions that change the biome and correct the dysbiosis also alter the intestinal permeability and change the course of experimental T1D. Of particular note is that a ‘leaky gut’ may predate the onset of T1D in humans, raising the question of whether the biome-related abnormality plays a role in pathogenesis of the disease and is not merely a consequence. Perhaps it is not only LPS but also antigens that enter the circulation and contribute to the auto-immune T1D? When the biome of diabetes-prone animals is manipulated by means of antibiotics or faecal transfer, there are changes in the incidence of diabetes. So perhaps the subject must be genetically or otherwise susceptible to the consequences of a leaky gut? The pathogenesis aside, prebiotics have been shown to increase colonization with Bifidobacterium, consequential increases in butyrate concentrations, and reductions in inflammatory changes in the epithelium. The Canadian study built on these various elements, using oligofructose-enriched inulin as the prebiotic for 12 weeks in 17 T1D subjects and comparing results with those of 21 similarly-aged and affected placebo-treated controls.  HbA1c, C-peptide, gut microbiota and intestinal permeability were assessed at baseline, completion of the intervention (12 weeks) and at 6 months.  C-peptide levels increased in the prebiotic group over the 12 weeks while reductions were seen in the controls. The authors interpreted this as a sign of preservation of β-cell function in treated subjects vs. controls. There was also a trend towards an improvement in gut permeability in the treated subjects (measured by mannitol and lactulose absorption). These changes were associated with a significant increase in the relative abundance of Bifidobacterium in the prebiotic-treated subjects. In this regard previous studies have shown that Bifidobacterium are under-represented in children with T1D. While the results of this study are far from conclusive they do suggest that this inexpensive, low-risk intervention may have a role in improving glycaemic control in T1D patients, and possible even in the genesis of T1D in susceptible individuals.

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J Clin Endocrinol Metab 2019; doi:10.1210/jc.2019-00481

Diabetologia 2014; 57: 1569-77

Rev Diabet Stud 2012; 9; 251-9

In a recent editorial in the SA Journal of Child Health, clinicians from the University of Cape Town (UCT) called for support for the draft Control of Tobacco Products and Electronic Delivery Systems Bill that is currently receiving Parliament’s attention. The editorial addresses several areas ranging from the need to further control environmental tobacco smoke inhaled by children and pregnant women, to controls over e-cigarettes and other electronic nicotine products.  UCT and the University of Western Cape have been active as members of the national Tobacco Control Advocacy Alliance, while UCT is also active internationally as a participant in the Forum of International Respiratory Societies. Both of these organisations have concerns about access to the various electronic delivery systems, particularly by children and adolescents. Much of the focus is on vaping as an introductory step to subsequent cigarette smoking and its clearly-established consequences, and the point has been made that devices that were developed to provide adults with a safer alternative or an aid to reduce or stop smoking, have in fact become an attractive entry point for adolescents. Marketing targets the young, the products are packaged in appealing ways and are visible in shops, malls and on the internet, and access is currently very easy. The draft legislation seeks to address the issues through steps that aim to control packaging, marketing, displays and internet sales. Nicotine content of products used in the devices is technically controlled by current legislation that has it as a Schedule 1 drug if ≤10mg (as in nicotine patches) and Schedule 3 if higher. But if that is the case then why does a simple internet search of vape shops in South Africa show that ‘salt nic’ with 35mg nicotine is freely available?  Salt nicotine involves benzoic acid and nicotine salt technology that delivers much higher nicotine content than conventional e-cigarettes. JUUL, one of the salt nicotine products, may have levels as high as 50mg/ml, which is multiples higher than other products. Increasing vaping rates seem to correlate with increasing nicotine levels in the products, and since it is nicotine that is addictive (and potentially brain-damaging for the young), the appeals of the anti-vaping advocates become even stronger. If the Bill is successful and introduced into the laws of the country one hopes that it will be heeded and policed. Canada is an excellent example of what happens in an environment in which legislation is relaxed and access to vaping is easy. In a recent study of 16-19-year olds, vaping increased significantly between 2017 and 2018, and there was also an increase in the prevalence of smoking. Use of JUUL among vapers also increased over the year, going from 0% in 2017 to 10% in 2018. What is particularly worrying in the Canadian situation is that access to cannabis has also been eased and the drug is increasingly available for vaping devices. As to whether the cost of vaping is a barrier to entry, several sources show that vaping is far cheaper than smoking, with some showing a 90% reduction in cost. So is the potential problem one of vaping being a path to subsequent smoking, or is it that in an uncontrolled environment it represents an end in itself?

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South Afr J Child Health 2019; 13: 4-5

BMJ 2019; 365: l2219

Eur Resp J 2018; 51: 1800278  

TB drug treatment for contacts of patients infected with drug-susceptible strains of TB is effective in preventing disease in the contacts. However the jury is still out when it comes to management of child contacts of patients with drug-resistant TB.  The intention here is not to encourage clinicians to go against any specific institutional policies, but to highlight the fact that there is ongoing debate. Review of an on-line presentation representing the University of Stellenbosch and Desmond Tutu Centre and also linked to the World Health Organization (WHO) makes it fairly clear that many clinicians are biased towards preventive treatment of such contacts, but in fact the WHO’s 2018 updated and consolidated guidelines state: “In selected high-risk household contacts of patients with multidrug-resistant tuberculosis, preventive treatment may be considered based on individualised risk assessment and a sound clinical justification.” The issues here are around the drugs that must be used in the context of drug-resistance to prevent disease in the child, and also possible side effects.  In South Africa, where risk of infection is increased through factors such as HIV and poor nutrition, the threshold to treatment is obviously lower and a number of studies have shown good outcome. However such studies were uncontrolled and as a result the experts are awaiting the outcome of at least three international trials (acronyms include TB CHAMP, V-QUIN and PHOENIx). Perhaps in stark contrast to the South African situation, a recent publication presented data from Armenia involving 150 child and adolescent subjects in contact with 79 patients with drug-resistant and multiple-drug resistant TB. Nutrition was adequate in all and 99.3% had previously been immunized with BCG. All were followed up for 2 years for prevalence of latent TB infection (LTBI) and incidence of LTBI and active disease. None received preventive treatment during the study period, but any developing active disease would have received appropriate treatment. At initial period 3 of the children were diagnosed with TB disease and prevalence of LTBI was 58.7%. The incidence of LTBI on follow up was 19.9 per 100 children per year but was seen particularly during the first 6 months of follow up. Importantly, no additional cases of incident disease were diagnosed during follow up. These prevalence figures on follow up are lower than figures from South Africa. Risk factors for LTBI included higher household density and index case’s age, positive TB-smear result and presence of lung cavities.  These results may be from an environment that represents lower risk for transmission than South Africa and as such may not be applicable to our situation. However the authors do make reference to suggestions that drug-resistant TB strains may be more infectious but less virulent than susceptible strains. Consequently contacts may be infected but less likely to develop active TB. This requires further study.

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Arch Dis Child 2019; 104: 622-8

Challenge to prevent MDR/XDR-TB https://www.who.int/tb/areas-of-work/children/SimonSchaaf_MDRTB.pdf

Tuberc Res Treat 2018 https://doi.org/10.1155/2018/3905890      

These three conditions represent a spectrum of disease with erythema multiforme (EM) being milder than the others. In fact EM is sub-divided into EM minor and EM major (EMM) based on the number of mucocutaneous sites involved.  In general, Stevens-Johnson (SJS) and toxic epidermal necrolysis (TEN) are clinically apparent on the basis of extent and severity of the affected skin and mucocutaneous sites, but there is likely some blurring of the margins between severe EMM and mild SJS. The conditions are manifestations of impaired T cell regulation, excessive activation of effector T cells, and the release of cytotoxic molecules such as granulysin and perforin that induce apoptosis and extensive keratinocyte death. Previous research has shown how the conditions can be differentiated immunohistochemically. Fourteen patients with SJS/TEN and 16 with EMM were studied. Skin biopsies taken at 4-5 days after presentation demonstrated significantly higher granulysin and perforin expression per CD8+ T cell in SJS/TEN, and a greater density of CD4+ cells in EMM. An alternative and easier test has also been reported viz. serum granulysin levels that become elevated 2-4 days before skin detachment or eroded mucosal lesions develop in patients with SJS/TEN. Aetiology differs between the conditions. SJS/TEN are mostly due to drug reactions, while various infections are more common in EM and EMM. While results of a recent systematic review of EM and EMM in children and adolescents most likely do little more than confirm what is available in many textbooks, it is nevertheless interesting and useful to note the results of a large-scale and well-done analysis. After an initial yield of almost 1000 articles, the final review included 113 articles (essentially case reports and case series) covering 580 patients. EM presented with typical target lesions, and mostly affected the oral mucosa. Mean age was 5.6 years. Infectious agents were the triggers in 48.6% (Herpes simplex virus >Mycoplasma pneumoniae>>EB virus, varicella, group A streptococcus, adenovirus, CMV and Chlamydia). Almost one-quarter of cases were drug-related (75% antibiotics and 18% anticonvulsants). Vaccines played a role in 4% of patients (DPT, Hepatitis B, HPV, MMR, polio and pneumococcal vaccines). Thirty-nine percent of subjects were diagnosed with EMM. In 19 younger subjects (mean age 4.4 months) vaccines were the main trigger, most (90%) not progressing to EMM. Recurrent EM occurred in 14.3% of subjects, mostly males, and older than those with single episodes (9.5 vs 5.9 years). EMM was more common in this recurrent group. The exact incidence of EM is unknown, one reason being that milder cases are unlikely to be reported, but it is stated that overall up to 1% of children and adolescents may be affected. Chances are good that paediatricians will see EM patients from time to time and be called on to assign a cause. The reviews under discussion give an idea as to when to consider treatment, for example with an antibiotic, antiviral or steroid. The latter is controversial, with some authors showing results and others not.

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J Am Acad Dermatol 2019 https://doi.org/10.1016/j.jaad.2019.02.057

Clin Rev Allergy Immunol 2018;54:177-84

J Dermatol 2012; 39: 781-6

Summary 1723 dealt with osteoporosis risk and its relationship to peak bone strength. The magnitude of the latter achieved by early adulthood determines the risk for the former. Bone strength is related to peak bone mass achieved, as well as bone size, geometry and microarchitecture acquired during the growing years. Heritable factors account for 60-80% of variability in bone strength, but importantly, actually achieving one’s genetic potential requires optimal bone health through the first two decades of life. Likely related to these factors is the difference between fracture rates as reported for black, white and mixed-race adolescents who were included in the University of Witwatersrand Birth to Twenty cohort and studied at 17-18 years of age. Forty percent of white adolescents reported a fracture vs. 20% in the other two groups. Family relationships were observed, for example higher fracture rates if siblings had experienced a fracture or if mothers exhibited high bone mineral content. Overall, adolescent bone mass was increased among white males but surprisingly, fracture risk was also increased in this group. The authors suggested that the findings could be explained by factors such as greater history of contact sports such as rugby among white youth, or a poor relationship between bone mass and bone strength. This interplay between factors such as genetics, socio-economics and physical activity/stress should be considered when reviewing a recent study from the United Kingdom. A cohort of 6389 subjects were included and were followed up with bone scans from ages 10 until 25. The parameter of particular interest in relation to bone mineral density (BMD) and bone mineral content (BMC) was pubertal age determined from peak height velocity (PHV), which was at a mean of 13.5 years for males and 11.6 years for females. Males gained BMD at faster rates than females, with the greatest gains between the year before and the two years after PHV, but what was unexpected was the finding that later age of puberty was ultimately associated with lower BMD, this despite a period of rapid peri-pubertal catch-up. The authors recommend that individuals with older pubertal age should be advised on how to maximise bone density in later life to help prevent fracture and osteoporosis. An interesting question that arises in the context of modifiable factors is what could be done to promote earlier puberty in those who might be predisposed to later puberty. There is agreement that 60-80% of variability in bone strength is genetic, and genetics also plays a role in pubertal age. However, from studies into secular trends one knows that internationally the age of pubertal onset is progressively decreasing, indicating an effect of external factors. Nutrition may be important in this regard but there are likely others that may also play a role. Clearly work remains to be done to fully understand why in this age of earlier puberty and menarche some individuals have delay and possible adverse consequences.

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JAMA Network Open 2019; 2: e198918

Curr Osteoporosis Res 2017 doi 10.1007/s11914-017-0371-2

Osteoporos Int 2013 doi 10.1007/s00198-013-2477-4

It is stated that GDM affects 3-25% of pregnancies worldwide and is apparently on the increase. The latter may be due to improved screening, lower thresholds for diagnosis or increases in population risk factors such as obesity. The condition poses risks to the immediate and long-term health of mother and child. Treatment includes the use of insulin and/or glucose-lowering agents such as metformin. Many guidelines favour metformin as a first resort on account of difficulties with insulin, which range from the practical issues around administration and monitoring to symptoms such as maternal hypoglycaemia and weight gain. In low- and middle-income countries, in which GDM rates are increasing at a higher rate than in others, insulin may be particularly problematic because of cost and the need for refrigerated storage. On the other hand, whereas metformin crosses the placenta and may attain levels between 50 and 100% of those in the mother, exogenous insulin does not reach the foetus and may be regarded as being safer. Various studies have shown metformin effects on birthweight and body composition. To explore such effects, compare them to effects of insulin treatment for GDM, and also assess impact of growth during infancy and childhood, researchers from the UK carried out a systematic review and meta-analysis. A review of several databases initially yielded >2500 records that were ultimately reduced to 28, representing 3,976 pregnancies. The key findings were that metformin was associated with lower birthweights (-107.7g) and lower ponderal indices (-0.13kg/m³). Metformin exposure was also associated with lower risk of macrosomia and being born LGA (ORs 0.59 and 0.78 respectively). While based on limited evidence the analysis also showed that the metformin-exposed group was on-average 440g heavier at 18-24 months (two studies), while three studies indicated that at 5-9 years BMI was higher by 0.78kg/m² in the metformin group. The authors conclude that their results may apply to previous findings that children “born small” who undergo rapid catch-up growth are at increased risk of developing cardiovascular disease and diabetes later in life. However it is difficult to regard the population under review as having been born ‘small.’ Granted the birthweights of metformin-exposed infants were lower by ~108g, but in the 17 studies included in the analysis of birthweight (~2800 infants), the averages were overwhelmingly between 3.0 and 3.5kg in the metformin-exposed group and around 3.5kg in those exposed to insulin. So is the 107.7g birthweight difference important, and is the 440g difference at 18-24 months of significance when expected average weight is around 12kg? On the other hand, while based on small numbers and limited data, the BMI and ponderal index differences between the groups may be significant in terms of predicting future risk. No doubt this review asks as many questions as it answers and further investigation is required before one considers a wholesale revision of guidelines for management of GDM.

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PLoS Medicine https://doi.org/10.1371/journal.pmed.1002848

Ann Nutr Metab 2017; 70: 236-40

BMJ 1999;318:427-31     

Summary 1737 highlights a fairly common and also an increasing problem viz. the long-term outcome and management of adolescents and adult patients successfully treated for serious conditions arising during pregnancy, the neonatal period, infancy and childhood. In many disciplines the paediatricians will manage their patients for as long as possible, but ultimately it becomes unrealistic for the cardiac, neurology or endocrine patient to continue attending follow-up clinics together with much younger counterparts. Additionally, advancing age brings its own set of conditions which impact to a greater or lesser extent on the underlying problem and are more-appropriately managed by the relevant sub-specialist in internal medicine. The cited summary speaks to the emergence of transitional clinics and specialists in adult congenital heart disease (ACHD) but focuses on the lifelong medical and surgical issues. Equally important are the mental illnesses that may accompany congenital heart disease. These are the focus of an article that recently appeared in the American Journal of Cardiology. The authors extracted data from five Colorado databases and analysed results for 2192 eligible adolescents and 6924 eligible adults who accessed services between January 2011 and December 2013. Cardiac conditions were classified as mild (e.g. simple VSD), moderate (e.g. coarctation) or severe (e.g. transposition), and number and type of interventions were captured. Presence of a genetic condition such as Down, DiGeorge, Prader-Willi or Turner syndrome was also noted. Mental illness was according to ICD-9CM and Clinical Classification Software (CCS) categories 650-670. Twenty-percent of adolescents were diagnosed with mental illness disorders (affecting development, anxiety, attention, behaviour, impulse control or mood). In the adult population 33% had evidence of mental illness (mostly related to mood, anxiety or substance abuse). Likelihood of mental illness increased with greater severity of the cardiac defect/s, the number of cardiac procedures during the surveillance period, and the presence of a genetic syndrome. The data highlight the importance of acknowledging the risk of mental illness in such patients and screening and referring where necessary. For an excellent review of pathogenesis of mental illness across the lifespan readers are referred to an article in Circulation which deals with dysmaturation and injury in the perinatal brain, white matter injury and neurodevelopmental anomalies in childhood, and problems for the ageing brain that is at risk for reduced cerebral blood flow and volumes as well as dementia. In that article the authors show that in this population, particularly in those with significant genetic syndromes or more-complex CHD, adverse neurocognitive outcomes are multifactorial, interrelated, cumulative and synergistic over time. In summary, mental illness may be structural and/or functional in origin, with potentially significant personal, medical and societal consequences.

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Am J Cardiol 2019; 124: 618-26

Circulation 2016; 133: 1951-62

Cardiol Clin 2015; 33; 503-12

Paediatricians and neonatologists treating neonates with HIE in private and public sector Neonatal ICUs will no doubt ask why anyone is writing about primary drug treatment of a condition that is widely regarded as best treated with therapeutic hypothermia (TH). This would be a legitimate question for first-world/developed settings, but until recently there have been questions about the success of TH in low- and middle-income countries (LIMCs) in which cost of equipment and competence of staff were factors to be considered. A study codenamed HELIX (hypothermia for encephalopathy in low- and middle-income countries) was set up to address and overcome problems, and positive results emanated from India in 2018. Using a low-cost servo-controlled device (Tecotherm HELIX) which is a modified version of the widely-used Tecotherm-Neo device, the authors showed in 82 patients treated for moderate to severe HIE that induction and cooling times and effectiveness were good. Eighteen percent died before discharge. A high percentage of subjects (51%) had gastric bleeds and 12% had pulmonary bleeds. Aetiology of the bleeding was not clear, possibly related to HIE-associated coagulopathy. An additional finding was that non-survivors tended to have higher heart rates (mean around 120bpm) and for longer periods of time vs survivors. Further contributions to the multi-centered HELIX study and dataset are expected. Reverting to the title of this summary and the question of pharmaceutical management of HIE, the topic has been addressed in previous summaries in this series (see 1536 and 1735). Magnesium is mentioned in 1536 as an adjunct to mild hypothermia, while 1735 explores adjunctive treatments for formal TH. Erythropoietin, melatonin, xenon, N-acetyl-L-cysteine, lithium and polyphenols have all been studied for a role in limiting post-asphyxial damage. The less-exotic magnesium sulphate appeared again in a recent paper from Nigeria. Largely based on a study from India but with less-convincing results, the Nigerian study suggested that administration of earlier (vs. later) doses of magnesium sulphate to patients with HIE appeared to be associated with restoration of tone and reflexes such as sucking and grasp, and resolution of encephalopathy. Related to the latter was the finding that feeding at <5 days was associated with a greater likelihood of survival without a neurological deficit. In contrast to the Indian study the Nigerian study was not placebo-controlled, so further studies are recommended. The important background to the use of magnesium sulphate is that animal models have identified two phases of hypoxic-ischemic brain injury, each characterized by energy depletion. Primary neuronal injury occurs during the process of asphyxia and stops with resuscitative measures. Secondary neuronal injury continues for hours to days, with many factors involved in this phase of neuronal death. Excitotoxicity is one of the important damaging mechanisms during which glutamate acts on the N-methyl-d-aspartate (NMDA) receptor, a postsynaptic ion channel in the brain. During asphyxia, there is excessive release and reduced uptake of glutamate in the newborn brain. High concentrations of glutamate open NMDA channels, allowing excessive calcium influx into the neurons and inducing irreversible neuronal injury. This secondary phase may last as long as 72 hours. Magnesium is a naturally occurring NMDA receptor antagonist that blocks neuronal influx of calcium. If the extracellular concentration of magnesium is increased then this block can be restored.

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Open J Pediatr 2019; 9: 89-102

BMJ Paediatr Open 2018; 2:e000245

Pediatrics 2009; 123: e764-9

The balance between maternal iron status and foetal iron demands is an important one with the potential to adversely affect mother, foetus and child if disturbed. Iron is necessary for a number of developmental processes such as myelination and dendrite arborisation, as well as synthesis of monoamine neurotransmitters, the latter implicated in the aetiology of autism spectrum disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). Animal studies have linked prenatal iron deficiency to irreversible neurological effects, and human studies have linked neonatal anaemia to cognitive and behavioural deficits. In one study, offspring of anaemic mothers had a 5-fold greater risk of severe intellectual disability (ID), while another has shown a dose-response relationship between maternal haemotocrit during pregnancy and children’s IQ at 4 and 7 years of age. With moderate prenatal anaemia there was a 59% greater chance of IQ below 70 at age 7. Studies into the impact of maternal supplementation on subsequent diagnosis of ASD have yielded inconsistent results. Given the importance of this topic in terms of the significance of abnormal neurodevelopment and the possibility of prevention by means of maternal diagnosis and supplementation, researchers continue to study the relationships. In this regard Swedish investigators have drawn on a national database and studied >500 000 offspring of almost 300 000 women, with the outcomes of interest being prevalence of ID, ASD and ADHD, specifically related to whether the maternal anaemia was diagnosed before or after 30 weeks of gestation. Only 5.8% of pregnancies had a diagnosis of anaemia during pregnancy (far lower than global statistics that show rates of 15-20%) and >90% of these occurred at >30 weeks of gestation. In contrast to anaemia diagnosed towards the end of pregnancy, early anaemia was associated with an increased risk of ASD, ADHD and particularly ID in offspring. Odds ratios were 1.44 for ASD, 1.37 for ADHD and 2.20 for ID. While these greater risks were obviously statistically significant, the actual unadjusted ‘high’ prevalence rates with early anaemia were around 4.9% for ASD, 9.3% for ADHD and 3.1% for ID vs. the lower rates of around 3.8% for ASD, 7.2% for ADHD, and 1.1% for ID. The latter rates were almost the same as rates for mothers without a diagnosis of any anaemia during pregnancy.

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JAMA Psychiatry 2019 doi: 10.1001/jamapsychiatry.2019.2309

BJOG 2016; 123:2087-93

Ann Epidemiol 2006; 16: 448-54     

On physiological grounds and based on a substantial amount of clinical data there is indeed a place for magnesium in the management of status asthmaticus in children and adolescents. Magnesium causes bronchodilation via modulation of calcium ion flow, thus inhibiting the release of acetylcholine from nerve terminals. Magnesium also stabilizes T cells, preventing their activation, and inhibits mastocyte degranulation, thereby limiting the production of inflammatory mediators. Paediatricians involved in paediatric high- and intensive care units will have an idea of the incidence of patients requiring admission for severe asthma while current US literature states that it is a common cause of admission to the PICU. Numbers are confirmed in an article from Kentucky which showed that over an 18 month period some 313 patients were admitted to this level of care i.e. around 1 every second day. The focus of the Kentucky article was the safety of continuous magnesium infusion for management of these severe cases. The unit has a long history (>20 years) of using magnesium sulphate as second tier therapy for moderate to severe asthma. In contrast to other units, their preferred mode of administration is by continuous infusion. For their retrospective review they focused on the 154 patients who received magnesium for >24 hours. In addition to the magnesium all patients also received nebulized albuterol, either continuously or 2-hourly, in addition to ipratropium bromide and systemic corticosteroids. Forty patients also received adjunctive therapies including aminophylline and/or terbutaline while on the magnesium. Despite these additional medications the authors were able to ascribe outcome events to the magnesium in almost all the cases (~97%). Adverse events of interest were hypotension, muscle weakness/myopathy, need for escalation of mechanical ventilatory support, or sedation. Magnesium was initiated with a bolus of 50-70mg/kg (max 2g) administered over 20 minutes, followed by infusion initiated at 25mg/kg/hr (max 2g/hr) and titrated in 5mg/kg/hr increments to maintain serum magnesium between 4 and 6mg/dl. Levels were typically monitored every 6 hours. Patients received infusions for a median of 53.4 hours (IQ range 36.6-74.8 hours). Hypotension was observed in 48.1% of patients, almost exclusively only affecting diastolic blood pressure and only limited to one BP measurement. Administration of saline or reduction of the magnesium infusion rate was necessary in <3% of these events. Nausea or emesis was a problem in 22.7% of patients and was treated with odansetron. Transient weakness was experienced by 14.9%, and 6.5% experienced flushing.  On balance the problems were not regarded as being overly significant in the context of severe status asthmaticus. In the few patients whose adverse events included hypotonia (1 patient), increased ventilatory assistance (3 patients) and sedation (1 patient), the deterioration during magnesium treatment was attributed to progression of the underlying disease (e.g. pneumonia).  Importantly, none of the 154 patients required endotracheal intubation. An excellent review of adjunctive treatments and a progressive care pathway can also be found in the recent literature. In that review magnesium also features high on the list once first line therapy has failed.

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Pediatr Pulmonol 2019 doi.org/10.1002/ppul.24499

Respir Care 2017; 62: 849-65

Recent Pat Inflamm Allergy Drug Discov 207; 11: 12-21 

Summary 1924 highlighted the actions of staff at two Western Cape universities who are advocating for improved legislative control of tobacco products and electronic delivery systems. In the intervening weeks since that summary the US Centers for Disease Control have drawn attention to morbidity and mortality among ‘vapers’ with some 500 cases of lung disease and six deaths. Investigations pointed to oils used in the preparation of flavoured vaping products and/or vaping of cannabis. Vaping ‘bans’ in the US exist in most states but usually apply to where vaping is legal (e.g. bans refer to vaping inside restaurants or public space) and limitation of the sale to minors. Since the CDC’s alerts at least one state (Massachusetts) has followed up with a total ban of online and retail sales of both marijuana and tobacco vaping products, whether flavoured or otherwise.  But should one wait for more reports of severe lung disease and deaths before considering action? For healthcare workers involved in the care of children and adolescents, perhaps we should be taking note of reports such as a meta-analysis of 21 studies covering almost 130 000 Danish subjects aged between 10 and 24 years. These studies were essentially undertaken because of concerns such as the developmental and addictive effects of nicotine, the pulmonary effects of vaping, the likelihood of vapers progressing to cigarette smoking, and associations between vaping and progression to cannabis and other drugs.  Whereas e-cigarettes were introduced as a strategy to reduce or quit smoking, it is becoming clear that vaping has taken on a life of its own. In both longitudinal and cross-sectional studies included in the meta-analysis it was clear that the odds of marijuana use were significantly higher in youth who had an e-cigarette history (OR 3.47 vs. those with no history).  Odds were also higher in those aged 12-17 than in the 18-24 age group OR 4.29 vs. 2.3), possibly because the younger brain is more vulnerable to substance use and addiction through effects of both nicotine and marijuana on neural pathways involved with pleasure and reward. . The risk of marijuana use was even higher (5.39) if subjects had a history of multiple modes of access to tobacco (e.g. vaping plus cigarettes). In 12 studies published in or after 2017 the risk of progression to marijuana was higher than in the 9 earlier studies. While the authors do not comment on this particular aspect, one must wonder whether the almost-global move towards decriminalisation of marijuana and ease of vaping the drug has also contributed to the observed results. There is no doubt that in South Africa we already have a significant drug problem in our schools, with evidence that children are exposed even before their teens. We also have a problem among the homeless and unemployed. So, while it is easy to categorise the vaping-marijuana issue as a first-world problem and ignore it, perhaps one should again think about how to support those who are striving to regulate of online and retail access to of devices and cannabis. The Massachusetts bans may be a step too far, but are at least in the right direction.

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JAMA Pediatrics 2019; doi 10.1001/jamapediatrics.2019.2574

The South African 2018 https://www.thesouthafrican.com/news/synthetic-marijuana-drug-south-africa-pretoria/

JAMA Psychiatry 2016; 73: 292-7

Based on 2017 recommendations from the Global Advisory Committee on Vaccine Safety it would appear that active surveillance is still necessary to fully assess the long-term benefit and safety of  RV vaccines. Chinese researchers have taken such recommendations regarding safety seriously and undertaken an important meta-analysis of randomized controlled RV trials (vaccine vs. placebo) that spanned a 20-year period (January 1999-December 2018).  After following strict protocols for meta-analysis the authors were left with 25 studies covering 200 594 subjects (104 647 vaccinated vs. 95 947 not) from 33 countries and 4 continents. Vaccines included monovalent (Rotarix), pentavalent (RotaTeq), monovalent human-bovine (Rotavac), oral bovine pentavalent (Rotasil), and human neonatal preparations, with ±90% of participants vaccinated with Rotarix and RotaTeq. The research excluded any studies that involved Rotashield, the early tetravalent vaccine that was previously associated with a high risk of intussusception. The studies were fairly homogeneous in terms of design but endpoints differed, with outcomes reported as relative risk at one month, one year and two years. Twenty cases of definite intussusception were diagnosed within 31 days after rotavirus vaccination, with 11 cases in the vaccine group and 9 cases in the placebo group. Seventy-four cases were reported within 1 year, with 37 cases in the vaccine group and 37 cases in the placebo group. Fifty-nine cases were reported within 2 years, with 29 cases in the vaccine group and 30 cases in the placebo. These results don’t require any statistical analysis to prove that the intussusception rates were identical in the vaccine and placebo groups. However there is one important caveat. While safety of Rotarix and RotaTeq appears to be proven, because of the small numbers there is less certainty for the 10% of subjects vaccinated with the other products. On balance it appears that there is recognition that the early product (Rotashield) should not be used, overall rates of intussusception are low and similar for vaccine and placebo, Rotarix and RotaTeq are safe, but active surveillance is still required if/where/when other products are used.    

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JAMA Network Open 2019; 2(10): e1912458

WHO Global Advisory Committee on Vaccine Safety, 6-7 December 2017

Int J Clin Exp Med 2016; 9; 1306-13

Familial hypercholesterolaemia (FH) is another example of a disease/condition that requires specialist paediatrician management during childhood and adolescence, and appropriate transfer to a specialised lipid or endocrinology clinic for coordinated care into adulthood.  Current South African guidelines recommend that children with a family history of FH should be tested at 8 years of age and treated with statins if found to be affected.  This is important in a country in which three sub-populations may have FH prevalence rates as high as 1:70. The goal of treatment is the prevention of atherosclerotic vascular disease and in this regard experts agree that it is both the absolute LDL cholesterol level and the cumulative exposure of the arterial wall to cholesterol that determine the severity of disease. In other words the goal of treatment should be both ‘the lower the better’ and ‘the younger the better.’ Short-term studies have followed treated children for a few years in placebo-controlled trials, but with the emergence of clear benefits and low risks of treatment it became unethical to extend such studies, so control subjects were then switched to drug treatment. One such study situation has been continued for an additional 20 years. It involved 214 children born into 156 families. To introduce control elements the researchers also studied 95 unaffected siblings and the parents of the patients treated with the study drug (pravastatin) during childhood. In this way it was hoped that environmental, socioeconomic and other genetic factors that might play a role in the evolution of atherosclerosis would be minimized. Because the 8-year threshold for initiation of pravastatin had not yet been introduced when some of the children were enrolled the average age of initiation of statins in 184 patients available for long-term follow-up was 14.0±3.1 years. Seventy-seven ‘control’ siblings were included in the long-term follow-up. The mean LDL cholesterol level decreased in patients from 6.13mmol/l at baseline to 4.16mmol/l, a decrease of 32%, but treatment goal  of LDL of <2.59mmol/l was only achieved in 20% of patients. More importantly, the mean progression of carotid intima-media thickness over the entire follow-up period was only 0.0056mm/yr in patients vs. 0.0057mm/yr in siblings. Furthermore, when compared with parents (many of whom had not started treatment until into adulthood) the cumulative incidence of cardiovascular events (e.g. angina, infarction, coronary artery intervention) was only 1% in study subjects vs. 26% in ‘parental controls,’ and incidence of early death was 0% for study subjects vs. 7% for parents.  Around 80% of the patients appeared to have adhered to statin treatment on a long-term basis without adverse effects. The results show the positive benefits of early and sustained treatment of FH with statins, and the authors speculate that results might be even better once specific drugs are ‘tailored’ according to the genetic variant of  FH.

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New Engl J Med 2019; 381: 1547-56

S Afr Med J 2018; 108: 973-1000 

J Lipid Res 2017; 58: 1765-76

The increased risk and incidence of infection in diabetics is well known to patients, parents and the full spectrum of healthcare providers, but it is nevertheless worthwhile to occasionally review some current issues on the subject. This has been done and reported in a recent article published by Brazilian specialists in the fields of endocrinology and paediatrics. In terms of infections that are prevalent in children, those affecting the respiratory system are most common, with Strep pneumoniae and viruses responsible for most lower tract infections. In the case of pneumococcus this does not appear to be due to a higher rate of carriage of the organism, but rather a greater susceptibility to disease and possibly also resulting in higher rates of morbidity and mortality. For the viral infections, influenza-related admission rates during the annual ‘season’ are higher for diabetics than for non-diabetics, and are more likely to be associated with complications. Urinary tract, Candida and skin and soft tissue infections are also common. So what is the relationship between the diabetes and the infections? More and more evidence is emerging that the immune system is impaired. This ranges from impairment of the complement system to abnormal cytokine secretion, cellular abnormalities and role of the patient’s microbiome, both superficial and intestinal. Within the complement system which is responsible for opsonisation, phagocytosis and lysis of organisms it has been shown that diabetics may have a C4 component deficiency, leading to leukocyte dysfunction and a decreased cytokine response. It has also been shown that diabetics have lower levels of IL-1, IL-6, IL-10 and IL-22. Decreased IFN-γ release from T-cells and NK cells, decreased TNF from T-cells and macrophages, and under-expression of the major class I histocompatibility complex have also been recorded, all of which may impair cellular immunity. Hyperglycaemia and/or acidosis may independently exert effects, not only on leukocyte mobilisation, chemotaxis and phagocytosis, but also on leukocyte apoptosis. As we learn more about the intestinal microbiome it is emerging that perturbations may in fact play a role in development of type 1 diabetes. Data suggest that the gut microbiota is involved at two different steps. The first step involves is colonisation by a microbial community unable to provide an adequate ‘education’ of the immune system. Consequently the infant becomes susceptible to immune-mediated diseases, including type 1 diabetes. At the second step the child seroconverts to positivity for diabetes-associated autoantibodies. This is preceded or accompanied by a decrease in the diversity of the intestinal microbiota and an increased abundance of Bacteroides species. These changes affect the disease process, promoting progression toward overt type 1 diabetes. Counter-measures that have been proposed include probiotics, human milk oligosaccharides and modified starches that may influence the numbers and activities of both autoreactive and regulatory T cells and provide protection against autoimmune diabetes.

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Jornal de Pediatria 2019. Calliari LE, Almeida FJ, Noronha RM www.jped.com.br

Curr Diab Rep 2017; 17: 105

Acta Diabetol 2013 ; 50: 743-52

South Africa has the 8^th highest rate of suicide in the world and suicide is the 3^rd highest cause of unnatural death in the country after homicide and accidents. Young adults in the 19-24 age group are considered to be most at risk. Year-end appears to be a hazardous time for many children, adolescents and young adults within our school and university environments, and every year there are reports of attempted and successful suicides before, during or after exams. On the other hand, with the advent of smartphones, mass uptake of social media and various forms of cyber-bullying, victims are also driven to suicidal thoughts and actions. Teachers, parents and friends frequently express surprise after the fact, even when aware of the pressures experienced by the victims. Rates may be different between countries, but the underlying problems are often very similar. In the US suicide is the second highest cause of death among youth aged 10-19 years. Incidence has increased over recent decades with pronounced increases among girls aged 10-14 years and black children aged 5-12 years. These are frightening figures that demand measures that could assist in identifying children, adolescents and young adults who are at risk. In 2012 researchers from the US National Institute of Mental Health published an article on the ‘ASQ,’ an acronym for Ask Suicide-Screening Questions that were designed as a tool to be used in the paediatric emergency department. A sample of 524 patients aged 10-21 years presenting with medical, surgical or psychiatric issues were studied over a three-year period. Their model of four questions had a sensitivity of 96.9%, specificity of 87.6% and negative predictive value of around 99.7% . The questions assessed thoughts of being better-off dead, current wish to die, current suicidal ideation and past suicide attempt. This screening tool was subsequently applied to 15 003 patients aged between 8 and 18 years presenting to the Johns Hopkins Hospital Pediatric Emergency Department between March 2013 and December 2016. One sub-group included selectively-screened patients with psychiatric or behavioural issues, while a universally-screened sub-group also included patients with medical or surgical problems. In order to screen positive the patients required a positive to one or more of the four questions, while a negative response implied four negative answers. Almost 8% of patients in the universal group screened positive as did almost 30% in the selective group. Within the selective group there were subsequently 275 suicide-related emergency department visits and 3 deaths by suicide, while in the universal group there were 118 subsequent suicide-related emergency department visits but no suicides. Adjusting for demographic variables, a positive screening test was associated with a significant risk of suicide-related outcome with hazard ratios of 6.8 (95% CI 4.2-11.1) in the universal group and 4-8 (95%CI 3.5-6.5) in the selective group. This is clearly a simple tool that is easily applied by non-specialised staff in an emergency department and provides valuable information. A fairly obvious question that arises is whether it could be applied in a university or school environment during times of stress to identify those at risk before they present to a casualty/emergency department.

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JAMA Network Open 2019;2(10): e1914070

Prev Sci 2017; 18: 174-82

Arch Pediatr Adolesc Med 2012; 12; 1170-6    

Attention to antimicrobial stewardship has gained traction over the past decade as a result of the emergence of resistant strains of a number of organisms. This resistance is found in both community and hospital settings, with significant health and economic consequences for patients and healthcare systems. Various restrictive interventions exist such as formulary restrictions, pre-authorisation, therapeutic substitution and automatic stop orders. Some of these are ‘system-driven’ and will not allow a particular drug-condition combination to be processed by the pharmacy, while others such as pre-authorisation require contact between prescriber and approver.  Other forms of academic stewardship include unit, ward or hospital audits involving staff, ranging from nurses, pharmacists and allied health workers to the doctors involved in care of the patients. At the hospital level a 6-year retrospective analysis of a Chinese programme in a Beijing academic hospital that involved 820 doctors’ prescriptions for almost 18 million outpatients and ~350 000 inpatients, showed impressive results. Management of the programme was in the hands of 13 clinical pharmacists who formulated the ASP, performance managed staff involved, advised on antibacterial prescriptions and undertook training. The outcomes of interest were antibiotic utilization, prophylaxis and antimicrobial resistance. Consumption intensity was according to the frequently-utilised defined daily dose (DDD) which uses total consumption as the numerator and ‘100 bed-days’ as the denominator. Among outpatients the rate of antibiotic prescriptions decreased from 19.4% to 13.2%, and in inpatients from 64.3% to 34.7%. The resultant effect on consumption was a drop in DDD/100 bed-days from 102.5 to 37.4. In terms of prophylaxis, the focus was on the routine use of antibiotics to cover patients during various surgical procedures. Results here were a reduction from almost 100% to around 20%, with improvements in both the timing of the initial dose and duration of treatment. Resistance rates of E coli and P aeruginosa to fluoroquinolones decreased, as did the incidence rate of methicillin resistant Staph aureus. However resistance rates of E coli and K pneumonia to carbapenems increased, demonstrating that ASPs are not a universal ‘quick fix,’ and resistance remains a function of consumption/utilization/exposure. A number of short-term, limited patient-number studies have emerged from ICUs, for example one showing reductions in DDD and cost, but no impact on isolation of resistant organisms or on nosocomial infections per 100 patient days, while another showed the reductions in consumption, a reduction in bloodstream infections, but no impact on hospital  mortality or length of stay. At the community level a labour-intensive Spanish study involving 214 primary health centres serving a population of around 2 million. Some 24 000 educational interviews were carried out with 1387 doctors over 4 years during which their prescribing practices were reviewed. Additional educational interventions included online health courses, general sessions at each centre covering protocols for management of common conditions, and quarterly reports to all centres. Results were analysed for a pre-intervention period (2012-13) vs. intervention (2014-17). Inappropriate prescribing dropped from 36.5% to 26.9% and the intervention was associated with a sustained reduction in the use of ciprofloxacin and cephalosporins, and a sustained increase in the use of amoxicillin. For this study, in contrast to many studies that have focused on respiratory infections, the emphasis was on urinary tract infections, and the specific outcome was the incidence/1000 inhabitants of extended-spectrum β-lactamase producing E coli. Here the ASP resulted in an incidence density reduction of 65.6% for the pre- vs the intervention periods. Perhaps a concern is that despite the intensity of the programme the rate of inappropriate prescribing only changed from 1 in 3 to 1 in 4.

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Clin Microbiol Infect 2019 doi:10.1016/j.cmi.2019.10.021              

BMJ Open 2019;9(8):e026072

Lancet 2019  http://dx.doi.org/10.1016/S1473-3099(19)30573-0

Henoch–Schönlein purpura (HSP), also known as anaphylactoid purpura or IgA vasculitis, is the most common leukocytoclastic systemic small-vessel vasculitis in childhood. It is usually characterised by non-thrombocytopenic purpura with purple, non-blanching papules primarily on the lower extremities and buttocks. It can also be associated with abdominal discomfort, joint symptoms such as arthritis or arthralgia of large joints of the lower extremities, and renal involvement ranging from asymptomatic microscopic hematuria to acute kidney injury of various degrees up to rapidly progressive glomerulonephritis with risk of chronic renal impairment. Cerebral vasculitis, ureteral or bladder disease, and scrotal, penile or testicular hemorrhage are also possible. A 2013 review estimated the annual incidence of HSP in children to be between 3 and 26.7/100 000, however when considering incidence there is always the question of whether all cases, particularly the mildest, are brought to the attention of those doing the counting. As such it is possible that the incidence is higher than cited. It is usually a self-limiting disease with an average duration of 4 weeks, but a remitting-relapsing course is possible, usually within 3 months after initial resolution. It is generally thought to be the result of genetic predisposition and various environmental factors. Diagnostic criteria for HSP were recently revised by various study groups and currently include palpable non-thrombocytopenic purpura (mandatory criterion) with lower limb predominance, in the presence of at least one of the following four features: abdominal pain; histopathology showing typical leukocytoclastic vasculitis with predominant IgA deposition or proliferative glomerulonephritis with predominant IgA deposition; arthritis or arthralgia; renal involvement (any hematuria and/or proteinuria). Pulmonary involvement in HSP is a rare but severe complication and its presence increases morbidity and mortality. To gain insight into this complication a group of Italian researchers carried out a literature search that included all reports of HSP plus lung involvement in patients aged between 0 and 18 years. Twenty-three cases were discovered for the 40 years surveyed. Average age at the onset of HSP with pulmonary involvement was 10.2 years, with similar incidence between males and females. The time between onset of HSP and the occurrence of the respiratory symptoms ranged from 2 days to 3 weeks, with a mean of 12 days. Pulmonary symptoms included cough, hemoptysis, epistaxis, dyspnea, tachypnea, chest pain, shortness of breath and even acute respiratory failure requiring intubation and mechanical ventilation. An interesting observation was that patients treated with oral steroids prior to presenting with respiratory signs and symptoms did not progress to a requirement for mechanical ventilation. Diffuse alveolar haemorrhage (DAH) was the most frequent pulmonary finding and almost all children with DAH had renal involvement of varying severity from hematuria to acute kidney injury. The co-occurrence of rapidly progressive glomerulonephritis and DAH is also known as “pulmonary renal syndrome,” primarily related to an autoimmune etiology as seen in Goodpasture’s syndrome. While these 23 cases represent the most obvious and severe end of the disease spectrum, where routine investigation of HSP cases has been carried out there was evidence of more-generalised pulmonary involvement. Sub-clinical lung impairment without respiratory symptoms was seen in 28 of 29 patients in a study using ‘lung transfer of carbon monoxide’ (TLCO). This occurred during the active phase of the disease, suggesting that the course of the disease involves a malfunction of the alveolar-capillary membrane due to the deposition of immune complexes containing IgA within the vessels of the alveolar septa.

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Pediatr Rheumatol 2019; doi.org/10.1186/s12969-019-0381-y

Clin Exp Rheumatol 2006; 24 (2 Suppl41): 548-59

Semin Respir Crit care Med 2011; 32: 254-63

Despite increased awareness regarding severe neonatal hyperbilirubinemia (SNH) and its sequelae, kernicterus still occurs. In many hospitals in developing countries guidelines for screening and management of SNH may not exist or are not implemented, thus increasing the risk of kernicterus. For example, in Nigeria SNH persists as a major contributor to neonatal mortality and developmental disability, and a recent study from Cairo reported that 12% of 674 babies admitted with SNH suffered from acute bilirubin encephalopathy, and 9 died. Kernicterus as defined by choreoathetoid cerebral palsy, impaired upward gaze and hearing loss has always been the synonym for bilirubin-induced neurological damage. However recent literature has highlighted subtle forms of neurological dysfunction such as cognitive impairment, diminished executive function, and behavioural disorders that may pass unnoticed until childhood. Whether these subtle changes are caused by hyperbilirubinemia at levels previously considered safe needs to be confirmed, and the issue has been addressed by researchers from an academic level 3 NICU in Egypt. The aim of their study was to evaluate the spectrum of motor and mental impairment in hyperbilirubinaemic neonates, and to monitor the evolution of the condition over the first year of life. Over a five month study period 177 eligible term/near-term neonates (≥35wks) were admitted with unconjugated SNH that required intervention (phototherapy or exchange transfusion) of which 139 were available for follow-up at 1 year. Neurological assessment included the Bilirubin Induced Neurological Dysfunction (BIND) score that is used to detect and grade the presence of acute bilirubin encephalopathy by assessing mental status, muscle tone and cry pattern. Scores of (1–3), (4–6), (7–9) indicate mild, moderate and severe acute bilirubin encephalopathy. Neurodevelopmental assessment was performed at 3, 6 and 12months chronological age using the Bayley Scales of Infant Development (BSID) which yields both mental developmental index (MDI) and psychomotor developmental index (PDI) Auditory brainstem response (ABR) was recorded for all babies at the first follow up appointment at 3 months of age and repeated at 6 months if abnormal.  BIND scores at admission ranged from 0 to 7 with a median of 0, total serum bilirubin (TSB) ranged from 10 to 63 mg/dL (179.6–1077 μmol/L) with a mean of 25.5 ± 6.5 mg/dL (436 ± 112.9 μmol/L), and duration of exposure to hyperbilirubinemia before admission ranged from 1 to 10 days with a median of 2 days. Persistent neurological dysfunction at 12 months of age was seen in 19/139 patients (13.6%). The spectrum of dysfunction included 8/19 with classic kernicterus (6 with associated mild mental delay), 3/19 with isolated auditory impairment, 1/19 with severe motor and mild mental delay, and 7/19 with mild motor delay. The cutoff value for TSB at which classic kernicterus was noted at one year of age was ≥27.5 mg/dL (470.3 μmol/L); however 65% of babies with bilirubin levels above the cutoff value had normal outcome at follow up. Persistent poor neurodevelopmental outcome and hearing impairment at 12 months were positively correlated with high TSB, high BIND scores, and longer duration of exposure to severe hyperbilirubinemia. Low PDI tended to improve over the 12 months, whereas low MDI did not. The variability of response of different babies to the same TSB level may be due to variation in the permeability of the blood brain barrier to free bilirubin or genetic predisposition to bilirubin injury_. Time-dependent bilirubin neurotoxicity has been attributed to loss of tight junctions between blood-brain barrier endothelial cells with subsequent increased permeability, and also to loss of defensive dynamic properties of microglia if exposed to SNH for long periods.

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Early Hum Dev 2019; doi.org 10.1016/j.earlhumdev.2019.104909

Front Cell Neurosci 2012; doi: 10.3389/fncel.2012.00022

Indian J Pediatr2012; 79: 202-6

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