Recently there has been greater use of non-invasive ventilation in very low-birth-weight preterm infants as initial respiratory support after birth or post-extubation. The commonest devices to provide nasal intermittent positive pressure ventilation (NIPPV) are the standard short bi-nasal prongs (BNPs) which unfortunately are associated with discomfort and pressure-related nasal injury. The RAM cannula (Neotech) is made of softer material with long and narrow tubing (LNT) for transmitting the pressure through thin-walled prongs. This results in easier application, greater comfort, and less nasal trauma. However, there is concern that this long thin interface delivers reduced and suboptimal pressure transmission, tidal volume, and support, especially when the leak at the nose is more than minimal. Despite widespread use the clinical efficacy of LNT has not been thoroughly studied. To this end researchers from Israel compared the ability to prevent intubation in preterm infants by using NIPPV for the initial treatment of respiratory distress syndrome (RDS) or post-extubation with either LNT or BNP devices. This randomized prospective, controlled, non-inferiority dual-centre study was conducted in the NICUs of Rambam and Bnai-Zion Medical Centers between December 1, 2017, and December 1, 2019. The study population included preterm infants born between 24 and 34 weeks. Inclusion criteria were the need for non-invasive ventilatory support for initial treatment or after the first extubation after birth. The need for ventilatory support was based on clinical signs of RDS, need for oxygen supplementation for saturation >90%, and/or pCO₂ level of ≥60 mm Hg. The initial treatment group included infants who needed non-invasive ventilation during the first 7 days of life without prior endotracheal ventilation. The post-extubation group included infants who needed non-invasive ventilation during the first 28 days of life after any period of endotracheal ventilation in the NICU. Eligible infants were randomly assigned to NIPPV with either LNT or BNP. The LNT size was selected to fill approximately 80% of the nares. The short CPAP NIPPV prongs size was selected to fill close to 100% of nares without causing local pressure. Mouth occlusion was allowed with a pacifier or passively. Initial NIPPV settings were peak inspiratory pressure (PIP) of 14 to 18 cm H₂O, positive end-expiratory pressure (PEEP) of 6cm H₂O, respiratory rate of 10 to 30 per minute, and inspiratory time of 0.30 to 0.35 seconds. Saturation targets were 90% to 94%. Maximal settings allowed were PIP of 24, PEEP of 8 and respiratory rate of 40 per minute Weaning from NIPPV to no support or to low flow was considered if there was clinical improvement and the infant was receiving a fraction of inspired oxygen of ≤0.3, PIP of ≤16, PEEP of ≤6 and respiratory rate of ≤20. Caffeine was given to all infants younger than 32 weeks during the first day of life and to symptomatic infants 32weeks or older with apnoea. Exogenous surfactant was given as rescue therapy if inspired oxygen requirements of ≥35%. The primary outcome was treatment failure within 72 hours after initiation of NIPPV i.e. a need for endotracheal ventilation. In total, 166 infants were randomly assigned to the treatment groups, 83 to LNT and 83 to BNP. One infant died in each group from late onset gram-negative sepsis. Baseline demographic and clinical characteristics were comparable between the 2 groups. The use of LNT was similar to BNP with regard to the primary outcome. Endotracheal ventilation within 72 hours from randomization occurred in 12 infants (14%) in the group using LNT and 15 (18%) in the BNP group (risk difference, −3.6%; 95% CI −14.8 to 7.6; p=0.53). A subgroup analysis by birth weight (<1250 or ≥1250g) showed similar results. A multivariable regression analysis for the stratified variables revealed that treatment failure with LNT compared with BNP had an odds ratio of 0.74 (95% CI, 0.32-1.70) that was not significant. Infants who failed LNT and BNP were comparable in characteristics and reasons for failure. Moderate and severe nasal trauma were significantly less common in the group using LNT (4 [5%] vs 14 [17%]; 95% CI, 0.02-0.22; p=0.01). Surfactant administration rate was similar in both groups. From this study and the few others that have been performed it appears that a key factor in success of LNT lies in minimising the leak around the cannula and possibly allowing slightly higher ventilator pressures.

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JAMA Pediatr. 2021; 175: 36-43.

Neonatology. 2019; 115: 28-35

Cochrane Database Syst Rev. 2017; 2: CD003212

Childhood pneumonia is an important cause of mortality in children aged less than 5 years, with much of the disease acquired in the community. Of all community-acquired pneumonia (CAP) cases, 7-13% are severe enough to require hospitalisation and some are severe enough to require transfer to the paediatric intensive care unit (PICU) due to disease progression and/or complications. Identifying the risk factors in those patients who deteriorate may assist in providing timely treatment and reduce morbidity and mortality. To this end researchers in Guangzhou, China studied hospitalised paediatric patients with severe CAP who were admitted between June 2013 and June 2017 and transferred to the PICU within 48hrs of admission. Children with co-morbidities such as neuromuscular or metabolic disease, severe immunodeficiency or malignancies were excluded. Demographic characteristics, clinical presentation, radiological and microbiological characteristics, laboratory parameters, treatment, response to therapy and outcome were collected for each patient. In addition to collection of clinical data the authors used the Paediatric Early Warning Score (PEWS) as calculated during the admission. The PEWS is an easily-scored tool that is based on only 5 domains: behaviour, cardiovascular and respiratory status, nebuliser use, and persistent postsurgical vomiting.  All patients underwent testing of nasopharyngeal secretions for adenovirus, respiratory syncytial virus (RSV), influenza, parainfluenza, rhinovirus, and other less-common viruses. Patients were also tested for Mycoplasma pneumonia, and cultures were obtained for bacterial or fungal infection. A total of 15,711 patients with CAP were admitted over the 4-year period. These included 511 patients directly admitted to the PICU and 15,200 patients who were first admitted to a general ward. A total of 222 patients with a final diagnosis of severe CAP were transferred to the PICU from a general ward, but after exclusion (e.g. if transferred to the PICU >48 hrs after admission) there were 113 patients, 73 transferred to the PICU within 24hrs of admission and a further 40 within 48hrs. Ages ranged from 1 month to 9 years (median 5.0 (2.0, 13.0) months) with 72.6% aged <12 months. The commonest reason for admission was premature birth (19.5%), followed by airway abnormality (16.8%) and congenital heart disease (13.3%). A total of 65.5% had received antibiotics, while 34.5% had received corticosteroids prior to hospital admission. Complications occurred in 82.3% before transfer to the PICU: 77.0% had respiratory failure, 12.4% had septic shock, multi-organ dysfunction occurred in 6.2%, and acute renal failure in 2.7%. A total of 87.6% required assisted ventilation, mostly mechanical ventilation in 78.8%. The median PEWS score on hospital admission was 4.0 (2.0, 6.0), and non-survivors had a higher median PEWS score than survivors. The mortality rate was 12.4%. A viral agent was detected in 66.4% of cases and a bacterial agent in 41.6%. There were 40 cases of mixed infection (35.4%) with bacterial-viral mixed infection the most common in 19.5% of cases. Adenovirus was the most common viral pathogen (22.1%) followed by RSV (15.9%), and influenza A and B (8.0%). Of the bacterial agents, H influenza was the most common (8%) followed by Strep pneumoniae (6.2%) and Klebsiella pneumonia (6.2%). Mycoplasma accounted for 14.2%. Underlying co-morbid conditions were found in 50.4%. Wheezing, cyanosis, oxygen saturation <90%, PEWS score>3 on hospital admission, not receiving corticosteroid therapy prior to hospital admission, the need for mechanical ventilation, septic shock, multi-organ disease and renal failure prior to ICU transfer were all associated with mortality (p< 0.05). Laboratory findings associated with mortality were increased ALT (>100 U/L) and AST (>100 U/L), decreased haemoglobin (<80 g/L) and albumin below <35 g/L (all p< 0.05). On multivariate analysis the independent risk factors for death were oxygen saturation <90% on hospital admission (OR 8.77) and decreased albumin (OR 4.73). No association was noted between mortality and underlying comorbidities or specific pathogens. While RSV is reported as the leading cause of viral respiratory disease in both high and low-income countries, in this study adenovirus was the most common viral pathogen, followed by RSV. Also contrary to previous studies the authors found no increased risk of mortality in patients with mixed bacterial-viral infections, possibly because two-thirds of patients received antibiotic treatment prior to hospital admission that might have protected them. In terms of low albumin being a risk factor, Aman et al. found that decreased serum albumin levels are associated with increased pulmonary vascular permeability and lung injury in critically ill adult patients, irrespective of underlying disease and fluid status. The number of patients in this study with septic shock, multi-organ disease and acute renal failure prior to being transferred to the PICU suggest that paediatricians should consider more aggressive therapies and methods that prevent development and/or progression of these conditions. In this regard the PEWS assessment tool shows the potential to play a key role in assessing patient status, detecting clinical deterioration and altering care in response to changing patient status. An interesting finding in this study that is topical in terms of current management of COVID, is the association between the use of corticosteroids and CAP-related mortality. The study found a significant difference between survivors receiving corticosteroid therapy prior to hospital admission and those who did not (P < 0.05). While one would not want steroids to be administered routinely to all CAP at the time of diagnosis, perhaps by using a tool such as the PEWS after admission to hospital one could select patients as soon as there are signs of deterioration.

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Pediatrics Neonatol 2020; 61: 577-83

Crit Care Med 2011; 39: 89-97.

Pediatrics 2010; 125: e763-9

Surfactant has traditionally been administered to neonates with respiratory distress via an endotracheal tube with a subsequent period of mechanical ventilation. More recently many clinicians have adopted an alternative approach involving administration via a catheter inserted into the trachea during spontaneous breathing. This has come to be known as minimally invasive surfactant therapy (MIST). Meta-analyses of this approach have shown that in comparison with administration by endotracheal tube, MIST is associated with reductions in mechanical ventilation, bronchopulmonary dysplasia, and death or bronchopulmonary dysplasia combined. In fact, the 2019 European Consensus Guidelines on Management of RDS recommends MIST as the preferred method of surfactant administration for spontaneously breathing infants receiving CPAP. However the procedure is not without complications and a registry study covering >2600 neonatal intubations in 10 academic NICUs reported the occurrence of ≥1 adverse events in 18% of administrations and 4% complicated by severe adverse events. First attempts were successful in only 49% of procedures and complications included coughing, surfactant reflux, desaturation, bradycardia and subsequent need for positive pressure ventilation (PPV). The use of sedative premedication for MIST remains a subject of debate, with recent studies reporting that premedication is associated with an improvement in infant comfort scores but also with an increase in complications such as desaturation and need for PPV. A recent article from Australia and published in the Journal of Pediatrics reported on results of MIST in 122 preterm neonates requiring CPAP support with a clinical and/or radiologic diagnosis of RDS, adequate spontaneous respiratory drive, and a required fraction of inspired oxygen (FiO₂) of 0.30-0.35 or higher to maintain oxygen saturation (SpO₂) of 91%-95%. Study subjects also received sucrose for analgesia, intravenous atropine before the procedure to decrease the risk of bradycardia, and caffeine was recommended for infants of <32 weeks’ gestational age or <1250 g at birth and any other infant with a history of apnoeic episodes. A vascular catheter was used for laryngoscopic placement via the mouth and surfactant was administered in small boluses over a period of 30-180 seconds, pausing if surfactant reflux or irregular breathing was observed. It was left to clinicians to decide whether or not to remove nasally-administered CPAP during the procedure. Almost all (98.4%) of subjects were preterm, with 70.5% born at <32 wks and 25.4% at <28 wks gestation.  The median age at which the first MIST procedure was performed was 7 hours but those who were <28wks were treated at a median age of 2 hours. First attempt success was achieved in 54.1%, with success within 2 attempts in 84.4%. The maximum number of attempts required was 5. Procedural success rates differed

by clinician experience level with attending neonatologists successful in 39 of 47 attempts, neonatal fellows in 79 of 121 attempts, and paediatric residents in 2 of 13 attempts. Desaturation to an SpO₂ of <80% occurred in 73.3% of infants but the median recovery time for SpO₂ of >80% was only 31 seconds. Desaturation rates were similar whether the CPAP interface remained in place or was removed. Bradycardia occurred in 13.9% of procedures, mainly in the infants who had not received atropine. Improvements were seen in pH from a median of 7.27 to 7.32 and in the partial pressure of carbon dioxide from 55.5 mm Hg to 47.7 mm Hg. The FiO₂ at all post-MIST time points was significantly lower than the pre-MIST FiO₂ and at 4 hours had decreased from a median of 0.40 to 0.22. The majority avoided mechanical ventilation, both during the first 72 hours of life and during admission. Thirteen infants received MIST twice. Complications within the MIST-treated group included pneumothorax in 8.2%, bronchopulmonary dysplasia in 36.5%, Grade 3-4 intraventricular haemorrhage in 4.1% and death before discharge in 4.1%, but since the study was not a comparative study e.g. vs. surfactant via an endotracheal tube, the authors draw no conclusions in this regard. The main points are that the intervention is certainly possible (albeit extremely operator-dependent) and appears to be effective. Certainly worth noting is not only the use of sucrose for analgesia but also the planned use of both atropine and caffeine. Despite the fact that MIST is currently favoured in many NICUs, it is not entirely clear why a vascular catheter would be superior to a small bore endotracheal tube if all other variables are similar.

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J Pediatr 2021; 229: 141-6

Arch Dis Child Fetal Neonatal Ed 2017; 102: F17-23.

Cochrane Database 2016 https://www.cochrane.org/CD001069/sucrose-analgesia

Increasingly, children and adolescents are engaging in training in a single sport at the exclusion of other sports. Studies over the past few years have shed light on poor health outcomes that result from such sport specialisation among adolescent athletes, and health care providers and public health policymakers are concerned about musculoskeletal injury risk, altered movement patterns and negative psychosocial outcomes. On the other hand the benefits of sport are clear: greater self-esteem, social integration, enhanced motor control, and increased potential for healthy behaviours in the long term. Medical associations and sports bodies are beginning to provide guidance and have published position statements, with the American Academy of Pediatrics and American Medical Society for Sports Medicine actually discouraging sports specialisation before onset of adolescence due to concerns about burnout and overuse injuries. However where such specialisation is pursued, significant financial resources and time are allocated with families being responsible for equipment, competitions, travel costs and training fees. These costs can be prohibitive, particularly for families with lower household income and studies show that participation is in fact proportional to family income and socioeconomic status (SES). Disturbingly, a recent study described how high school sports specialisation and injury rates were also associated with SES, and injuries often required treatment of longer than 1 month and rest from sports. To further explore the relationship between sport specialisation and affluence, in 2019 researchers from Colorado in the USA conducted a cross-sectional study of 13-18 year-old athletes from a single school district. All participants recorded their medical history, demographic characteristics, level of competition and amount of time spent training per week, and completed questionnaires relating to sport specialisation and family affluence. Level of sport specialisation was graded as low, moderate or high. Fifty-two percent of the 195 participants reported low, 33% reported moderate, and 15% reported high sport specialisation. Sport specialisation groups were similar in age (mean = 15.3 ± 1.6 years), proportion of females (49%), and time spent training (mean = 11.9 ± 5.0 hours per week). The high specialisation group reported significantly greater family affluence than the low specialisation group (Family Affluence Scale = 10.4 ± 1.7 vs 9.2 ± 1.9; p =0.005).  The authors conclude that this type of study allows researchers, clinicians and policy makers to better identify youth athletes more likely to specialise in a single sport. Future work may lead to advancements and/or recommendations in cross-training, time allocation per sport, sport progression, and neuromuscular skill pattern development in order to decrease injury risk and improve mental health outcomes for these adolescents. From a South African perspective the study highlights yet another ‘divide’ among our youth. Unless there are programmes that provide financial and other support to disadvantaged young athletes with the potential to excel in a specialised sport we will be denied the contribution they are capable of making.

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Clin Pediatr 2021; 60: 50-55

J Athl Train 2019; 54: 1061-1066

Br J Sports Med 2014; 48: 287-288

Am J Prev Med 2007; 33: S195-S208

It is assumed/believed by many that pain in preterm infants can adversely affect their development, affecting nociception, brain development, stress systems, and functional abilities. Prolonged exposure to pain has also been associated with impaired brain development while preterm infants are in the NICU. Pain assessment is assessed by means of physiological (e.g. heart and respiratory rate) and behavioural criteria (crying time, changes in facial expression and limb movements). The Premature Infant Pain Profile (PIPP) is a set of measurable behavioural and physiological responses such as facial expression changes (squeezing eyes, raising eyebrows, wrinkling nasolabial groove) as well as changes in heart rate, oxygen saturation (SaO2), and behavioural status of the infants. Various non-pharmacological interventions are being explored for relieving pain, one of which is based on the fact that the sense of smell is fully developed at birth and maternal odour supposedly has a soothing effect on newborn infants. It has also been established that infants are able to detect their mother’s breast odour even in the absence of breastfeeding at birth, and even the breast milk odour can enhance sucking via the facial and trigeminal motor nerves, thereby stabilising the neonate’s physiological state. Related to this is research showing that breastfeeding in human neonates can eliminate pain responses, likely mediated by opioid and non-opioid mechanisms. Given contradictory results of studies into breast milk odour, and in light of the importance of pain relief for preterm infants, Iranian researchers studied the effects of inhaling the odour of human milk on the behavioural pain responses caused by administration of Hepatitis B vaccine. Infants of 28–37 weeks of gestation were randomly assigned to one of three groups: MBMO (neonate’s mother’s breast milk), another mother’s breast milk (ABMO) or control group exposed to distilled water. Considering 80% power and 0.05 error probability, at least 30 neonates were required in each group. Heart rate, blood pressure and SaO2 were recorded before the intervention and immediately after vaccination. The breast milk odour was derived from pouring 2 ml of breast milk onto a cottonwool swab vs 2 ml of distilled water. The MBMO, ABMO and water swabs were placed 3cm from the baby’s nose, starting 3 minutes before vaccination and continued until the vaccination was completed. The PIPP was used as the primary outcome variable and scores were recorded immediately before and after vaccination. The PIPP includes the behavioural state, changes in heart rate and SaO₂, brow bulge, eye squeeze and nasolabial furrow. A score between 0 and 6 points reflects that the pain level is mild; 7-12 is moderate; 13-21 is severe. Video recording of behavioural responses was captured from the beginning to the end of the process and PIPP scoring performed by a single observer unaware of the test group. Throughout the intervention, any actions on the neonates such as contact, movement and so on were avoided. All 90 subjects completed the study. The infants of the three groups were not significantly different in terms of gender, gestational age, Apgar scores, anthropometry or clinical diagnoses and no significant differences were found between the three groups in mean heart rate, blood pressure or SaO₂ before the intervention. However, after the intervention the means for heart rate in groups MBMO, ABMO and control were 146 ± 14.3, 153 ± 17.5 and 155 ± 17.7, respectively (P = 0.012), and the means for PIPP scores were 6.6 ± 1.3, 10 ± 2, and 11.4 ± 1.9, respectively (P < 0.001). No differences were found between groups in SaO₂ or blood pressure after the intervention (P > 0.05). These results are broadly in agreement with studies that have used maternal breast milk odour but differ from a study that studied maternal breast milk odour as well as amniotic fluid odour and body odour and also had methodological differences. While the authors express some concern about not observing an effect of the intervention on oxygen saturation, overall they conclude that maternal breast milk odour can be used as a familiar smell to manage the preterm infant’s pain before performing a procedure such as vaccination. Perhaps an important question in studies such as this is whether these non-pharmacological agents are analgesics or sedatives. In summary 2103 sucrose was used prior to surfactant administration and while the authors of that study cited its analgesic properties, others have emphasised that it mainly has sedative effects. The same may apply to breast milk odour.

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BMC Pediatr 2021; 21: 61

Int J Childbirth Educ. 2018; 33: 6–8.

Pain. 2011; 152: 2575–81

Massage therapy (MT) is one of the most popular complementary therapies in North America and has a long history of practice. It has been described as hands-on manipulation of the soft tissues of the body, specifically the muscles, connective tissue, tendons, ligaments and joints, in order to relieve physical dysfunction and pain, reduce stress, promote relaxation, reduce anxiety or depression, and improve general well-being. Various types of MT have been practised in children around the world. Close to 1% of American children use MT. Frequencies range from 8.7% to 29% in children with oncological disorders, as high as 47% in patients with neurological disorders, 38% in patients with cardiac disorders and 34% in patients with respiratory disorders. Specific mechanisms by which MT exerts therapeutic effects are not known, yet clinical trials in infants <6 months of age found significant effects on anthropometry, sleep duration, bilirubin levels and frequency of diarrhoea. In children aged 2–18 years MT has been shown to improve arthritis pain and muscle tone and decrease anxiety. Most systematic reviews of paediatric MT have focused on the effectiveness of MT rather than its safety.  Adverse events (AEs) reported for adults are diverse, including cerebrovascular accidents, disc herniation/spinal cord injury, thromboembolism, soft tissue trauma and genitourinary injuries. To gain further insight into AEs in subjects aged 2-18, researchers from Alberta in Canada conducted a systematic review of studies published in 11 countries between 1991 and 2018. To their knowledge this was the first study to primarily assess AEs associated with paediatric MT. As per the Cochrane handbook, AEs were defined as unfavourable or harmful outcomes occurring during or after the use of a drug or other intervention, but not necessarily caused by it. Severity was categorised into five grades, from grade 1 (mild, asymptomatic) to grade 5 (death) based on information provided by the studies, and as ‘direct’ if directly caused by the intervention or ‘indirect’ if the intervention caused a delay in diagnosis or treatment which resulted in an AE. Searches yielded 12 286 citations of which 938 were retrieved for full-text evaluation and eventually 60 were included. Half of the studies made no mention of AEs, 13 reported no AEs and 16 (26.6%) reported at least one AE after MT. There were 20 mild events that resolved with minimal intervention, 26 moderate events (grades 2–3) that required medical intervention, and 18 cases of severe AEs (grades 4–5) that resulted in hospital admission or prolongation of hospital stay. Of the latter group 17 AEs were volvulus without malrotation (VWM) in premature (mostly VLBW) infants. Four of the 17 cases ultimately died. Volvulus without malrotation is considered a rare event that is associated with preterm birth (<30 weeks GA) and low birth weight (<1000 g). In five of the reported cases in the review the authors did not consider MT to be a risk factor for the volvulus, while in 12 cases MT was considered to be the risk factor. This led to a policy change to avoid abdominal massage in preterm infants, following which no further events of VWM occurred. On the other hand, various authors have speculated on other risk factors for VWM including intestinal immaturity, prolonged transit times, stool retention and continuous positive airway pressure or other forms of respiratory support. Several of these risk factors were also identified in the included systematic review, thus making it difficult to relate MT to the development of VWM. An additional consideration is that the majority of the 60 reviewed studies did not report if an AE occurred or not, leading to publication bias. Nevertheless the most significant finding of the review is the association between abdominal massage and VWM in preterm infants, and while there are indeed several confounders, abdominal massage should be undertaken with caution in this population.

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BMJ Paediatrics Open 2020; 4: e000584. doi: 10.1136/bmjpo-2019-000584

Neonatal Netw 2015;34:165–77

Evid Based Complement Alternat Med 2007; 4: 23–34

With recent practice changes towards less frequent and less proactive treatment of patent ductus arteriosus (PDA), clinicians nevertheless have to decide which infants will benefit from PDA closure and when and how PDA closure should be attempted or facilitated. Medical management has focused on drugs such as ibuprofen and indomethacin, but there is now some interest in whether platelet numbers and/or function have a role to play. In 2010 it was reported that platelets contribute to ductal closure and subsequent vascular remodelling in mice. The researchers showed that platelets are recruited to the luminal aspect of the ductal endothelium within minutes after birth, and that formation of a platelet-plug within the ductus contributes to remodelling. Furthermore, after genetic disruption of platelet biogenesis and function, it was demonstrated that platelet dysfunction was associated with haemodynamically-significant PDA (hsPDA). Similar results were observed with antibody directed against platelet collagen receptor GP VI and in this model, administration of cyclooxygenase inhibitors did not compensate for impaired platelet function. These results suggest that platelets play a pivotal role in ductus arteriosus closure, but the clinical significance in preterm infants is still controversial. Low platelet counts are frequent in preterm infants but studies into the role of platelet numbers in spontaneous or pharmacological PDA closure have yielded conflicting results. However several investigators have indicated that thrombocytopenia within the 1st week of life does contribute to prolonged ductal patency, and a meta-analysis from 2015 that included 11 cohort studies involving 3,479 infants also concluded that low platelet counts within the 1st day(s) of life were marginally but significantly associated with PDA or hsPDA. In studies that have looked at the combination of thrombocytopaenia and pharmacological intervention, a meta-analysis (eight studies, 1087 infants) revealed a moderate but significant association between pre-treatment thrombocytopenia and failure of pharmacological PDA closure. While cyclooxygenase inhibitors adversely affect platelet plug formation in adults, the available data from preterm infants suggest that inhibition of platelet plug formation may occur but is of limited clinical significance. However, one might speculate that even moderate alterations in platelet function may become relevant in severely thrombocytopenic infants. Perhaps more exciting than the studies involving platelet numbers are the studies involving platelet function. Studies have consistently identified sepsis/inflammation, lower gestational age, and feto-maternal conditions such as preeclampsia as risk factors for PDA in preterm infants. All these factors are associated with altered platelet function, and speculation has been that platelet function rather than platelet number is the key determinant of PDA. A significant association between lower platelet count, higher CRP level and incidence of PDA has been demonstrated, with CRP being the only independent predictive factor for PDA in a regression model. Taking a different line of investigation, a proteomics-based study on neonatal plasma identified six differentially expressed proteins (platelet factor 4, fibrinogen, von Willebrand factor, collagen, mannose binding lectin-associated serine protease-2, fibronectin), which were associated with PDA. These proteins are closely related to platelet activation and the coagulation cascade. There are also developmental differences in platelet function between preterm infants, term infants and adults, and newly released platelets differ in function as compared to older, more mature platelets. A lower number of mature platelets during the latter half of the 1st week of life has been shown to be associated with PDA in preterm infants, but immature platelets were not independently associated with PDA. Despite the experimental and epidemiologic evidence for an association between platelets and ductal closure, current clinical evidence strongly suggests that boosting platelet numbers should not be an option. This is because of evidence showing adverse effects (specifically IVH) in infants that were liberally transfused.

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Front Pediatr 2021; doi:10.3389/fped.2021.612242

Nat Med 2010; 16: 75–82  doi: 10.1038/nm.2060

Pediatr Neonatol 2018; 59: 640–1  doi: 10.1016/j.pedneo.2018.08.006

There is growing evidence that immune-related cells and proteins play a role in brain development and function and that maternal immune activation, whether from infection, autoimmune disease (AID) or chronic inflammation during pregnancy, increases the risk of neurodevelopmental disorders among offspring. Maternal autoantibodies and proinflammatory cytokines are hypothesized to cross the placenta and alter foetal brain development. Potential mechanisms include epigenetic modulation of neurodevelopmental genes, activation of microglia (the innate immune cells of the brain), and modification of synapse formation and function. Neurodevelopmental disorders caused by disrupted brain development include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and learning disabilities. Previous studies have focused on the link between maternal AIDs and ASD, and a 2016 systematic review and meta-analysis of 10 studies showed an overall increased risk of autism among offspring of women with AID. In contrast, the link between maternal AID with ADHD has been studied to a lesser extent, with one study reporting an increased incidence of ADHD among children of women with any AID and others reporting increased risk with specific autoimmune conditions including type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, autoimmune hepatitis, psoriasis and ankylosing spondylitis, but these latter studies have been limited, most involving very small numbers. To further explore the relationship between maternal AID and ADHD in childhood, Australian researchers studied all infants born in the state of New South Wales at ≥20 weeks gestation or weighing at least 400g. Birth data were linked to all hospital admissions between July 1, 2000 and December 31, 2012 for both mother and child. Birth data were also linked to pharmaceutical data for the child for treatment of ADHD which was the main outcome. Multivariate Cox regression was used to assess the association between maternal AID and ADHD. There were     831 718 singleton, term infants of which 12 767 (1.5%) were linked to a maternal autoimmune diagnosis. Study infants were matched to >50 000 control infants for a total study cohort of 63 050 infants. In this total cohort any maternal AID was associated with ADHD in offspring (Hazard Ratio 1.30; 95%CI 1.15-1.46), as was type 1 diabetes (HR 2.23; 95%CI, 1.66-3.00), psoriasis (HR 1.66; 95%CI, 1.02-2.70) and rheumatic fever or rheumatic carditis (HR 1.75; 95%CI, 1.06-2.89). A meta-analysis was then done on these data plus from five additional studies. Any maternal AID (2 studies: HR 1.20; 95%CI, 1.03-1.38), type 1 diabetes (4 studies: HR 1.53; 95%CI, 1.27-1.85), hyperthyroidism (3 studies: HR 1.15; 95%CI, 1.06-1.26) and psoriasis (2 studies: HR 1.31; 95%CI, 1.10-1.56) were associated with ADHD. These findings suggest possible shared genetic vulnerability between AID and ADHD or a potential role for maternal immune activation in the development of childhood neurodevelopmental disorders. Potential mechanisms include shared genetic and environmental risk factors or direct effects of maternal autoantibodies or cytokines crossing the placenta and altering the foetal immune response, in turn leading to changes in the CNS. Interesting data from other studies that have linked type1 diabetes to ADHD showed that the increased risk of ADHD was independent of whether it was diagnosed in mothers (HR 1.36), fathers (HR 1.21) or the children themselves (HR 1.31). These findings suggest that the association may in part be due to shared genetic risks, and these risks could be immune-related genes. Future studies measuring disease activity in mother and child, various modifiers, and medication use are required to better understand the mechanisms underlying all these associations.

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JAMA Pediatr. 2021; 175: e205487

Diabetes Care. 2018; 41: 2502-8

Science. 2016; 353: 772-7

Spastic cerebral palsy (SCP) is the most common CP subtype, accounting for 77% of all cases. It typically presents with increased muscle tone, hyperreflexia, exaggerated deep tendon reflexes and, in some cases, clonus. Children with severe SCP are usually categorised on levels III–V of the Gross Motor Function Classification System (GMFCS). Spasticity often results in the development of muscle and joint contractures, torsional deformities of bone, and joint instability at the hip, knee, and ankle that can impact activities of daily life. Treating lower limb spasticity is an important rehabilitation goal. Current interventions include oral medications (e.g., baclofen, tizanidine, and dantrolene), physio- and occupational therapy, splinting and casting, botulinum toxin injections, and surgical methods such as selective dorsal rhizotomy and intrathecal baclofen. However, many of the latter are associated with adverse effects. There is thus a need for alternative treatments for SCP, particularly conservative interventions with the fewest side effects. Non-invasive brain stimulation (NIBS) has been proposed as a modality to manage spasticity since it can be used repeatedly to targeted cortical regions, activating or inhibiting neural activity in the cortex. This purportedly influences inhibitory input to the dorsal reticulospinal and corticospinal tracts and reduces excitatory inputs from the medial reticulospinal and vestibulospinal tracts that cause spasticity. NIBS studies on CP children, using transcranial direct current stimulation (tDCS) have shown significant improvements in upper limb function, but these studies a) did not include severe SCP children with GMFCS levels III–V, and were not focused on lower limb spasticity. Transcranial pulsed current stimulation (tPCS) is a novel type of NIBS that has recently gained attention in experimental settings, delivering pulsed currents at a predetermined frequency to the cortex, as opposed to the direct current provided by tDCS. While there are yet no studies done involving tPCS and children with SCP, the safety of tPCS has been investigated in the treatment of Parkinson’s disease, with no adverse events recorded and post-treatment results showed significant improvement in gait and balance. According to the literature, tPCS has been demonstrated to reliably induce enhanced corticospinal excitability, increase the power and connectivity of endogenously generated brain oscillation in a frequency-specific manner, and has a facilitatory effect on interhemispheric connectivity. Another treatment modality is transcutaneous electrical nerve stimulation (TENS), a form of non-invasive peripheral stimulation that is commonly used in the rehabilitation of children with CP. TENS involves the application of electric currents onto the skin using surface electrodes to target spastic muscles and/or their antagonists. The reduction of spasticity caused by TENS is supposedly due to the recruitment of sensory afferents that can suppress moto-neuronal excitability through the depression of propriospinal interneurons, or the induction of long-term synaptic changes in primary afferents in the dorsal horn. Several TENS studies have reported positive effects on lower limbs of children with CP such as decreases in hip adductor spasticity, decreased knee jerk impulses, and increased walking speed and cadence. However data are limited. A combination of the above non-invasive neuromodulation interventions has been investigated in various medical conditions such as chronic pain, chronic stroke, and spinal cord injury. These studies reported enhanced treatment benefits that seemed to surpass levels reached by single intervention alone, including improved hand function, gait ability, reduced chronic pain and increased ankle movements. Because of a lack of data on combined modalities in children with CP, researchers from Guangdong, China studied combination treatment with tPCS and TENS vs physiotherapy alone. Sixty-three SCP children aged 2–12 years, classified on levels III–V of the GMFCS were randomly assigned to one of two groups, resulting in 32 children in the experimental group and 31 children in the control group. The experimental group underwent a combination therapy of tPCS (400 Hz, 1 mA cerebello-cerebral stimulation) and TENS (400 Hz, max 10 mA) for 30 min, followed by 30 min of physiotherapy five times per week for 12 weeks. The control group underwent physiotherapy only 30 mins per day five times per week for 12 weeks. The primary outcome measures were the Modified Ashworth Scale (MAS) and Modified Tardieu Scale (MTS). Evaluations were performed 3 days before and after treatment. The authors found a significant improvement in MAS and MTS scores of the lower limbs in the experimental group compared to the control group in the hip adductors, hamstrings and gastrocnemius. MTS scores in the knee and ankle joints also showed significant improvements. While a third study group of TENS treatment alone would have strengthened the research, the authors of the Chinese study conclude that a combination of tPCS and TENS can improve lower limb spasticity in SCP children classified on GMFCS levels III–V with minimal side effects.

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BMC Pediatr  2021; 141 doi.10.1186/s12887-021-02615-1

Dev Med Child Neurol. 2007; 49: 534–8

PLoS One. 2014; 9: e102313

Lung ultrasound (LUS) is proving to be very useful in the NICU. Studies show that the modality diagnoses respiratory diseases with greater accuracy than X‐ray and predicts failure of non-invasive ventilation, the need for surfactant in preterm infants and bronchopulmonary dysplasia (BPD) in VLBW infants in the first week of life. The LUS score is a semi-quantitative assessment that correlates with oxygenation status and severity of respiratory diseases, and can be used to monitor progression of lung diseases. It also detects pulmonary oedema in neonates, is a real‐time indicator of extravascular lung water and correlates with lung inflammation in preterm neonates. LUS scores typically remain high from birth until a postmenstrual age (PMA) of 36 weeks in VLBW infants with BPD. Despite little evidence to support long-term efficacy and safety of diuretics they are often used in preterm infants with established BPD. Some studies have demonstrated that furosemide may improve respiratory function through removal of fluid from lung tissue, and a recent one shows a decrease in BPD or death in preterm infants on the drug. On the other hand there are studies that failed to show benefit. Adverse effects related to long‐term use include decreased bone mineralization, hearing loss and nephrotoxicity. As an NICU that utilises both diuretics and LUS, a group of Spanish researchers investigated whether LUS scores changed after initiation of diuretic therapy in infants diagnosed with BPD. Diuretics included furosemide, hydrochlorothiazide and spironolactone. The LUS score was obtained at birth, at 3 days, and weekly thereafter until 36 weeks postmenstrual age. The score was calculated as previously described (see summary 2032).  Eighteen subjects were divided post-hoc into two groups according to their response to diuretics in terms of a decrease in respiratory support. The groups had similar median gestational ages but differed in the median number of days on invasive mechanical ventilation: 27 in responders vs. 76 in non-responders (p=.03) and in the number of infants with moderate‐severe BPD: 3 vs. 8 (p =.025). The responders showed lower LUS scores 2 days after diuretics (median of 6 vs. 14 in the non-responders; p=.03), 1 week after diuretics (median 3 vs. 12; p=.04), and 3 weeks after diuretics (median 5 vs. 12; p=.01). Overall 7 of 9 were extubated in the responder group vs. 1 of 9 among non-responders (p=.02). Because of the small sample size the authors are not strong in their conclusions or recommendations. However they make the point that BPD is a multifactorial disease not just influenced by an increase in extravascular lung water. Lungs with BPD also show damage from inflammation and a decrease in the number of alveolar‐type cells and elastin fibres in the extracellular matrix. There is also an increase in collagen fibres and a decrease in pulmonary microvasculature. It is therefore conceivable that diuretic therapy could be introduced in neonates with evolving BPD and continued in those that on LUS appear to be responsive but discontinued in those that are refractory. In responsive patients the LUS could also serve as a guide as to when to reduce respiratory support.

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Pediatr Pulmonol 2020; 55: 3312–18

J Perinatol 2020 doi.org/10.1038/s41372-020-0724-z

Am J Perinatol 2019; 36: 1357‐61.

Several studies published over the past 6-7 years have focused on the use of oral dextrose gel for the prevention of neonatal hypoglycaemia. New Zealand and Australia have been particularly interested in this approach. While dextrose gels are available commercially it appears that study gels have mostly been prepared in on-site hospital pharmacies. Results have included increased blood glucose concentrations, reduced need for intravenous dextrose or neonatal intensive care unit (NICU) and reduced mother-infant separation Results prompted many nurseries to introduce oral dextrose gel together with feeding adjustments and breastfeeding promotion in the prevention and management of hypoglycaemia in neonates considered to be at risk. Infants unable to maintain euglycemia via feeding modification and dextrose gel would be admitted to the NICU for IV dextrose administration and hypoglycaemia evaluation. Notably, a 2016 Cochrane review concluded that treatment of infants with 40% dextrose gel reduces the incidence of mother-infant separation for treatment and increases the likelihood of full breast feeding after discharge compared with placebo gel. Despite this lukewarm conclusion about efficacy, the review went on to state that oral dextrose gel should be considered first-line treatment for infants with neonatal hypoglycaemia. In support of this approach is the argument that glucose gel is more effective in raising blood glucose than breast-feeding alone because the mucosa to which it is applied is a thin, permeable epithelial structure. Blood vessels drain directly into the jugular vein, thereby bypassing hepatic first-pass metabolic processes and providing improved bioavailability over enteral dosing. A further advantage of using the mucosal surface is that it limits the amount of glucose to be absorbed due to the saturability of the dextrose carriers. In order to study the value of the approach, a multicentre, double-blind, placebo-controlled randomized trial was conducted in 18 New Zealand and Australian maternity hospitals from January 2015 to May 2019. Babies at risk for neonatal hypoglycaemia (maternal diabetes, late preterm, or high or low birthweight) without indications for NICU admission were randomized to 0.5 ml/kg 40% dextrose or placebo gel at 1 hour of age. Blood glucose concentration was measured at 2 hours of age and then according to hospital practice for monitoring babies at risk for hypoglycaemia (This usually involved pre-feed blood glucose for at least the first 12 hours and until there had been 3 consecutive measurements ≥2.6 mmol/l). Primary outcome in the study was NICU admission. Secondary outcomes included hypoglycaemia, NICU admission for hypoglycaemia, hyperglycaemia, breastfeeding at discharge, formula feeding at 6 weeks, and maternal satisfaction. A total of 2,149 babies were randomized. NICU admission occurred in 10.4% randomized to dextrose gel and 9.4% randomized to placebo (p=0.44). Babies given dextrose gel were less likely to become hypoglycaemic which was defined as blood glucose < 2.6 mmol/l (37%, versus 42%; p=0.02), with 21 babies needing to be treated to prevent 1 case of hypoglycaemia. NICU admission for hypoglycaemia was actually similar between groups (6.1% versus 4.5%; p= 0.10) and there were no differences between groups in breastfeeding at discharge from hospital, receipt of formula before discharge, and formula feeding at 6 weeks. No adverse effects were attributable to dextrose gel. A limitation of the study was that most infants (81%) were born to mothers with diabetes, which may limit generalisability. The authors concluded that prophylactic dextrose gel did not reduce NICU admission in babies at risk of hypoglycaemia but did reduce hypoglycaemia. Clinicians and clinical guideline groups should consider whether needing to treat 21 babies to prevent 1 case of hypoglycaemia warrants introduction of this prevention strategy into practice. Long-term follow-up is needed to determine the clinical utility of this strategy.

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PLOS Medicine 2021; doi.org/10.1371/journal.pmed.1003411

Clin Med Insights: Endocrin Diab 2020;13:1-2

Cochrane Database Syst Rev 2016; CD011027

It is important to diagnose developmental dysplasia of the hip (DDH) as early as possible because delayed diagnosis is associated with unnecessary morbidity, increasing complexity of treatment and a sevenfold increase in short‐term costs. Children who have a delayed diagnosis are also more likely to have a poor prognosis, exhibit growth disturbance and develop early degenerative hip disease. How one screens for the condition is important and all training institutions include neonatal hip examination in their programmes for students, interns and registrars. However there is world‐wide variation in screening practices for DDH and strong debate exists between selective and universal screening programmes. In Australia late diagnosis of DDH after three months of age is an increasing problem despite routine screening for all neonates on day 3 followed by  ultrasound examination for those with clinical hip instability or risk factors such as breech presentation or positive family history. To gain greater insight into the problem, researchers from the Children’s Hospital at Westmead in Sydney compared the surgical intervention required and the 5‐year radiological outcomes of children with DDH dislocations in children with early presentations compared to those that presented after walking age. Three groups were compared: successful Pavlik Harness treatment (SP), failed Pavlik (FP) and late diagnosis (LD). A total of 90 patients (involving 115 dislocated hips) met the inclusion criteria. There were 31 (40 hips) in the SP group, 24 (34 hips) in the FP group and 35 (41 hips) in the LD group. The average age of follow‐up was 7.4 years. Similar to usual characteristics of DDH, 81.1% were female, 50.0% involved the left hip, 22.2% the right and 27.8% were bilateral. The mean age of presentation was 1.3 months (range 0.2–6.3) in the SP group, 1.9 months (range 0.1–5.8) in the FP group and 22.8 months (range 9.9–61.7) in the LD group (P < 0.001). Not surprisingly, more hips in the LD group underwent open reduction (97.6%) than in the FP group (52.9%) (P < 0.001). As per entry criteria for the study, no patients in the SP group underwent operative reduction. More femoral osteotomies were performed in the LD group vs. the FP or SP groups (51.2% vs. 0%). More acetabular osteotomies were also performed in the LD group (85.4% vs. 44.1% in the FP group and 0% in the SP group; p< 0.001). Growth disturbance was more common in the LD group with 53.7% hips affected vs. 20.6% in the FP group and 5% in the SP group (P < 0.001). Nevertheless there were excellent results in 61.0% of the LD group while outcomes were good in 79.4% of the FP group and 100% of the SP group. Selective ultrasound screening is generally proposed as a practical and cost‐effective alternative to universal ultrasound screening which has also been challenged on the grounds of potential overtreatment of cases that would resolve spontaneously without intervention. On the other hand, countries employing universal ultrasound screening have the lowest reported rates of open reduction in the world. To overcome the problem of over-diagnosing DDH because of early acetabular immaturity that largely resolves without intervention, it has been recommended that screening should be performed after 6 weeks of age. Failure of screening may be due to a number of factors beyond (in)experience of the examiner. These include the failure to recognise risk factors, failure to refer despite the presence of risk factors, or technical and geographical limitations. Interestingly, because breech presentation is an easy risk factor for selection for an ultrasound screen, in Australia breech presentation is now a protective factor against late diagnosis of DDH. The finding that one-third of the subjects in this study were diagnosed late at between 10 and 60 months was of great concern but the authors conclude that the future is more along the lines of utilising emerging technologies such as combining artificial intelligence with portable ultrasound probes that plug into tablets or smartphones. Rather than focusing on the cost‐effectiveness of various current ultrasound examination methods, they believe  the debate needs to move to what form could cost‐effective universal screening take in order to eliminate the morbidity of late presenting cases of DDH.

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J Paediatr Child Health 2021; 57: 41–5

J. Child. Orthop 2014; 8: 381–6.

Pediatr. Radiol. 2014; 44: 410–24.

Community‐acquired pneumonia (CAP) is among the most common infectious diseases in children and is the leading cause of death among the under-5s in developing countries. Diagnosis of CAP in children is mostly based on clinical history and physical examination, especially in patients who do not require hospitalisation. Chest X‐ray (CXR) is recommended in severe cases or where diagnosis is uncertain, however the use of lung ultrasound (LUS) is increasing, especially in the Emergency Room. Advantages of LUS include the increasing availability of portable devices and reduced exposure to ionising radiation in children. A recent meta‐analysis that included 12 observational, retrospective and prospective studies compared the diagnostic accuracy of LUS and CXR in the diagnosis of CAP. The analysis included 1,510 children but had major limitations due to the heterogeneity in diagnostic criteria for pneumonia with the ultrasound technique, and variable experience of operators of the equipment. To complement available data, researchers from Rome assessed concordance between LUS and CXR in analysing signs of CAP, and determined LUS sensitivity and specificity in CAP diagnosis compared to CXR. They enrolled 41 patients <16 years of age who were hospitalised for CAP between October 2018 and September 2019, and 27 controls hospitalised for non‐respiratory diseases All study subjects underwent LUS and CXR within 24hrs of admission. 19 of the 41 children were re‐evaluated 30 days post discharge, again with LUS and CXR. Controls underwent a CXR for clinical indications and a LUS. Clinical signs and symptoms (fever, acute respiratory symptoms and signs on auscultation), confirmed by consolidation on CXR, suggested a diagnosis of pneumonia. Ultrasonographic evaluation was performed as described by Copetti et al. and discussed in previous summaries (2032, 2110). The average time needed to perform LUS was 5–10 min. The CAP group had a mean age of 4.8 (± 3.7) years, while controls were aged 5.1 (± 2.1) years. Chest X‐ray found unilateral consolidation in 31/41 patients (75.6%) and bilateral consolidation in 10. Overall, LUS was able to confirm the diagnosis of CAP in 40/41 (97.5%) patients, showing single or multiple areas of consolidation (31 unilateral and 9 bilateral). LUS showed a sensitivity of 97% and a specificity of 96%. Chest X‐ray showed pleural effusion in 7/41 patients (17.1%) and LUS confirmed all cases with a sensitivity of 100%. Furthermore LUS revealed the presence of a minimal amount of pleural effusion in seven other children that were not detected by CXR. In one case LUS identified a small intraparenchymal abscess cavity (22×20mm), not visualised on the CXR. The presence of the abscess cavity was confirmed with a CT scan of the lung. LUS failed in one patient in whom the consolidation did not reach the pleura. This is consistent with evidence that one of the limitations of LUS is that only those lesions reaching the pleural line can be explored with the probe, however the number of children with pneumonia that does not reach the pleural line is very low. Overall the authors concluded that LUS sensitivity and specificity in paediatric CAP are higher than in adult studies. Because of smaller thoracic diameters and smaller lung dimensions, a better exploration of the lung fields is possible in children than in adults.

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Pediatr Int 2021; 63: 448–453

Pediatr Pulmonol 2018; 53: 1130–9.

Radiol. Med 2008; 113: 190–8.

In the mid-1970’s perinatologists and pathologists published on the existence and importance of amniotic fluid infection (AFI) as a cause of preterm labour, premature rupture of membranes and neonatal pathology, frequently in the context of neonatal respiratory disease and sepsis. The AFI abbreviation has largely fallen away and been replaced by chorioamnionitis, a better descriptor of the infiltration of neutrophils into the chorion and amnion. According to world literature it occurs in 0.1%–2% of all pregnancies, 25%–40% of all preterm births, and 40%–70% of cases of spontaneous labour with premature rupture of membranes. Obstetricians often refer to acute chorioamnionitis as a clinical syndrome characterised by fever, maternal and/or foetal tachycardia, uterine tenderness and foul-smelling amniotic fluid. However, clinical signs and symptoms are not as specific as placental pathology or amniotic fluid culture. Staging of histological chorioamnionitis (HCAM) according to the location and intensity of neutrophil infiltration more accurately assesses the severity of the inflammatory response. There are conflicting reports on the importance of HCAM in the development of chronic lung disease in preterm neonates. Some have reported that chorioamnionitis is associated with an increased risk of chronic lung disease but a reduced risk of respiratory distress syndrome (RDS), suggesting that chorioamnionitis exposure accelerates lung maturation but increases the vulnerability of the preterm lung to postnatal injury. In a recent meta-analysis of 158 studies, chorioamnionitis was indeed associated with a higher risk of chronic lung disease, but this association may be modulated by gestational age and RDS. To explore this further, researchers from Taiwan embarked on a retrospective study into relationships between HCAM and respiratory outcomes, including RDS, Wilson-Mikity Syndrome (WMS) and BPD in VLBW preterm neonates. Wilson-Mikity syndrome, defined as early cystic emphysema in the first month of life without early manifestation of RDS and with subsequent progression to chronic lung disease, was included because it is also believed to be associated with intra-amniotic infection. It is an atypical chronic lung disease previously known as cystic interstitial emphysema, noted in the first days of life with subsequent progression to chronic lung disease. This progression is in the absence of an early respiratory insult such as RDS. It is now rarely mentioned and is considered an anachronism because of a broadening range of chronic lung diseases. In fact, in Japan WMS is classified as a type III chronic lung disease (CLD), accounting for 13.5% of all CLD. Further investigation is required into the pathogenesis of intrauterine inflammation/infection related to these early cystic-emphysematous lung changes in preterm neonates. The Taiwanese study involved preterm neonates of <1500g who were admitted to the NICU of the academic hospital between January 2011 and December 2017. Multiple clinical outcomes were tracked and related to whether subjects were positive or negative for HCAM. Formal placental histological examination was carried out in all subjects, and maternal and neonatal prenatal and postnatal records reviewed. Microscopic examination of the placentas allowed staging from mild disease (Stage 1) to overt advanced necrotising chorioamnionitis (Stage 3). The total group consisted of 129 subjects of which 68 had HCAM (52.7%). Twenty-three were stage 1, 30 intermediate (stage 2), and 15 advanced (stage 3). There were no significant differences in gestational age, birthweight, neonatal complications, ventilatory requirements or mortality rates between HCAM and non-HCAM groups. Mothers with HCAM had a significantly lower incidence of pre-eclampsia but a higher rate of premature rupture of membrane. They also had higher white cell counts and C-reactive protein levels before delivery. Neonates with HCAM had a lower incidence of RDS but were at a higher risk for developing WMS and BPD. After multivariate analysis adjustment, HCAM was still negatively associated with RDS (aOR = .069, p < .001) but without correlation with BPD. However, neonates with intermediate to advanced-stage HCAM had a higher risk of developing WMS and increased home oxygen usage rate compared to those with early-stage HCAM. These results are interesting and counterintuitive to the extent that ‘first principles’ would lead one to expect that a foetus exposed to infected membranes and amniotic fluid would be more likely to present with early lung disease rather than be protected against RDS.

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Pediatr and Neonatol 2021; 62: 258-264

JAMA Netw Open 2019; 2: e1914611.

Pediatr Pulmonol 2008; 43: 1004-12.

Recent summaries have dealt with aspects of community-acquired pneumonia (2102, 2113) but have not discussed treatment. It is surprising to learn that in the United States most antibiotic courses prescribed to children for common infections (including pneumonia) are 10 days in duration. In part this is due to the lack of strong evidence for shorter duration in children. Globally speaking, 10 days of treatment is too long, considering that the WHO recommends 3 to 5 days of therapy. A recent Cochrane review of antibiotic therapy for non-severe community-acquired pneumonia (CAP) in children aged 2 to 59 months found that 3 days was as effective as 5 days, which is the recommended duration for adults with CAP in the US. However, guidelines from the Paediatric Infectious Diseases Society and the Infectious Diseases Society of America do not recommend a specific duration of antibiotic therapy for paediatric CAP. Muddying the waters to some extent is the knowledge that many cases presenting as CAP are due to viral rather than bacterial infection, a situation partly driven by vaccination e.g. against pneumococcus and a reduction in CAP from the latter. To further explore the efficacy of a 5 day course of antibiotics, Canadian researchers compared 5 vs 10 days of amoxicillin for children presenting with pneumonia to one of two academic paediatric emergency departments in Ontario. Children aged 6 months to 10 years were included if they met several criteria for the diagnosis of pneumonia, including chest X-ray, and were well enough to be treated as out-patients. Participants were randomized to receive either 5 days of amoxicillin plus 5 days of placebo or 10 days of amoxicillin, and were blinded to the interventions. The primary outcome was clinical cure at 14 to 21 days, requiring defervescence within the first 4 days, no more than 1 additional fever spike after day 4, improvement in work of breathing, resolution of tachypnoea, and no need for additional antibiotics or hospital admission due to worsening symptoms. Secondary outcomes were duration of absence from school or daycare, caregiver work disruption, drug reactions, adherence, and recurrence. Among 281 participants with median age of 2.6yrs (IQR 1.6-4.9), clinical cure rates were similar in both groups: 88.6% in the 5-day arm vs. 90.8% in the 10-day arm for the per-protocol analysis and 85.7% in the 5-day arm vs. 84.1% in the 10-day arm in the intention-to-treat analysis. Among secondary outcomes, there were no differences, except that median caregiver work absenteeism was 2 (IQR, 0-4) days for those receiving 5 days of therapy vs 3 (IQR, 0-6) days for, the standard therapy. However this was likely a chance difference because it occurred before 5 days. The researchers attempted to bring participants with persistent or recurrent fever back to the study sites for re-evaluation, but if they sought medical care elsewhere they were often reflexively prescribed additional or broader-spectrum antimicrobials, most likely due to under-appreciation of how commonly paediatric CAP is caused by pathogens unaffected by amoxicillin (most commonly respiratory viruses and Mycoplasma pneumoniae). For non-hospitalised children with CAP this study shows that the short course is not inferior to the longer course but it may be prudent to perform nasopharyngeal testing to document viral or atypical coinfections at baseline to guard against needless escalation of antibiotic therapy should fever persist or recur. Important to note is that comprehensive South African guidelines for management of CAP were published in 2020. These guidelines recommend the use of an ampicillin-aminoglycoside combination for patients <1 month of age, amoxicillin for 5 days for ambulatory patients >1 month of age, and amoxicillin-clavulanate for severe pneumonia. The question is always whether clinicians adhere to the guidelines and tenets of stewardship and resist the temptation to resort to perceived ‘stronger’ antibiotics.     

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JAMA Pediatr. 2021; 175: 475-482

S Afr Med J 2020; 110: 734-40

Ann Intern Med. 2019; 171: 210-11