Two billion people worldwide are infected with Mycobacterium tuberculosis (Mtb) with 10 million new cases of active tuberculosis (TB) and 1.7 million deaths each year. The epidemic is particularly important in SA because of its association with HIV and AIDS. The only licensed TB vaccine, BCG (live, attenuated Mycobacterium bovis), is administered intradermally at birth. It provides protection against disseminated TB in infants but has variable efficacy against pulmonary disease in adolescents and adults. T cell immunity is required to control Mtb infection and prevent clinical disease. One therefore requires induction and maintenance of T cell responses in the lung to control infection, while also eliciting a reservoir of systemic memory cells to replenish the lung tissue. The most common routes of vaccine administration of are intradermal and intramuscular, neither of which induce high levels of resident memory T cells in the lung. Studies from 5 decades ago suggested that administration of BCG by aerosol or intravenous (IV) routes enhanced protection in non-human primates. Recently American researchers revisited those experiments in order to understand mechanisms by which dose and route of BCG influence systemic and tissue-specific T cell immunity. Their hypothesis was that a sufficiently high dose of IV BCG would elicit high levels of systemic and tissue resident T cells, thereby mediating durable protection against Mtb infection. In experiments involving highly susceptible rhesus macaque monkeys they showed that IV administration of BCG profoundly altered the protective outcome of Mtb challeng. Compared with intradermal or aerosol delivery, IV induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, broncho-alveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Challenge with virulent Mtb six months after BCG vaccination showed that 9 of 10 animals were highly protected and 6 showed no detectable levels of infection as determined by positron emission tomography, mycobacterial growth, pathology and granuloma formation. These findings could possibly have important implications for control of resistant disease, particularly since resaerch from 1997 showed that immunotherapy with Mycobacterium vaccae introduced intramuscularly had potential as an adjunct to chemotherapy in patients suffering from multidrug resistant TB (MDRTB).  While IV BCG vaccine would not be suitable for mass immunization programmes, based on the recent American research perhaps it would be superior to intramuscular M vaccae and add to the limited armamentarium available to treat MDR and XDR tuberculosis.

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Nature 2020; 577: 95-102

Med J Armed Forces India 1997; 53: 207-13

Why aren’t vaccines given intravenously? www.forbes.com 

Nasal nitric oxide (nNO) refers to NO measured in air aspirated from the nasal cavity and sinuses. It is synthesised from l-arginine by NO synthases (NOS) by epithelial cells of the paranasal sinus. Nitric oxide synthases exist in three distinct isoforms - neural (nNOS), endothelial (eNOS) and inducible (iNOS). The first two are active under physiological conditions, releasing small amounts of NO, while iNOS results in large amounts of NO in the respiratory tract, especially after upregulation of its expression by pro-inflammatory cytokines. Nitric oxide is involved in modulation of cilia motility, improvement of oxygen uptake and reduction of pulmonary vascular resistance. In the sinuses, NO is important for maintenance of local host defense mechanisms against bacteria, fungi, viruses and parasites. Measurement of nNO is used as an indicator of local inflammation and responsiveness to treatment with corticosteroids. The gold standard for measurement is chemiluminescence, but electrochemical analysers are also available. In a study from Poland, nNO was measured in 179 patients aged 7-15 years diagnosed with asthma, allergic rhinitis or a combination of the two. Similarly aged children were used as controls. nNO was significantly higher in patients with allergic rhinitis (2316.3 ± 442.33 ppb, p < 0.001) and with asthma-allergic rhinitis (2399.9 ± 446.73 ppb, p < 0.001) compared to asthmatic and healthy children (1066.4 ± 416.75; 836.2 ± 333.47 ppb, respectively). Receiver operating characteristic curves revealed that cut-off values of 1545 ppb nNO for allergic rhinitis and 1459 ppb nNO for asthma-allergic rhinitis had sensitivities and specificities of 100% in distinguishing the conditions vs. healthy subjects. The authors found no association between nNO level and clinical parameters including percent of eosinophils and total IgE. One is left wondering about the clinical relevance of these findings which ultimately only showed a good correlation between nNO measurements and allergic rhinitis diagnosed on the basis of objective symptoms of nasal congestion, rhinorrhea, nasal itching or sneezing for >4 days/week and occurring after exposure to allergens. If clinical signs are that objective, why does one need the nNO test? These results are contrasted to others that have used NO measurements for diagnosis and management of asthma. In this situation NO is measured using a mouthpieces rather nosepiece, and concentrations are much lower than the high 100’s and 1000’s shown in the Polish study. Fractional exhaled nitric oxide (FeNO) is a validated, noninvasive biomarker for T2-driven (i.e., allergic) airway inflammation that correlates with sputum eosinophils at or greater than 3% across various asthma phenotypes. Its use as a biomarker in asthma is supported by numerous peer-reviewed articles and guidelines. There is also evidence that its use in clinical settings for patients with uncontrolled asthma is cost effective, given its ability to improve the accurate diagnosis of asthma, monitor treatment response, optimize inhaled corticosteroid dosing and identify patient non-adherence. It may also have a role in identifying patients who are possible candidates for treatment with biologics as a result of refractory disease.

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Advances Med Sci 2020; 65: 127-33

Manag Care July 2018; 27 :34-41

Am J Respir Crit Care Med 2015; 192: 660-8

Renal transplant have been performed in Johannesburg at the Witwatersrand University-affiliated Johannesburg Hospital since 1969. The number of patients continued to increase and results from the early years (1984-2003) were analysed and published in 2006. One-year patient survival was 97% and graft survival was reasonable at 82%, but 5 and 10-year graft survival was found to have dropped to 44% and 23% respectively. Important changes over the years have included access to more effective immunosuppressive drug regimens and consolidation of the transplant team. The latter, together with the establishment of an academic private facility at the Wits Donald Gordon Medical Centre (WDGMC) has extended services to privately-funded paediatric patients covered by medical aid/insurance schemes. In a recent article, results for the period 2004-2017 were provided for a second cohort of patients treated by the team at the Johannesburg Hospital (now the Charlotte Maxeke Johannesburg Academic Hospital/CMJAH) and for patients treated at the WDGMC. A dramatic difference between the time periods is the number of transplants performed; 281 in 183 recipients at the Johannesburg Hospital between 1984 and 2003 vs. 131 in 143 patients treated at CMJAH and WDGMC between 2004 and 2017. This translates to a drop from 14.1 transplants per year per site to around 5.1 per year per site. The authors do not comment on reasons for this significant reduction. For the public sector patients the later cohort included more black children than before, more organs were from living donors, and more procedures were first-time transplants. For both periods glomerular disease predominated in black children as the cause of end-stage disease, while congenital anomalies were the major cause in the whites. Recipient and graft survival were similar for the two time periods, with graft loss rates of 72.2% and 61.6% respectively. Analysis was also carried out comparing the public sector (CMJAH) vs. private sector (WDGMC) patients for the second time period. Children at WDGMC were younger at the time of transplant, more were white, and more received kidneys from related living donors. There was a significantly higher risk of death for CMJAH patients (Hazard Ratio 3.57; 95%CI 1.55-8.23) which was related to factors such as cadaver vs. living donor kidneys, re-transplant vs. first transplant, and younger age at the time of transplant. Graft failure and loss were also greater at CMJAH (61.6%) vs. 25.7% at WDGMC. The authors speculate on the reasons for the poorer outcomes at CMJAH, citing differences in available services, “the biopsychosocial makeup of a sick child with end-stage kidney disease,” and poorer family and social support systems for patient and caregiver/s. In contrast to other studies, in this study kidneys from living donors conferred a survival advantage for patients but not for their grafts. There is probably little doubt that the greater prevalence of glomerular disease in black patients played a role in the results, given its association with post-transplant recurrence and worse outcomes, but data were insufficient in this study for exploration of this question. Specific shortcomings at the CMJAH are cited, including lack of: a dedicated anaesthetist, antibiotic stewardship programme, fully-equipped transplant theatre, post-operative ICU admission for transplant patients, appropriately-trained transplant nurses, and ongoing support for patient and family. The answer could be in a private-public partnership arrangement that bases all care at the WDGMC. It remains to be seen whether such an arrangement would be promoted or inhibited as the country moves towards universal healthcare via NHI (National Health Insurance). Another approach could be a greater focus on preventing and/or treating glomerular disease and its inherently poorer prognosis.

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Pediatr Transplant 2020; doi:10.1111/petr.13644

Expet Opin Investig Drugs 2018; 27: 839-79

Lancet Glob Health 2017; 5: e408-17     

Out-of-hospital cardiac arrest is an important public health problem, albeit mainly affecting adults. Paediatric cases account for as few as 1% of all OHCA but the impact is significant because of its emotional burden on families and the greater number of lost years of life per individual. However less evidence supporting interventions for paediatric OHCA exists compared with adult OHCA, particularly in pre-hospital advanced life support such as adrenaline administration. Despite this shortcoming, adrenaline is recommended in current international guidelines for non-shockable rhythms as soon as vascular or intraosseous access is obtained. For adult OHCA some studies have shown a positive effect of adrenaline on return of spontaneous circulation (ROSC) and survival, but neither a randomized controlled trial nor large observational study have investigated the effectiveness of adrenaline for paediatric OHCA, suggesting a critical gap in our knowledge. This ‘gap’ was addressed by Japanese clinicians and statisticians using a sophisticated national OHCA database. Emergency medical care standards were high although staff were not permitted to obtain intraosseous access in patients during the review period (2007-2016). A total of 5,922 patients aged 8 to 17 years were considered. After excluding those who met exclusion criteria, 3,961 patients were included: 306 (7.7%) patients received adrenaline and 3,655 (92.3%) did not. The primary endpoint was 1-month survival and secondary endpoint was 1-month survival with favourable neurological outcome. Interesting points were that around 80% of patients were adolescents (i.e. OHCA was far less common in younger children), around 70% occurred ‘after-hours’ between 17h00 and 09h00, and the ratio of medical:non-medical cause was around 45:55. Almost 90% were ‘non-shockable.’ The researchers studied the total groups (306 OHCA with adrenaline vs. 3655 without, and also matched 304 study subjects with 304 ‘controls.’ This matching took into account the important factor of duration of resuscitation. In general, the longer the duration the higher the chance of receiving adrenaline, and also the higher the chance of poor outcome. This could falsely suggest that adrenaline was associated with poorer outcome. For both analyses (full groups or matched groups) there were no significant differences in 1-month survival (~9% in both groups) or 1-month survival with favourable neurological outcome (in only around 3% in both). However adrenaline administration was significantly associated with pre-hospital ROSC in around 11% vs. 3%. The beneficial effect of adrenaline is considered to be the increase diastolic pressure and coronary perfusion pressure through its strong alpha-adrenergic effect, leading to the higher chance of ROSC. On the other hand, animal studies have shown that adrenaline administration during CPR reduces cerebral perfusion through the alpha-1 agonist action, potentially contributing to neurological injury. While adrenaline administration appears to be associated with a greater chance of ROSC, its impact on long-term outcomes such as survival or neurological outcome may be smaller and contingent upon other factors such as patient baseline status and quality of care. However, ROSC is a necessary first step to favourable neurological outcome, so there is currently no room to question the administration of adrenaline for paediatric OHCA.

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J Amer Coll Cardiol 2020; 75:194-204

Resuscitation 2018; 125; 79-82

Circulation 2015; 132: S526-42

Histamine is one of the most important mediators of allergy, inflammation, anaphylaxis and gastric acid secretion. Concentration is particularly high in tissues that contain mast cells, such as the respiratory tree, intestinal mucosa, and skin. Histamine can act on four types of receptors: H1, H2, H3, and H4. Stimulation of H1 receptors causes itching, stimulates secretion from the nasal mucosa, contracts smooth muscle in the bronchi and intestines, and relaxes smooth muscle in small blood vessels. Gastric acid secretion is an H2 response. H3 receptors are mainly expressed in the CNS, modulating the release of histamine and other neurotransmitters. H4 receptors are found on cells of the immune system, in the gastrointestinal tract and in the CNS. The action of histamine on H4 receptors induces chemotaxis, cytokine secretion, and upregulation of adhesion molecules. Antihistamines are used in children to treat symptoms that depend on histamine release, mainly allergic conditions such as rhinitis, asthma and urticaria. It is important to distinguish between the use of first‐ and second‐generation antihistamines. Pharmacological effects and therapeutic indications are similar, but second‐generation antihistamines have fewer adverse effects because they are more selective for peripheral H1 receptors. Although they have been on the market for several years there are still many adverse effects linked to the antihistamine safety profile, especially in the first years of life. In practice many antihistamines are prescribed off‐label, especially in children younger than 2 years of age, which is the age‐group where most of the data on drug safety are lacking and many antihistamines are not recommended. Some second‐generation antihistamines have important anti‐inflammatory effects through a decrease in production of cytokines, decreased release of other mediators by mastocytes and basophils, recruitment of eosinophils in the late phase of allergic reactions, and expression of membrane receptors in nasal epithelial cells and vascular endothelium. The latter effect involves ICAM‐1, the adhesion molecule that favors leukocyte migration from the blood to the respiratory mucosa and constitutes the main receptor for rhinovirus implicated in asthma exacerbation. Antihistamines, especially first‐generation antihistamines, have central effects that cause drowsiness, tiredness, increased appetite, or worsening of cognitive functions. These drugs are relatively inexpensive and widely available without a prescription. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic (anticholinergic) antagonists as well. These agents also commonly act on α-adrenergic and/or 5-HT receptors. This lack of receptor selectivity is the basis of the poor tolerability profile of some of these agents, especially when compared with the second-generation H₁-antihistamines. Also available as non-prescription drugs the latter are more selective for peripheral H₁ receptors as opposed to the central nervous system H₁ receptors and cholinergic receptors. The reason for their peripheral selectivity is that most of these compounds are zwitterionic at physiological pH (around pH 7.4). As such, they are very polar, less likely to cross the blood–brain barrier and act mainly outside the central nervous system. However, some second-generation antihistamines, notably cetirizine, can interact with CNS psychoactive drugs such as benzodiazepines.  No doubt most/all of the above information will not be new to paediatricians but the problem is that with the easy availability of non-prescription antihistamines, many children are being exposed. Advertising and market forces as well as lax regulation of non-prescription medicines further compound the problem. What this summary therefore highlights is once again the advocacy role of paediatricians in educating parents whose children are affected by histamine-related conditions.    

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Pediatr Allergy Immunol 2020 31(Suppl 24): 34-6

Pharmacoepidemiol Drug Saf 2017; 26: 1164

Arch Dis Child Educ Pract Ed 2015; 100: 122

Differentiation of cancers into biologically meaningful classes is the basis for treatment and patient care. Histopathology has been the gold standard for cancer diagnostics but measurement of DNA methylation has recently acquired a prominent role in tumour classification. Paediatric brain tumours have been the drivers for this classification because they are rare, medical expertise is often lacking, and inter-laboratory comparisons show low agreement for some tumour entities. Consequently paediatric brain tumours are often categorized according to histological similarities to the more-frequent adult counterparts. This is particularly problematic for assessment of paediatric glial tumours and can result in an overestimation of malignancy for some patients. The consequences of a misdiagnosis are grave in the paediatric context, potentially resulting in unnecessary brain irradiation, lifelong cognitive, endocrine and cerebral vascular dysfunction and the risk of radiation-induced secondary brain tumours. Several layers of epigenetic control interact to modulate gene expression. These include histone variants, nucleosome remodelling, DNA methylation and non‐coding RNAs. The interplay of these mechanisms orchestrates chromatin structure and dynamics. DNA methylation occurs almost exclusively at the carbon‐5 position of specific cytosines in sequences of a cytosine followed by a guanine separated by a phosphate group (a ‘CpG’ site). At any given time point around 75% of CpG sites in the human genome are expected to be methylated. The gene expression regulation actioned by DNA methylation ranges from genomic stability maintenance via repetitive element silencing, to developmental roles such as spatiotemporal and tissue‐specific gene expression, cell differentiation orchestration, genomic imprinting and X chromosome inactivation in females. In humans, during early embryonic development, DNA methylation patterns are ‘reprogrammed’ through a process of demethylation followed by de novo re‐methylation associated with the upregulation of DNA‐methyltransferases. Changes are then introduced in a cell lineage specific context in coordination with differentiation. These changes are then maintained throughout cell divisions. The development and maintenance of the cancer methylome are not entirely understood. In non‐cancerous tissues a general stability of DNA methylation patterns across cell division has been reported resulting in universal conservation of the cellular methylome. For cancer, and in particular for brain tumours, the persistence of the DNA methylation profile needs further verification. For ependymomas it has been noted that methylation patterns are retained over many years and treatments. However for adult glioblastoma some degree of temporal evolution has been reported. Nonetheless there seems to be a relative persistence of the tumoral methylation pattern which provides the foundation for the utility of DNA methylation‐based analyses for cell lineage tracing, the identification of the origin of metastases of unknown primaries, and the rapidly developing field of DNA methylation‐based tumour classification. Measurement in the laboratory is particularly attractive because of the robustness of samples and possibility of recovery even from between old slides. Consistency between laboratories also makes possible the development of large databanks. At present, DNA methylation profiling offers relevant diagnostic information for the vast majority of paediatric brain tumours. A rational implementation into pathological routine, especially for cases with ambiguous histology or non‐informative or contradictory molecular information, will improve diagnostic precision and have a substantial impact on patient management.

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Neuropath and Applied Neurobiol 2020 doi: 10.1111/nan.12598

Lancet 2018; 392: 777-86

Nature 2018; 555: 469-74

An early report on the corona virus epidemic in China provides insights into how this epidemic (now a pandemic) may unfold. The data cover 72 314 case records: 44 672 (62%) classified as confirmed cases (positive viral nucleic acid test on throat swab); 16 186 (22%) suspected cases (diagnosis based on symptoms and exposures); 10 567 (15%) with diagnosis based on symptoms, exposures, and presence of lung- imaging features consistent with coronavirus pneumonia); and 889 (1%) as asymptomatic (positive viral nucleic acid test result but lacking typical symptoms including fever, dry cough, and fatigue). Age distribution of the confirmed cases was 3% ≥80 years, 87% 30-79 years and 1% <10 years (416 cases). Most cases (81%) were classified as mild i.e. absent- or mild pneumonia. However, 14% were severe (dyspnoea, tachypnoea ≥30/min, oxygen saturation ≤93%, pO_2:FiO₂ ratio <300, and/or lung infiltrates >50% on x-ray within 24 to 48 hours). Five-percent were critical (respiratory failure, septic shock, and/or multiple organ dysfunction or failure). The overall case-fatality rate (CFR) was 2.3% (1023 deaths among 44 672 confirmed cases). No deaths occurred in the group aged 9 years and younger, whereas those aged 70 to 79 years had an 8.0% CFR and those aged ≥80 years had a 14.8% CFR. No deaths were reported among mild and severe cases. The CFR was 49.0% among critical cases. CFR was also elevated among those with pre-existing comorbid conditions. Among the 44 672 cases a total of 1716 were in health workers (3.8%), 14.8% of whom were classified as severe or critical, and 5 died. The current outbreak is both similar and different to the prior severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) outbreaks. All three commonly present with fever and cough that frequently lead to lower respiratory tract disease with poor clinical outcomes in the elderly and in those with underlying health conditions. However, despite much higher case fatality rates for SARS and MERS, COVID-19 has led to more total deaths due to the large number of cases. In fact the total number of COVID-19 cases is likely higher due to inherent difficulties in identifying and counting mild and asymptomatic cases. In-hospital transmission is not a major means of spread, rather, it appears that transmission follows close contact: 64% of clusters documented thus far have been within households. Knowing that specific treatment and prevention options such as targeted antiviral drugs and vaccines were not yet available for COVID-19, China focused on traditional public health outbreak responses—isolation, quarantine, social distancing and community containment. Focusing on the 416 paediatric cases in China under 10 years of age, most had fever (76.1%) and viral pneumonia-like changes on chest imaging (70.4%). Other features were cough, vomiting, diarrhoea and other gastrointestinal symptoms. Most children had mild symptoms similar to other seasonal viral infections. Diagnosis mainly followed epidemiological screening, indicating exposure to the familial clustering. The mostly-asymptomatic nature of infection in children may conceal a potential source of infection. This is a cause of concern and needs to be taken seriously, while in those who show symptoms the disease is significantly milder, with faster recovery, shorter virus shedding time and better prognosis than in adults. Only two critical cases were reported, one a child of 7 months with congenital heart disease, the other aged 13 months with bilateral hydronephrosis. Both cases progressed rapidly to respiratory failure after onset. To date, no effective antiviral agent has been confirmed, while interferons (IFN), Lopinavir/Ritonavir, Arbidol and Oseltamivir have been considered for clinical trials. However IFN has shown little effect in a variety of respiratory viral infections and the latter three are for influenza or HIV infection. Remdesivir has been effective in a few cases of adult disease, but there is little evidence in children. Overall the authors do not consider that antiviral drugs should be used routinely, unless in critical cases. The goals of treatment should be to alleviate symptoms and maintain the immune balance. Of particular note is that in this series there was no evidence of mother-child transmission in 21 pregnant women with confirmed infection in late pregnancy.  No doubt this report represents the first of many, and time will tell whether the findings are consistent across countries and populations.

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JAMA 2020  doi: 10.1001/jama.2020.2648

J Infect 2020 doi: 10.1016/j.jinf.2020.02.024

New Engl J Med 2020 doi: 10.1056/NEJMc2003717

Childhood obesity is a global public health problem, resulting in an increased risk of type 2 diabetes, cardiovascular disease, metabolic syndrome, and obesity in adolescence and adulthood. Cardio-metabolic risk (CMR) is a composite measure for monitoring children's cardiovascular and metabolic risk, including obesity, hypertension, hyperglycaemia, and dyslipidaemia. Rapid childhood growth, often assessed using body mass index (BMI), is associated with later adverse health outcomes. Compared with BMI assessment at one time point, growth trajectory assessment includes multiple BMI measurements. Several studies have shown that rapid BMI gain trajectories during early childhood and adolescence are associated with CMR outcomes in adolescence and adulthood. Three studies have examined the relationship between early childhood BMI trajectories and CMR in preschool children and have shown three or four trajectories. In all there was a correlation between higher CMR/obesity and either the stable-high or rapid catch-up trajectories. Sophisticated statistical design was also used in a Canadian study covering 1166 study-eligible children enrolled between 0 and 5 years and followed up until 10 years of age. The primary outcome was a continuous CMR score derived from the sum of age‐ and sex‐standardized measures of waist circumference, blood pressure, blood glucose, triglycerides, and high‐density lipoprotein cholesterol. The researchers’ position was that understanding the association between early BMI trajectories and CMR outcomes could help identify those at higher risk for future cardio-metabolic disease. Four trajectories were identified based in BMI z-scores. The mean number of observations was six per child. The majority of the children (838; 71.9%) were assigned a ‘stable low’ trajectory, followed by the ‘stable high’ trajectory (269, 23.1%). Only 4.0% of children exhibited a ‘catch‐up’ trajectory, and 1.0% showed a ‘rapidly accelerating’ trajectory. The stable low trajectory was the closest to the WHO BMI z-score standards and, as the largest group, was set as the reference trajectory. Growth patterns were mainly established by 20 months of age, after which three plateaued while the rapidly accelerating trajectory kept rising. After adjusting for all covariates, children in the rapidly accelerating trajectory had increased total CMR score and increased waist circumference compared to the stable low group. Gender, birthweight and breastfeeding duration had no effect on the associations. Further research is required to determine the extent to which the growth trajectories predict adolescent and adult cardio-metabolic status, particularly since growth patterns are also predicted by other factors such as maternal and preconception risk factors, children's lifestyle and behavioural factors. Perhaps the highlight of this study is the confirmation that there appears to be value in understanding growth trajectories and assigning one’s patients to one of the three or four that have been established.  Summary 1502 commented on growth trajectories for SGA babies, this one focuses on those normally-grown in utero but likely also includes the SGA’s within the groups.

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Int J Pediatr Obesity 2020 doi: 10.1111/ijpo.12633

Am J Clin Nutr 2019; 110: 1175-85

Ann Epidemiol 2017; 27: 708-15

There is strong evidence that duration of sleep in children is inversely related to overweight and obesity. Children sleeping for shorter durations have significantly increased odds of being overweight or obese compared with those who slept for longer/‘sufficient’ durations. The explanation is that insufficient sleep leads to an energy imbalance via mechanisms such as altered hormone regulation and/or higher caloric intake. However, there are other potentially-important dimensions of children's sleep that might play a role. These include efficiency, quality, and sleep timing. Sleep duration is simply the quantity/length of sleep. Sleep quality is the ‘measured architecture’ of sleep (adequacy of time spent in the different sleep wave cycles) or subjective satisfaction or perceived problems with sleep. Sleep efficiency is a measure of sleep continuity, incorporating the ease to initiate and maintain sleep, or the percentage of sleep time achieved between bed and wake times, and sleep timing is the placement of sleep within the 24‐hours of the day. A recent systematic review of the subject was undertaken by Australian and American researchers who extracted 34 248 studies from various databases. Following the usual criteria for inclusion/exclusion, 112 articles were deemed relevant and included in the analysis. Sleep duration was the most frequent dimension analysed, with all but nine of the 112 studies assessing this parameter. Seventy-three studies reported solely on the association between children's sleep duration and their weight status, 22 assessed duration and one other dimension, and seven assessed at least another two. Of the nine articles not reporting sleep duration, six reported on sleep timing factors, two on sleep quality, and one on sleep efficiency. Overall, there was strong evidence in support of an inverse relationship between primary school‐aged children's sleep duration and measured weight status. Only 15 articles (14%) found no significant association between children's sleep duration and measured weight status. Interestingly there was also some evidence for gender patterning, with nine articles on sleep duration also showing an association between sleep duration and overweight/obesity only affecting boys. Overall, the systematic review confirmed the relationship between shorter sleep duration and overweight/obesity, but also highlighted other potentially-important dimensions of sleep. The authors found few studies examining these dimensions, but where studies exist there were associations, particularly supporting a positive association between later bed timing and increased weight status. Less consistent findings were among studies exploring components of sleep efficiency and sleep quality. To many of us these findings are counter-intuitive i.e. one would usually associate less sleep and more mental and/or physical activity at night with lower weight. However, the inverse relationship cited above has been accepted, not only in children but also in adults

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Int J Pediatr Obes 2020 doi: 10.1111/ijpo.12619

J Early Adolesc. 2014; 34: 1145‐1166.

Sleep. 2008; 31: 619‐626.

As the world battles against the ravages of the COVID pandemic two issues emerge: 1) we don’t yet know what we don’t know, and 2) modelling is proving to be wrong more often than not. Even before countries in Europe and states in the USA have COVID-19 under control there are discussions on whether school closures should be continued as a strategy to reduce corona virus transmission. WHO declared the COVID-19 outbreak to be a pandemic on March 12^th 2020.  On March 18^th it was estimated that 107 countries had implemented national school closures, affecting 862 million children and young people, roughly half the global student population. This situation had rapidly escalated from 29 countries with national school closures a week before. The authors of an article in the Lancet series performed a systematic review of school closure literature and concluded that based on recent modelling studies of COVID-19, school closures alone would prevent only 2–4% of deaths, much less than other social distancing interventions. They stated further that policy makers need to be aware of the equivocal evidence when considering school closures for COVID-19. Unfortunately, almost all of the data covered in the review were based on school closures in the context of influenza, and to some extent on SARS and MERS data. In this regard, one thing we do know is that there is a reason for the COVID-19 virus being called a novel corona virus. It is indeed novel, and we are still learning about its characteristics and behaviour, so comparisons with influenza, SARS and MERS may not be particularly relevant. For example, it is apparent that school closures during flu epidemics may be the main or only mitigation strategy, preventing children who are apparently significant carriers of the virus from spreading disease within schools and infecting family members. Research has also shown that if the mitigation strategy is indeed limited to school closure, then children have more contact with other children and adults when they not at school, thus defeating the object of the exercise. Another adverse effect of school closure cited in the literature is economic harm to working parents, health-care workers, and other key workers who are ‘forced’ into childcare. Society also suffers due to loss of parental productivity, transmission from children to vulnerable grandparents, loss of education and nutritional problems in children for whom free school meals are an important source of nutrition. Creative options for reopening are reducing mixing by closing playgrounds, cancelling non-essential activities and meetings, increasing spacing between pupils in classes, shortening the school week, and staggering school start and lunch or break times across year groups or classes. Data such as these are influencing COVID-19 decisions abroad, possibly inappropriately. For example, the Governor of Florida recently stated that schools should be opened because children are not dying from COVID-19.  Surely this is not the object of an exercise which should be to prevent children who are carrying the virus from infecting other pupils and teachers, and transferring the virus back into communities? Several reports from China are clear that while children are less affected by COVID-19 than adults they may certainly be infected, may be asymptomatic carriers of the virus, and may also show virus on anal swabs for weeks after. In South Africa, particularly in public schools with large numbers of children from high-density townships and squatter camps, there is likely a strong case for keeping schools closed, certainly until one has a clearer idea of the extent to which each residential area is involved. One also needs to know the extent to which family/cohabitants who are members of the essential services workforce might be introducing infection into such environments and infecting the children.

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Lancet Child Adolesc Health 2020; doi: 10.1016/S2352-4642(20)30095-X

Emerg Microbes Infect2020; 9: 707-13

J Med Virol 2020; doi: 10.1002/jmv.25807

Telomeres are repetitive DNA sequences at the end of chromosomes. To quote Wikipedia, “Telomeres are the caps at the end of each strand of DNA that protect chromosomes, like the plastic tips at the end of shoelaces.^” Their main function is to stabilise and as much as possible protect chromosomes from physiological DNA repair proteins that result in telomeres shortening with each cell division. Factors that contribute to ultimate telomere shortening include telomere length (TL) at birth and aging. However telomere shortening is independent of chronological age i.e. TL is a marker of biological rather than chronological age, suggesting that rate of telomere attrition is a modifiable factor. Studies have demonstrated that a healthy lifestyle in combination with a Mediterranean Diet help to maintain telomere length. Obesity is characterised by a low-grade chronic inflammation that is accompanied by oxidative stress, so obesity-inflammation may also be a factor in telomere shortening. In this regard, children with obesity have shown shorter telomeres than normal weight, age, and gender controls and higher cellular aging than healthy subjects. In a meta-analysis of 87 observational studies, TL was negatively associated with Body Mass Index (BMI). In addition, shorter baseline TL has been associated with unfavourable metabolic syndrome outcomes in adults. Weight loss is associated with reduced excess adipose tissue and also with reduced inflammation and oxidative stress. The reduction in inflammation could help prevent telomere attrition. Based on previous studies showing that higher baseline TL was associated with lower weight, BMI and blood glucose levels after a 2-month lifestyle intervention, Spanish researchers hypothesised that TL could be a predictor for changes in both anthropometric and metabolic measures. They studied girls and boys between 7 and 16 years of age with a waist circumference above the 90th percentile. Exclusion criteria included eating disorders or other major psychiatric disease, pharmacological treatment, pre-diabetes, special diets, regular alcohol consumption or food intolerance. The major intervention consisted of 8 weeks of a moderately hypocaloric Mediterranean diet and 200 additional minutes of physical activity per week at 60–75% of maximum heart rate. In this first component of a longer 2-year study, anthropometry, biochemistry and telomere length were assessed at baseline and after the 8 weeks. Complete data were available for 108 participants (mean age 11.3±2.5 years). Participants successfully achieved weight loss and improvements in anthropometric indices (weight, waist circumference, height, etc.) and glucose metabolism indicators improved significantly. Overall there was an inverse relationship between TL and age of participants (i.e. even in this young age group telomeres were shortening as the subjects grew older), but there were no significant TL changes over the duration of this element of the study. Children with shorter TL at baseline had higher weight, BMI and waist circumference at 8 weeks, and there was an association between baseline TL and changes in blood glucose levels with higher TL at baseline significantly predicting a greater reduction in blood glucose levels. These inverse associations may be explained by adiposity being linked to a low-grade inflammatory state, oxidative distress and telomere attrition. The findings are consistent with previous study results that showed longer TL at baseline predicting a greater decrease in weight and BMI after an intensive multidisciplinary intervention in adolescents with obesity. In contrast to this Spanish study under review, another showed that weight loss was able to reduce the rate of TL attrition, the difference between studies possibly related to a longer duration of intervention and follow up.

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Nutr Metab Cardiovasc Dis 2020; 30: 694-700

PLoS One 2014; doi: 10.1371/journal.pone.0089828

Int J Obes 2014; 38: 177-82

Tympanostomy tube/grommet insertion, the most common ambulatory surgery performed in children in the United States and also commonly performed in South Africa’s private sector, has origins stretching back more than 200 years. Sir Astley Cooper, a British surgeon observed in the 18th century that some patients with tympanic membrane perforations stabilised their middle ear disease. However, attempts to duplicate this with myringotomy were short-lived because the perforations closed rapidly. One century later Politzer realised that prolonged middle ear ventilation was needed for success, but it was not until 1954 that Armstrong resolved middle ear effusion (MEE) using a ventilating tube. The rise in tympanostomy tube (TT) use in the 1990s raised allegations of overuse, but it was only in 2013 that national guidelines were published in the United States. Rates of adherence to the guidelines by clinicians have been high, estimated at 95%. However, some issues remain and new procedures have become available such as TT insertion in the doctor’s rooms without general anaesthesia. To address these issues an expert with significant experience in the field has published an evidence-based review, and provided guidance on some of the current issues. Current best evidence recommends the following:  1) No tube insertion in children with a single episode of otitis media with effusion (OME) of <3mths duration; 2) No TT’s in children with recurrent acute otitis media (AOM) who do not have effusion in either ear at the time of assessment; 3) Bilateral TT’s should be offered  to children with recurrent AOM who have unilateral or bilateral effusion at the time of assessment 4) Bilateral TT’s should be offered for bilateral OME for ≥3mths and documented hearing difficulties; 5) Unilateral or bilateral OME of ≥3mths may be an indication for TT’s if there are symptoms that may be attributable to OME (e.g. vestibular problems, poor school performance, reduced quality of life); 6) TT’s may be performed in at-risk children with unilateral or bilateral OME that is unlikely to resolve quickly, as evidenced by a flat tympanogram or persistence of effusion beyond 3mths. This at-risk group also includes the subgroup of children with OME at increased risk for developmental difficulties because of comorbid, baseline conditions such as autism spectrum disorder, Down syndrome, cleft palate or developmental delay. Apart from the above indications, more-urgent TT insertion is appropriate where otitis media is associated with tympanic membrane retraction, a retraction pocket with keratin debris (pre-cholesteatoma), or suppurative complications of AOM (e.g. acute facial paralysis). At this time TT insertion in awake children is based on clinician experience and caregiver preference, but existing literature is too sparse to generalize conclusions about safety or efficacy. It is also too early to judge the potential impact, if any, of new devices for rapid, automated tube insertion.

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Ear Nose Throat J 2020, doi: 10.1177/0145561320919656

Int J Pediatr Otorhinolaryngol 2015; 79: 2416-23

Otolaryngol Head Neck Surg 2013; 149(suppl 1: S1-35)

The short answer to the above question is Yes, we probably should, but some discussion is warranted. Firstly, while the medical literature is sparse with only one case report at this time, the association between the two conditions is receiving significant attention in the lay press. For example on April 29 the Guardian newspaper in the UK recently reported on around 100 COVID-linked Kawasaki Disease (KD) cases from the UK, USA, France, Italy, Spain and Switzerland, stating inter alia that the NHS had alerted paediatricians in the UK, and the World Health Organisation had asked the global network of clinicians to be on the alert. The Guardian also commented that the ‘new syndrome’ or KD-variant has yet to be named, perhaps because cases may be older than is usual with KD and some present with toxic shock and multi-organ involvement that are not classical features of KD. International news channels have subsequently reported around 100 cases in New York alone. Classical features of KD are fever for ≥5 days plus 4 of the following 5: conjunctivitis, polymorphous rash, erythema of the mouth and/or pharynx and/or ‘strawberry tongue,’ erythema or swelling of the hands and feet, and non-suppurative cervical adenopathy. The diagnosis can also be made with any 3 of the above features plus coronary artery abnormalities, the latter being the most significant consequence of KD. In fact, KD is listed as the leading cause of acquired heart disease in children in the developed world. KD is recognised as being an acute vasculitis generally resulting from the interaction between genetic susceptibility and causative antigen. The role of the immune system in morbidity and mortality in the current COVID pandemic appears to be clear, given that pathologies such as the ‘cytokine storm’, strokes and other thromboembolic manifestations have all been attributed to an immune response. Classical KD has been linked to preceding viral respiratory infections, with up to 40% of patients reporting an infection in the 30 days prior to admission. Previous KD research from 2015 showed that rhinovirus and parainfluenza were associated in around 40% of cases, with RSV, influenza, adenovirus and corona virus each contributing <5%. So how new is this association between corona virus and KD? Very relevant to the current discussion is a study that emanated from Yale in 2005 following the identification of what they also called a “novel” human corona virus in a 6-month old child with classical KD. Since the clinicians had access to stored respiratory samples from 11 of 53 KD children admitted between 2001 and 2004 but testing negative for the usual respiratory pathogens, they were able to test those samples for what they called      HCoV-NH, the ‘NH’ representing New Haven.  The 11 KD samples were matched against non-KD controls and results showed that 8 of the 11 were positive for the novel corona virus vs. only 1 of the controls. So, apart from the possibility that the presence of toxic shock may represent a variant, the association between KD and corona virus is not at all new. A very interesting question that should probably be asked is why the current reports of these KD or KD-variant cases are from Europe and the USA and nothing appears to have been reported from countries such as Japan, Korea or China? All have been affected by the COVID pandemic and KD incidence in these countries is generally acknowledged to be high (Japan ~300/100 000; Korea 217/100 000; China 116/100 000) while rates in the USA and Europe are at least 10 times lower, so why the paradox? Perhaps this strengthens the argument for the condition being a new syndrome? Clearly there is much we still have to learn about this virus that is all but paralysing the planet.

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Hosp Pediatr 2020, doi: 10.1542/hpeds.2020-0123

Korean J Pediatr 2019; 62: 292-6

J Infect Dis 2005; 191: 499-502 

Authors of a recent review article in Current Opinion have identified the likely importance of glycosylation of immunoglobulins for mother, foetus, neonate and infant. The topic is timely, given the COVID-19 pandemic and questions that are being asked about the basis for the relative protection from disease enjoyed by pregnant women, infants and young children when compared to adults.  Glycosylation is the process through which glycans or polysaccharides are added to proteins. In the case of immunoglobulins this occurs at the Fc region that facilitates the interaction between antibody i.e. immunoglobulin and cell surface Fc receptors that are found on many immune cells, including natural killer (NK) cells, macrophages and neutrophils. ‘Bi-antennary’ 2 n-acetyl-glucosamine (GlcNAc) and mannose make up the core glycan, and various ‘secondary’ glycosylation patterns are found according to the addition of a ‘bisecting’ GlcNAc, galactoses, sialic acids or fucose. Glycosylation patterns of the Fc region are affected by pregnancy, age (intrauterine or postnatal), gender, infection and vaccination. These patterns in turn affect materno-foetal antibody transfer, function and half-life, maternal and neonatal responses to vaccination, susceptibility to infection and disease severity. Research has shown that serum samples from women vaccinated against pertussis during pregnancy demonstrate preferential transplacental transfer of NK cell-activating IgG antibodies against pertussis antigens, with this preference specifically related to enhanced transfer of galactosylated and sialylated antibodies that interact with neonatal Fc receptors. This suggests that NK-cell activating antibodies might be important in the protection against pertussis. Similar results have been found with other viruses such as influenza and RSV, with all pointing to a possible role for glycosylation when designing vaccines to be used in pregnancy and early life. Other research into HIV-related IgG materno-foetal transfer divided mothers into groups based on efficient, variable or poor transfer from mother to foetus.  Differences in Fc region glycan profiles were demonstrated within the designated transfer groups. Further evidence of the importance of glycosylation was obtained from studies into Zika virus. Laboratory-engineered non-glycosylated immune sera from mice failed to neutralize epidemic Zika strains, indicating that the changes in glycosylation impact the accessibility of neutralising antibody epitopes on mature virus particles. Interesting results have also been obtained from BCG studies in mice that suggest a role for glycosylation of IgM in protecting against M.tuberculosis infection and also in ‘reprogramming’ the neonatal immune system resulting in a heterologous, non-specific’ protection and consequent reduction in all-cause mortality. This ‘spillover’ effect is possibly related to current research at Stellenbosch University into BCG administration to protect against infection with the corona virus. Further research is necessary to establish the extent to which factors such as immunoglobulin glycosylation, reduced nasal and/or pulmonary receptors and/or other as yet unknown factors play a role in children’s relative resistance to COVID-19.

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Curr Opin Infect Dis 2020; 33: 225-30

Nat Rev Nephrol 2019; 15: 346-66

Semin Immunol 2018; 39: 102-10

There is little science to this summary as much of it relies on the media for background information, but perhaps there should be more scientific engagement with the subject. As countries embark on phased returns from COVID-related lockdowns to economic and educational activity, and at a time when economies have shrunk and recession looms, there has been a resurgence in the e-commerce and online education spheres. Online conferencing, learning and interactive electronic gaming have become the norm for many. Given the absence of live action, several sports ranging from horse racing to football, basketball and motor racing have been simulated and provided deprived fans with high-tech virtual experiences. While that has been happening there is one form of e-sports that was firmly established well before the pandemic, namely the highly lucrative and rapidly expanding field of professional and semi-professional gaming. Children, adolescents and young adults may compete for millions of dollars, with large numbers of spectators on site and online. Stakes are high and hours are spent by players honing their skills. Not surprisingly doping has become a problem, with amphetamines such as Adderall (a mixture of d- and l-amphetamines, not available in South Africa) and other ADHD drugs taking the lead. To quote a recent article in the Washington Post, “Nobody talks about it because everyone is on it.” Attempts to ban the drugs appear to have been fairly futile for reasons ranging from cost to independent and unrelated gaming leagues according to the game being played, and also the question of how one tests for competitions in which virtual competitors are online around the country and possibly also around the world. As happens with traditional sports and international anti-doping bodies, players with conditions such as ADHD may obtain therapeutic exemptions, but current drug consumption appears to go way beyond the legitimate users. Furthermore there appear to be very low thresholds for players wishing to obtain a prescription. While gamers also turn to energy drinks and caffeine to enhance performance, many are turning to substances within the category of nootropics. Nootropics are supplements touted as enhancers of brain health and cognitive performance, boosting memory, focus, attention and alertness. The list of nootropics includes >80 supplements from vitamin B12 to prescription ADHD drugs that affect the brain through claims of enhancing mitochondrial efficiency, facilitating neurotransmission, improving cerebral circulation, reducing oxidation, and even promoting neurogenesis. The industry appears to be burgeoning, producing combination packs and/or all-in-one products that combine vitamins, lipids, phytochemicals and antioxidants. If paediatricians are not already being asked by parents whether their children should be on nootropics then it can only be a matter of time before they are. On the topic of abuse of prescription nootropics such as methylphenidate, modafinil and piracetam that are being abused by students and others, a recent article from Poland and Switzerland expressed concern about ecotoxicity. These substances have recently been detected in waste-, surface- and drinking water and the researchers recommend monitoring levels of nootropics and their metabolites to ensure that society is not unwittingly being exposed to these agents.

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Washington Post 13 February 2020. Esports and Adderall

Time Magazine. https://time.com/5509993/nootropics-smart-drugs-brain

Chemosphere 2020; 233: 771-85

Retinopathy of prematurity (ROP) is the leading cause of childhood blindness in high-income countries. It is a disorder of premature infants, involves abnormal vascularization of the retina, and is thought to be induced by a combination of factors that first lead to reduced retinal vessel growth and microvascular degeneration, followed by pathological retinal neovascularization (RNV). Despite close monitoring of administered oxygen, the condition still presents with significant morbidity in the preterm infant. Many therapeutic strategies for treating ROP are targeted at suppressing RNV, potentially causing retinal injury and impairing subsequent visual function. There is thus an urgent need to prevent ROP in order to maximize visual development and acuity. Preterm infants lack third-trimester lipid stores because of loss of placental and maternal growth factors following early birth. They also have a poor ability to synthesize docosahexaenoic acid (DHA), an omega-3 long-chain polyunsaturated fatty acid (PUFA), the main structural lipid in the retinal photoreceptor outer segment disc membrane. There is evidence that omega-3 long-chain PUFAs play a role in visual development and anti-inflammatory processes. Previous studies in humans and animal models of ROP suggest that supplementation with omega-3 long-chain PUFAs improves retinal angiogenesis and visual acuity. Because many/most preterm infants require parenteral nutrition in the early stages, omega-3 long-chain PUFA supplementation with fish oil may be beneficial. This was studied by researchers in Taiwan who evaluated different types of parenteral emulsions (fish oil-containing vs. soy-based) on ROP   in   very   low   birth   weight infants (<1500g). While the ideal format for such a study would be a randomised controlled trial, here the authors compared two epochs. The first involved 203 neonates treated between 2009 and 2014 with a 50% soybean oil/50% medium chain triglyceride (MCT) emulsion, and the second involved 193 neonates treated between 2015 and 2017 with  the fish oil-containing lipid emulsion (30% soybean oil, 30% MCT, 25% olive oil, 15% fish oil). The primary outcomes were the incidence of ROP and the number of ROP cases requiring bevacizumab therapy. The groups were well-matched for gestational age, Apgars, birthweight, anthropometry, antenatal steroids and caesarean section. Results showed a lower incidence of any stage ROP (24.1 vs. 11.4%, p < 0.001) and lower requirement for intravitreal bevacizumab therapy (12.8 vs. 5.2%, p<0.001) in epoch 2. Lower gestational age and higher glutamic-pyruvic transaminase, total bilirubin and alkaline phosphatase levels, as well as soy-based lipid emulsion in TPN were associated with higher ROP incidence. Multivariate logistic regression analysis revealed that the lipid emulsion containing fish oil was associated with a lower risk of development of ROP (Odds Ratio: 0.178, 95% confidence interval 0.095-0.330, p< 0.001). Subjects in epoch 2 also had less bronchopulmonary dysplasia (BPD) and less intraventricular haemorrhage. Studies have supported a role for inflammation in the pathogenesis of ROP and several cytokines and chemokines have been shown to be involved including IL-6, IL-7, IL-8, tumor necrosis factor, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1. DHA, the most abundant fatty acid in the brain and retina, protects against ischaemia, hypoxia, and hyperoxia through its anti-inflammatory action, and it might be a promising therapeutic intervention. Whereas omega-6 LCPUFA-derived products have an inflammatory effect, omega-3 LCPUFA-derived metabolites protect against RNV and inflammation via two groups of enzymes, the cyclooxygenases and lipoxygenases. Regarding the lower incidence of BPD in epoch 2, studies in preterm neonates have shown a relationship between development of BPD and elevated levels of inflammatory cytokines and chemokines in the serum and lungs of affected infants. Using lipid emulsions containing a higher ratio of omega-3 to omega-6 LCPUFAs might therefore also lower the incidence of BPD by altering the balance of pro- and anti-inflammatory forces.

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Pediatrics and Neonatol 2020; 61: 224e230

Int J Ophthalmol 2017;10: 300e5

Oxid Med Cell Longev 2017; 2017: 3940241.

A recent article in the International Journal of Clinical Practice reported on body composition in children with mild sub-clinical hypothyroidism (SH) and found that they had less trunk muscle mass (TMM) when compared to normal controls. There were no other anthropometric differences between the groups and the basal metabolic rates were similar. The TMM difference disappeared after 12 months of treatment with thyroid hormone, and fat-free indices increased. These changes suggested improvements in body composition in these children with mild SH, but what is the nature of this condition and should it in fact be treated? Sub-clinical hypothyroidism is defined as TSH above the normal range while free T3 and T4 are normal for age. This is further broken down to mild SH when TSH is between 4.5 and 10 µU/ml, and severe when TSH is >10 µU/ml. But how would the average clinician be diagnosing a sub-clinical condition that is based on levels of hormones? Turns out that much of it is not sub-clinical at all in terms of signs and symptoms and SH is often found with conditions that are associated with thyroid antibodies, for example in Hashimoto’s thyroiditis. Down and Turner’s syndromes, thyroid goitre and thyroid nodules may also be associated with this ‘sub-clinical’ condition. However there are also children in whom the SH is diagnosed as a result of routine screening, or identified as part of a work-up in children with constipation, obesity or depression, where the clinician is ruling out hypothyroidism as a cause. In both adults and children there are questions about treatment in patients with raised TSH but normal T3 and T4 levels. In adults there are concerns that if SH is not treated there may be dyslipidaemia, long term cardiovascular consequences and also depression, while treatment with thyroid hormone may result in sub-clinical hyperthyroidism and problems such as bone loss in postmenopausal women.  On the other hand there is evidence that an elevated TSH in adults may actually have independent beneficial effects on longevity. In children the decision to treat depends on whether the condition is mild or severe as defined above, and on the nature of any underlying condition. An Israeli study gives a good idea of outcomes in a population of >3500 subjects screened between 6 months and 16 years of age and followed up for up to 5 years. Irrespective of the TSH level, few subjects progressed to overt hypothyroidism, while 27% of those with TSH of 5.5-10µU/ml had persistent SH, vs. 58% with TSH >10µU/ml. Reversion to euthyroid status was seen in 76% with the lower TSH values vs. 40% with values >10 µU/ml. In contrast, an Indian study of teenage subjects with auto-immune thyroiditis followed up for 2 years showed that 13% progressed to overt hypothyroidism, 65% had persistent SH and 22% reverted to euthyroid status. Treatment is not recommended for children with idiopathic and mild SH in whom there is no goitre, no hypothyroid symptoms and no anti-thyroid autoantibodies. Treatment should be considered in others e.g. with Hashimoto’s thyroiditis, Down and Turner’s syndromes and/or other autoimmune disease, and also if there are pro-atherogenic metabolic abnormalities. In the absence of treatment there should be periodic monitoring, perhaps 6 monthly in the beginning and less frequently after 2 years if stable.

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Int J Clin Pract 2020, doi: 10.1111/ijcp.13554

Front Endocrinol 2019, doi: 10.3389/fendo.2019.00109

Eur J  Endocrinol 2013, doi: 10.1530/EJE-12-0656  

Proton pump inhibitors are among the most widely prescribed classes of medications with annual sales of more than $13 billion worldwide. PPIs remain an important therapeutic option for esophagitis and gastritis while recent studies demonstrate no benefit for infantile reflux or functional gastrointestinal disorders. Although PPIs have historically been considered exceptionally safe, this class of medicines has increasingly been implicated in a broad spectrum of adverse events. The predominant areas of concern are risk of infection, electrolyte disturbances and fractures. Adverse effects on microbiome diversity and immune function have also been demonstrated, resulting in increased rates of gastrointestinal infections and atopic disorders. Overall, PPIs influence a variety of cell types within the innate and adaptive immune systems. Most of the literature related to adverse effects stems from adult studies; however given the apparent widespread and long-term use of PPIs in the paediatric population, adverse effects are important. Concerns were raised in 2006 with evidence of an increased risk of fractures. Subsequent meta-analyses confirmed the risk, also showing that risk increased with longer duration of therapy. The underlying mechanism remains unclear, but postulates include osteoclast inhibition, decreased absorption of calcium, and hormonal effects leading to increased bone turnover. Paediatric fracture location in the setting of PPI has not been reported and researchers in the USA decided it was important to evaluate this aspect. Some 32 000 health encounters for patients aged 6 months to 15.5 years were identified between 2011 and 2015 and tracked over a 2-year period. PPI users were matched to non-PPI controls with fracture within 24 months. The PPI cohort was more likely to have had their initial encounter in the inpatient setting, while emergency, ambulatory surgery and observational settings were more likely among the controls. There were 1011 fracture encounters among both cohorts, including repeat fracture. Including multiple fractures, the total was in 581 in the PPI vs. 453 in controls. This represented a significantly higher rate of fractures among the PPI-exposed group (1.2% in controls vs 1.4%; p<0.02). In both cohorts, upper extremity (humerus, radius, ulna, wrist, or hand) was the most common location for fracture; however, the PPI cohort was statistically more likely to suffer from lower extremity (femur, tibia, fibula, or foot), rib, and spinal fractures compared with the control group (p<0.01). In another study involving almost 1 million children and followed for age of first fracture, 11% received acid-suppressing therapy (AST), either PPIs or H₂-receptor antagonists (H₂RAs) in the first year of life. Most (8%) received H₂RAs, 0.9% were prescribed PPIs, and 2% received both a PPI and H₂RA. Infants prescribed AST had an earlier median first fracture age (3.9 vs 4.5 years). After adjustment, increased fracture hazard was associated with the use of PPIs alone (21%) and PPI+H2RA use (30%), but not H2RA use alone. Longer duration of treatment and earlier age of first exposure was associated with increased fracture hazard.

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Curr Allerg Asth Rep 20(8);39 June 2020

J Pediatr Gastroenterol Nutr 2020;70: 815

Pediatrics 2019; 144 e20182625

Metabolic acidosis is a complication of CKD, developing in parallel with decreased renal function and typically surfacing in CKD stage 3 and beyond (eGFR < 60 mL/min/1.73m²). Low serum bicarbonate may have a distinct neurobiological impact on cognitive impairment in adults, and animal data suggest that low serum bicarbonate may lead to neuronal dysfunction via upregulation of excitatory synapses on GABA-ergic neurons. To assess whether children with CKD also show this relationship between low bicarbonate and neurocognition, data were reviewed by researchers involved in the Chronic Kidney Disease in Children Study (CKiD). This analysis was also informed by previous results indicating that elevated blood pressure (BP) is associated with decreased neurocognitive function specific to the domain of executive functioning (EF). The CKiD cohort study began some 15 years ago, collecting data from 54 paediatric nephrology centres in North America in order to examine various aspects of mild to moderate CKD progression, including the impact of disease on neurocognition. Participants are classified as hypertensive or normotensive based on previously defined CKiD study criteria, but in the hypertension-related studies published to date, various BP calculations are used whether ‘casual BP’ measured at the time of a follow-up visit at which other parameters are measured, or as ‘variability’ in BP calculated on the basis of measurements at various follow up visits (BPV). Various EF measures were included for this study (acronyms include D-KEFS, CPT-II, and subtests from the WISC-IV-I or WAIS-III), all of which are validated measures of EF. Each of the 865 participants included in this particular study completed the version of each scale appropriate to his or her age. Executive function scores were converted to a composite score. The research also include the Global Executive Composite (GEC) score from the parent-completed Behaviour Rating Inventory of Executive Function (BRIEF) or the adult version (BRIEF-A) for participants 18 years of age and older. Median age of the participants was 11.6 years; the group was 62% male, 22% African American, and 14% Hispanic. Median eGFR for the group was 53 mL/min/1.73m², representative of CKD stage 2–3. The primary renal disorder was non-glomerular (e.g., obstructive uropathy, renal dysplasia) in 70% and glomerular in 30%. Hypertension was present in 47% of the participants. Twenty-two percent had a low serum bicarbonate level, defined as a CO₂ ≤ 20 mmol/L. Those with lower serum bicarbonate levels (CO₂ ≤ 20 mmol/L) had higher rates of hypertension vs. those with CO₂ ≥ 21 mmol/L, and eGFR was comparatively lower and proteinuria comparatively higher in the low bicarbonate group. Contrary to expectation, neither serum bicarbonate nor hypertension were independently associated with EF. However a significant interaction (p = 0.01) between high CO₂ (≥ 26 mmol/L) and BPV was detected in the model with GEC (i.e. parent-reported EF) as the outcome. One possible interpretation is that high bicarbonate may be protective against the effect of high BPV on EF in the mild to moderate CKD population. Cerebrovascular tone is highly regulated to ensure appropriately matched blood flow to meet local and regional metabolic demands within brain substrate. The authors postulate that whereas hypertension typically promotes vasoconstriction, patients who have higher serum bicarbonate values may be more able to overcome the cerebral vasoconstrictive effect of hypertension, thus moderating the negative cerebral effect of hypertension on executive function that otherwise might be seen. This requires further investigation including detailed neuroimaging studies in the paediatric hypertension and CKD populations with parallel assessment of bicarbonate and cognition. What is not addressed in the article is why results of HT vs cognition in this subgroup of CKiD subjects differed from those found previously.

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Pediatr Nephrol 2020; 35: 1323-30

Kidney Int 2015; 87: 800–806

Clin J Am Soc Nephrol 2011; 6: 1824–1830

Infants born preterm are at high risk of gut dysbiosis which is characterized by overgrowth of pathogenic bacteria such as Enterobacter and Pseudomonas species. Such overgrowth may compromise the intestinal wall barriers, facilitate translocation of pathogenic bacteria and potentially result in necrotizing enterocolitis (NEC). Probiotics, which are live bacterial organisms that alter the gut microbiota, may reduce the risk of NEC. Potential benefits of probiotics in preterm infants include improved mucosal junctional barriers to decrease the translocation of bacteria, better modulation of the innate and humoral immune responses, promotion of protein and carbohydrate breakdown for better enteral absorption, and resistance to the overgrowth of potentially pathogenic bacteria such as Enterococcus. Several studies have reported that probiotic use reduces the incidence of NEC. These include a meta-analysis with 37 trials and >10 000 infants that showed probiotic supplementation in preterm neonates significantly reduced the incidence of NEC compared with a placebo. Although preparations containing lactobacilli alone or in combination with bifidobacteria seemed to be most protective, the population in the meta-analysis was highly variable in gestational age, birthweight, and strains and combinations of probiotics. Another retrospective cohort study of 652 infants of <29 weeks gestation treated with prophylactic probiotics (Bifidobacterium species, Lactobacillus rhamnosus, and Lactobacillus reuteri) found decreased risk for NEC, but not in infants less than 26 weeks. To further assess the value of probiotics in preventing NEC, bloodstream infection, fungal infections, meningitis, and mortality, researchers  in the USA performed a multicenter, retrospective cohort study of preterm infants admitted to NICU between 1997 and 2016. Data were retrieved from a multicenter clinical database including patients from 392 sites in 35 states. Infants born at 23-29 weeks gestational age and <120 postnatal days were included. Probiotic use was defined as the receipt of any probiotic during the first 120 postnatal days. Of 78 076 infants who met the inclusion criteria, 3626 (4.6%) received probiotics. By 2016, there were 118 infants exposed per 1000 admitted, a figure far higher than in 1997. The most commonly administered probiotic was lactobacillus (71%), followed by combinations of bifidobacterium, lactobacillus and streptococcus species.  Among the exposed infants 2178 could be matched with 33 807 unexposed infants. The overall median gestational age and birthweight of the matched cohort were 28 weeks and 1020g. The median start day of probiotics was 4 and the median duration of exposure was 50 days. Probiotic administration was associated with a decrease in NEC (OR 0.62, 95% CI 0.48-0.80) and death (OR 0.52, 95% CI 0.39-0.70), an increase in Candida infection (OR 2.23, 95% CI 1.29-3.85), but no increase in bloodstream infection (OR 0.86, 95% CI 0.70-1.05) or meningitis (OR 1.18, 95% CI 0.40-3.46). The unexpected finding of the increased risk for Candida infections is contradictory to previous studies. The study builds upon previous studies supporting the safety and effectiveness of probiotics, but given the emerging role of the gut biome in health and disease, future studies must evaluate the important issues of dosing of the various probiotics for particular strains, and mechanism of action to determine which treatment yields the greatest safety and efficacy.

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J Pediatr 2020; 222: 59-64

Semin Pediatr Surg 2018; 27: 39-46

Adv Nutr 2016; 7: 928-37

Vaccination is an important public health measure that saves and improves the quality of lives of humans and animals. Effective vaccination relies on the production of a robust, appropriate, and long-lasting immune response. Vaccine antigens differ in their immunogenicity and in the type of immune response that they stimulate, and vaccine formulation can also influence success of immunisation. Furthermore, host genetic makeup, physiological status, and infection history also influence the way an individual responds to vaccination. Several studies indicate that concurrent infections (unrelated to the vaccine target) may influence immunisation, meaning that individuals infected with helminths, protozoa, bacteria or viruses respond differently to vaccination compared to uninfected individuals. To further explore the relationship between host infection and vaccine success, researchers from Princeton University in New Jersey performed a meta-analysis. Criteria were intentionally very broad to include all mammalian hosts. Parasites were also defined broadly and for the analysis included helminths, protozoa and viruses. Studies were included if they a) compared the response to vaccination between an infected group and an uninfected control group, and b) measured the response to vaccination in some way (e.g. antibody titres, measure of cell mediated immunity, seroconversion rate, rate of resistance or survival in the face of a post-vaccination challenge with the vaccine target). The initial search returned 101 relevant articles, 50 of which met criteria for meta-analysis. This is a substantial number for this kind of analysis. Overall the authors found that parasitic infections at the time of vaccination were associated with worse vaccination outcomes. Immune responses to vaccination were on average weaker for groups that were infected with helminths, protozoa, and viruses when compared with uninfected controls. Furthermore, individuals who were infected at the time of vaccination were less likely to resist or survive infection by the vaccine target pathogen when challenged post-vaccination. Chronic helminth infections were more likely to negatively impact immunisation than acute helminth infections, and thymus-dependent vaccines were more susceptible to parasite interference than thymus-independent vaccines.  Other studies have reported that bacterial infections negatively impact immune responses and ability to resist the targeted infection post-vaccination, however too few bacterial studies met the criteria for this meta-analysis to be analysed. There have also been a number of studies on the role of the microbiome in influencing response to vaccination – some have shown that certain microbiome components improve immunisation, while others have shown no significant effect. While this review is somewhat limited because it included a variety of mammalian hosts, its findings are nonetheless important for populations with endemic parasite infections: vaccine campaigns in regions with neglected tropical diseases may be less likely to succeed than those in regions with fewer endemic parasites. Similarly, vaccines that are trialled in regions with parasites may fail and therefore not proceed further due to parasite interference rather than to a failure in vaccine design.

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Vaccine 2020; 38: 5582-90

Vaccine 2012; 30: 7621–4

J Infect Dis 2014; 210: 853–64

It is estimated that globally in 2015 as many as one in four men and one in five women had hypertension. An increase of 20 mmHg systolic blood pressure is associated with a doubling of relative risk of cardiovascular disease (CVD), while treatment of hypertension is associated with a 0.8 relative risk of CVD mortality. Even with treatment in those with identified hypertension it remains the leading single cause of premature mortality worldwide with more than 11 million deaths each year. Evidence indicates that adult hypertension can develop from early childhood, partly related to the growing prevalence of overweight and obesity in childhood. Hence, interventions to promote healthy lifestyle and diet in early childhood may be important to prevent the occurrence of hypertension and associated CVD burden later in life. The problem is that long-term benefits of treatment of elevated BP in childhood have not been fully documented because there are still questions around ‘tracking’ of hypertension between child- and adulthood i.e. not all individuals with elevated BP in childhood have hypertension in adulthood. Several cohort studies have been conducted to investigate the association between elevated BP in childhood and hypertension in adulthood with results showing as little as a 1.35-fold increase (1.18– 1.55) to as much as 3.35 (1.60– 7.01). On the understanding that no systematic review or meta-analysis has been performed to quantify this association, research collaborators from China, Sweden and Switzerland performed a meta-analysis of all published longitudinal studies that provided analysable data, and a systematic review of other longitudinal studies that did not provide meta-analysable data. Children and adolescents aged up to 19 years were included. Most articles included in the analyses used dichotomous categories of BP in childhood as the exposure (i.e. presence or absence of elevated BP) while a minority of studies used BP along a continuous scale. Overall 11 articles covering 39 714 participants were included in the meta-analysis and 5 studies were included in the systematic review. Median duration of follow-up varied from 6 to 35 years. Age of measurement of elevated BP in childhood ranged from 3 to 19 years, and age for measurement of outcome in adulthood ranged from 18 to 57 years. Results of the meta-analysis showed a significant association between elevated BP in childhood and hypertension in adulthood (OR 2.02, 95% CI 1.62– 2.53) and that a 1SD increase in systolic or diastolic BP in childhood was associated with an increased risk of hypertension in adulthood (OR 1.71 for systolic and 1.57 for diastolic BP in childhood). These results of the meta-analysis and systematic review of longitudinal studies from diverse populations demonstrate that elevated BP in childhood approximately doubles the risk of hypertension in adulthood. Although primary prevention of hypertension (healthy diet, regular physical activity, weight control) is important and recommended for all children irrespective of their BP, the substantial association between high BP in childhood and hypertension in adulthood appears to strengthen the case for a specific life-course approach to prevention and control of hypertension and CVD. But reverting to the question of tracking, studies have indicated that elevated BP in childhood may not have a detrimental impact on adult CVD if BP reverted to normal in adulthood. So overall, while the risk of subsequent hypertension appears to be doubled if children have hypertension, future studies should be based on more-detailed tracking of childhood BP and should follow those who progress to adult hypertension and CVD and those who do not. Clearly such studies must also distinguish between children with secondary hypertension that might have a higher risk of progression vs. those without an underlying cause.

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J Hypertens 2020 doi. 10.1097/HJH.0000000000002550

Circulation 2008; 117: 3171-80

Acta Paediatrica 2010; 99: 24-9

Humidified and temperature-controlled high flow oxygen treatment has enjoyed super-star status during the COVID pandemic. Global concerns about insufficient numbers of complex and expensive ventilators have to a large extent been allayed as clinicians have found that patients respond well to less-complex and cheaper high flow devices and in many cases avoid intubation and invasive ventilation. The modality of assisted ventilation by HFNC has been in use for many years as a non-invasive intervention for neonates with respiratory distress. More recently it has also been applied to paediatrics and has found a place as a support for patients during ambulance transport, in emergency departments for stabilisation and reduction in admissions to ICU, and in the management of patients with asthma and bronchiolitis. This despite the fact that Cochrane reviews have not been able to make a strong case for the intervention. However studies have shown that there is a strong physiological case for HFNC, certainly in the case of bronchiolitis. Firstly there is better oxygen delivery than if delivered by alternative systems, this because the high flow of oxygen washes out the oropharyngeal dead space that contains end-expiratory oxygen-depleted gas. This means that with each breath the patient inhales oxygen-enriched gas. Dead space washout also reduces CO₂ rebreathing. Of particular importance is that the extrathoracic dead space is proportionally 2-3 times greater in children than in adults. It is up to 3ml/kg in newborns and only reaches the adult value of 0.8ml/kg after 6 years of age, so the younger the patient the greater the effect of high flow on oxygenation and CO₂ clearance. A high flow mixture at 2ml/kg/min (the rate recommended by many) is likely to generate a positive pharyngeal pressure of ~4cm H₂O during expiration, but may go higher with higher flow. Such pressures stabilise the upper airway, reduce the inspiratory burden related to ‘auto-PEEP’ from air-trapping, and prevent small airway collapse during expiration. On balance, even though the patient is breathing against the flow, the work of breathing is reduced. So if there’s so much good news, why the suggestion that it might be time for a rethink? This is the question posed by Shawn Ralston from the Division of Quality and Safety at Johns Hopkins Children’s Center in Baltimore. He comments on the proliferation of literature relating to HFNC for bronchiolitis and widespread adoption of the modality. Two recent studies have compared patients treated by means of standard nasal cannulae vs. HFNC. These studies have focused on treatment failure rate of the former, and because some fail standard care and then progress to HFNC, the standard treatment has been judged to be inferior. However it should be noted that around 70% of those treated with standard care do not fail, and in fact overall, whether started with HFNC or progressing to HFNC after failing standard, the results for the two groups are similar. For example similar numbers ultimately failed and ended up in ICU, and for those that didn’t need ICU, outcomes such as time requiring oxygen treatment were similar. HFNC is not without complications such as pneumothorax, and it is in fact a more expensive intervention, particularly if 70% do not require it. Ralston states that the wrong question was asked. It should not have been a comparison of failure rates but a comparison of outcomes for those treated ab initio with HFNC vs. those who received HFNC as rescue treatment. This would however require clear guidelines as to when HFNC should be used, whether as rescue or ab initio. While criteria for failed standard care appear to be reasonable, criteria for initiation of HFNC are less so.

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JAMA Pediatrics 2020 doi. 10.1001/jamapediatrics.2020.0040

J Pediatr 2019; 215: 199-208.e8

Ann Intens Care 2014; 4: 29     

Foetal Alcohol Spectrum Disorder (FASD) is a leading cause of developmental delay in the world as a result of the teratogenic effects of alcohol on the developing foetus, especially during the first trimester. Manifestations of FASD are heterogeneous, including specific dysmorphia (e.g. smooth philtrum, thin upper lip, small palpebral fissures, and head circumference ≤ 10th percentile), pre- and/or postnatal growth deficiency, neurodevelopmental abnormalities and neuroanatomic defects. Long term effects include cognitive impairments, psychiatric disorders and social maladjustment. Diagnosis of FASD is important for patients and their families since early intervention, appropriate medical care and social support are essential for improving outcome, better school adjustment, enhanced interaction with peers, employability and social integration. The disorder is highly prevalent in many countries including South Africa, and in younger American and European school children the prevalence may be around 2–5%. The condition is particularly prevalent among children in orphanages and foster care despite the fact that the diagnosis is often missed. This important aspect was addressed by researchers in Israel where the official number of documented FASD children is extremely low. It was reported that during a ten year period (1998–2007) only 6 patients were identified in two of the four health maintenance organizations that provide universal health coverage for Israeli citizens. This despite the fact that significant maternal consumption of alcohol has been documented among Israeli women during pregnancy. In a previous study it was found that among 100 children seen at an adoption clinic, 15% of those under the age of 2 years met the criteria for FASD or would likely do so if followed up in later life when behavioural abnormalities and learning disabilities become more evident. Reasons for possible under-diagnosis of FASD range from a lack of awareness among health professionals regarding diagnostic criteria to lack of information from biological parents. To further explore the issue a study of older children aged 2–12 years was conducted among candidates for adoption or in foster care to determine whether there was an increase in the number fulfilling the diagnostic criteria of FASD. Of 89 children evaluated, 18 had mothers with a confirmed history of alcohol consumption during pregnancy. Two children had foetal alcohol syndrome and one had partial foetal alcohol syndrome. In addition, five had alcohol-related neurodevelopmental disorder, one had alcohol-related birth defects, and a single child had manifestations of both. Of the 71 children in whom foetal alcohol exposure could not be confirmed, many had manifestations that would have met FASD criteria if a history of maternal alcohol consumption had been obtainable and confirmed.  Features in the latter group included failure to thrive, neurological findings and birth defects. The overall frequency of neurocognitive and/or neurodevelopmental manifestations among the 71 was 63% and only 13 had no clinical manifestations that could be associated with FASD. Similar results for FASD and risk for FASD have been obtained in other countries. For example FASD features were found in >50% of orphans in Russia. The Israeli study adds to recent reports of an increase in alcohol abuse in Israel. This is reflected in statistics regarding the increasing abuse of alcohol in the general population, alcohol contribution to fatal motor vehicle accidents, and the number of children brought to the emergency room with alcohol poisoning. In their conclusions the authors focus on the importance of early diagnosis in affected children so that they can receive the appropriate intervention in order to minimise cognitive, behavioural and social problems associated with FASD. However, equally or more important is surely the need to inform prospective foster or adoptive parents and prepare them for the physical, developmental, behavioural and social problems that may accompany FASD in the child they are about to bring into their home.

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BMC Pediatrics (2020) 20: 275

Pediatrics 2015; 135: 264-70

Pediatrics 2013; 132: e980-95

Chronic abdominal pain is common in children and adolescents, affecting up to 19% of that population. In one US study almost 40% of school-age children reported abdominal pain occurring at least weekly, with most fulfilling criteria for a functional gastrointestinal disorder (FGID) as defined by symptom complexes that occur in the absence of organic diseases. The two most common pain-related FGIDs in youth are irritable bowel syndrome (IBS) and functional dyspepsia (FD). IBS is defined as pain in association with a change in stool frequency and form, or a change in pain with defaecation. FD is defined as epigastric pain or burning, early satiety, or postprandial bloating. It has been established that disaccharidase deficiencies (e.g. lactase, sucrase) are implicated in children with chronic abdominal pain. Utilizing mucosal biopsies, sucrase deficiency was found in 21% of youth with chronic abdominal pain who had normal histology. That study was unable to demonstrate any associations with specific symptoms and/or diseases. While histologic assessment is considered the gold standard for diagnosing disaccharidase deficiencies, this assessment is invasive and expensive as it requires endoscopy under sedation. Breath tests to assess disaccharide malabsorption have the advantage of being non-invasive and cheaper. Moreover, commercially available kits allow for tests to be administered at home and more convenient for patients. While the hydrogen breath test is used to assess lactose and fructose intolerance, US researchers from Missouri utilised a sucrase breath test to assess sucrase deficiency. Reference to the manufacturer’s website provides an overview of this and other breath tests (https://www.metsol.com/stable-isotope-analysis/applications/breath-tests).  To their knowledge the sucrose test had not been previously reported in a cohort of youth with chronic abdominal pain. The aims of the study were (1) to determine the diagnostic yield of sucrase breath testing in a cohort of children and adolescents with chronic abdominal pain, (2) to determine if specific symptoms were predictive of an abnormal sucrase breath test, and (3) to evaluate the feasibility of administering sucrase breath tests at home. The study was a single-site review of 75 patients aged between 8 and 17 years presenting to the abdominal pain clinic between October 2018 and June 2019. Patients had abdominal pain occurring at least once weekly for a minimum of 8 weeks and were asked about cardinal symptoms necessary to diagnose IBS and FD. All were assessed for sucrase deficiency. Testing involved a commercially available kit (Metabolics Solutions, Inc – website above). Tests and instructions were dispensed in the clinic, performed at home following an overnight fast, and mailed to the company for processing. A total of 75 kits were distributed and 46 were completed (61.3%). Sucrase deficiency was identified in 34.8% (16/43) of the patients. While there were trends toward an increase in flatulence/bloating, a change in stool frequency, and diarrhoea in those with an abnormal sucrase breath test, no symptom reached statistical significance vs. those with a normal result. There was also no difference in the frequency of patients fulfilling IBS criteria in those with an abnormal sucrase breath test vs. those with a normal test (50% vs 60%, P = .515). These results are similar to those from a study of 203 patients subjected to intestinal biopsy. The main carbohydrates in the diet are sucrose and starches, however processed foods may contain a significant amount of maltose if they contain barley malt, corn syrup, or rice syrup. Maltase and isomaltase are central in starch digestion. Thus sucrase-isomaltase (SI) is a particularly important disaccharidase as it is responsible for all sucrase activity, nearly all isomaltase activity, and approximately 80% of maltase activity. SI deficiency can occur as a congenital SI deficiency condition or secondary to mucosal injury. Non-absorbed carbohydrates cause an osmotic effect resulting in a change in stool frequency and consistency, resulting in diarrhoea and, following bacterial digestion, increased gas, bloating, and flatulence. The authors conclude that sucrose malabsorption occurs frequently enough for it to be considered in all children with chronic abdominal pain. The frequency warrants more widespread testing and a consideration for a trial of sucrose and starch restriction with evaluation for clinical benefit. Future studies need to assess the ability of the breath test to predict clinical improvement with either sucrose restriction and/or sucrase enzyme supplementation.

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Clin Pediatr 2020; 59: 1191–4

J Pediatr Gastroenterol Nutr. 2018; 66(suppl 3): S61-S64

J Parenter Enteral Nutr 2017; 41: 463-9

Patent ductus arteriosus (PDA) affects about 32%‐60% of extremely preterm infants born at 22‐28 weeks of gestation. An imbalance of vasodilatory stimuli, lack of contractile mechanisms, and the immaturity to react to regular postnatal constrictive stimuli can lead to delayed or absent ductal closure. There are multiple risk factors for PDA including prematurity, low birthweight, respiratory distress syndrome, sepsis, exposure to antenatal nonsteroidal anti‐inflammatory drugs (NSAIDs) and ventilatory support. If PDA closure does not occur spontaneously, common interventions are pharmacological treatment with drugs such as indomethacin and ibuprofen, and surgical ligation. Gentamicin and tobramycin are aminoglycoside antibiotics that are frequently used in preterm infants at high risk for sepsis. Regarding an association between PDA and use of these aminoglycosides, studies in mice and rats have found dose‐dependent vasodilatory effects of these drugs on the ductus. This has been corroborated by Vucovich et al who found increased PDA rates in aminoglycoside‐treated infants born at 23‐25 and 32‐38 weeks of gestation, but not in infants born 26‐31 weeks of gestation. However others have not confirmed the relationship at usual dosing levels. Most NICUs in Germany use combinations of ampicillin and aminoglycosides as first‐line antibiotic treatment, so to study the relationship between aminoglycosides and PDA researchers from several academic centres analysed centre‐specific antibiotic treatments and the association with surgical PDA closure. Infants with birthweight <1500g and gestational age <37 weeks were enrolled in 62 level III NICUs. Infants with a gestational age of 22-29 weeks or birthweight <1000 grams and born and discharged from hospital between January 2009 and December 2018 were included. The data extract included basic information on aminoglycoside use, PDA therapies such as indomethacin or ibuprofen, surgical ligation and steroid use. Some 11 913 infants with complete data sets were included from the 62 centres. There were 53 NICUs using aminoglycosides as first‐line antibiotics (n = 9965 infants; 83.6%) and 9 NICUs using other than aminoglycosides as first‐line antibiotics (n = 1948 infants; 16.4%). Baseline data for enrolees were not different when NICUs using aminoglycosides (n = 9965 infants) were compared to NICUs using other antibiotics (n = 1948 infants). Rates of surgical PDA closure were 5.9% for NICUs using aminoglycosides; 6.2% for units using gentamicin; and 5.0% for NICUs using tobramycin, compared to 4.1% in NICUs using other antibiotics (P < .001, P < .001 and P = .140 respectively). Indomethacin and ibuprofen use was also more common in NICUs using aminoglycosides (41% vs 33%, P < .001). Gentamicin trough levels were higher in NICUs with surgical closure rates above the mean. Logistic regression analysis showed that apart from exposure to the two aminoglycosides, the risk factors for PDA requiring surgical ligation included lower gestational age, sepsis and other indicators of more-severe disease e.g. oxygen requirement and exposure to other drugs such as dobutamine and furosemide. However because the aminoglycoside exposed and non-exposed groups were similar at baseline (i.e. similar birthweights and gestational ages and equally sick) the aminoglycoside exposure was an independent risk factor. In the vulnerable cohort of extremely preterm infants neonatologists should be aware of this additional risk factor for PDA and the greater likelihood of requiring pharmacological and/or surgical intervention to effect closure. Aminoglycoside trough levels should be checked carefully and adjustments of doses and/or intervals should be undertaken when needed.

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Acta Paediatrica 18 August 2020 doi.org/10.1111/apa.15541

Pediatr Neonatol. 2020; 61: 45‐50

Am J Physiol Heart Circ Physiol. 2014; 307: H732‐740

Compared with adults the majority of paediatric patients with COVID have been asymptomatic or had milder symptoms including fever, cough, sore throat and nasal congestion, but mid-April 2020 there were paediatric cases presenting with hyperinflammatory shock. Since then additional cases from across the globe have emerged with hyperinflammatory syndrome, potential for multi-organ failure and shock, and temporal association with COVID infection. The World Health Organization classified MIS-C as the following: fever ≥ 3 days, 2 of the following (rash, non-purulent conjunctivitis, mucocutaneous inflammation, hypotension or shock, myocardial dysfunction, pericarditis, valvulitis, coronary abnormalities, elevated troponin or NT pro-BNP (a measure of natriuretic peptide), coagulopathy, acute gastrointestinal problems), evidence of elevated inflammatory markers (ESR, CRP, procalcitonin), no obvious microbial cause, and evidence of SARS-CoV2 infection or likely contact with COVID-19. To obtain a clearer picture of the cases from around the world, clinicians collaborated and pooled data. The overall focus was on the cardiac manifestations of MIS-C but a limitation of the review is that not all cases were referred to cardiologists. The reviewed patients met the following criteria: age ≤ 18 years, no prior medical history, and presentation during the SARS-CoV2 pandemic. Echocardiograms were read by a pediatric cardiologist at individual sites and data provided on ejection fraction based on individual center protocols. Z-scores for coronary arteries were based on the Boston scoring system at all participating sites. Valvulitis was diagnosed based on any valvar regurgitation greater than trivial. Fifty-five patients met the inclusion criteria (mean age 7 ± 5.2 years): 16 patients from Barcelona (29%), 14 from London (26%), 13 from New York City (24%), 9 from Karachi (16%) and 3 from New Orleans (5%).  Patient symptoms included fever (52/55), rash (27/55), gastrointestinal symptoms including abdominal pain, nausea, vomiting or diarrhea, (32/54), conjunctivitis (18/55), mucous membrane changes (16/55), hand or foot swelling (12/54) and unilateral cervical adenitis (12/53). Of those tested for COVID, 20/53 were PCR positive for the antigen and 19/24 were IgG positive. Twenty-seven patients required ICU admission (49%), 35 patients (64%) had evidence of myocardial dysfunction with LVEF < 60%, 24 patients (44%) had evidence of shock and 2 (4%) patients did not survive. Among the patients with decreased LVEF, 18 (51%) had mildly decreased LVEF, 11 (32%) had moderately decreased LVEF and 6 (17%) had severely decreased LVEF. Seventeen patients (31%) had valvulitis, 12 (22%) had pericardial effusion and 11 (20%) coronary artery abnormalities. Patients with shock had significantly higher NT pro-BNP levels on admission compared to those without (11411 ± 2143 vs 2273 ± 638 pg/mL, p=0.001). Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular (AV) block, transient AV block and ventricular tachycardia.   Notably, eleven patients (20%) had complete features of Kawasaki disease (KD) based on established criteria and only 2/11 (18%) patients who fulfilled complete KD criteria had evidence of coronary changes. The KD group was younger (mean age of 5.4 ± 5.7 years vs 7.5 ± 5.1, p=0.01), had longer duration of fever (6.3 ± 1.3 days vs 4.8 ± 2.4 days, p=0.07) and had better left ventricular function (LVEF 58 ± 9% vs 46 ± 18%, p=0.05). None of the patients with complete KD criteria presented with shock or had evidence of valvulitis. Patients with complete KD criteria had lower levels of NT pro-BNP (1606 ± 1089 vs 8522 ± 2143 pg/mL, p=0.007), D-dimer (1.4 ± 0.7 s. 5.6 ± 1.0 ug/mL, p=0.025) and ferritin levels (171 ± 57 vs. 678 ± 107 ng/mL, p=0.008). These results strongly suggest that KD is a separate entity from MIS-C.  IVIG and steroid use varied between treating institutions, and while this was not commented on specifically in the review, it is likely that additional pharmacological treatments in addition to pressors for treatment of shock also varied between institutions. While follow-up data were not available for all patients, anecdotally left ventricular systolic function and electrocardiographic abnormalities (including complete heart block) normalized within 2 weeks of initial presentation. However coronary changes including ‘brightness’, mild dilation and aneurysms persisted during early follow-up. These data highlight the potential for cardiac involvement with MIS-C and the role of early cardiology consultation and work-up. However treatment/s and efficacy remain poorly defined. While long-term follow-up is limited, early reports are encouraging with improvement in electrophysiologic abnormalities and left ventricular dysfunction, though coronary changes appear to linger.

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J Am Heart Assoc 2020 doi: 10.1161/jaha.120.018007

Several studies have linked abnormal placental morphologic and histopathologic features to adverse foetal and neurodevelopmental outcomes. As a regulator of the foetal environment the placenta is critical to foetal health. Pathology may therefore adversely affect placental transport and endocrine functions, and lead to reprogramming of fetal organ development via epigenetic modifications. In South Africa perinatal infection has been shown to impact significantly on rates of stillbirth and neonatal death. Chorioamnionitis (CA), one of the intrauterine infection indicators, has not only been shown to impact on perinatal morbidity and mortality, but also on neurobehavioral development in offspring. Studies have shown speech delay and hearing loss at 18 months of age, moderate to severe psychomotor disability at 2 years of age, poorer cognitive outcome and weaker memory and learning functions at 5 years of age. A meta-analysis including 17 studies with >125 000 patients with CA and almost 6million controls found a significant association between preterm histologic CA and cerebral palsy. To further explore the relationship between CA and neurodevelopmental outcome, Chinese researchers accessed data from the Collaborative Perinatal Project (CPP), a prospective cohort study of pregnancy and child health conducted at 12 hospitals in the United States from 1959 to 1976. In the project pregnant women were enrolled at their first prenatal visit at 21.3±8.4 weeks. Only singleton births of 28-45 weeks were included. Following delivery, placentas were sent for pathologic examination and infants were assessed and followed to 7 years of age. Children without neurodevelopment assessment or placental examination were excluded, leaving 32 326 for the final analysis. At 8 months of age infants were assessed using the Bayley Scales of Infant Development. The motor score, ranging from 0 to 43 was categorised as low (0-19), suspect (20-26), or normal (27-43). The mental score, ranging from 0 to 103, was categorised as low (0-55), suspect (56-74), or normal (75-103). The Stanford-Binet IQ scale was used to assess child IQ at 4 years and categorised into 5 groups: <70, 70-84, 85-114, 115-129, and 130-181. The assessment at 7 years of age used the Wechsler Intelligence Scale for Children and scores were classified into four groups: <70, 70-79, 80-119, and ≥120. Maternal characteristics included age, race, SES index (based on family income as well as household head’s education and occupation), education levels, BMI before pregnancy, smoking and parity. Following exclusions, 7782 women (24.1%) had positive placental inflammatory pathology that was found to be associated with older age, race, overweight/obesity before pregnancy, smoking, multiparity, lower education and SES, preterm birth and a male foetus. Multivariate analysis after adjusting for confounders showed that placental inflammatory pathology was significantly associated with low Bayley motor (OR 2.15; 95% CI, 1.50-3.06) and mental scales (OR, 1.51; 95% CI, 1.05-2.17) at 8 months, and an IQ of 70-84 (OR, 1.13; 95% CI, 1.01-1.26) at 4 years of age. However the association diminished at 7 years of age (IQ of <70, OR 1.20 [95% CI, 0.97-1.48]; IQ of 70-79, OR 1.03 [95% CI, 0.89-1.18]). Further analysis demonstrated that associations between placental inflammatory pathology and development were primarily due to direct effects of placental inflammatory pathology rather than indirect effects of preterm delivery (that may have been precipitated by the CA itself or the result of medical intervention to save the foetus). As per previous animal research the authors conclude that placental inflammation activates the release of cytokines and chemokines. These affect cells in the central nervous system, resulting in neuroinflammation. The finding of lower functioning during early childhood but reversal at 7 years of age should be confirmed through further studies but could be related to compensatory parental care or physiologic recovery of the brain injury. Unfortunately the CPP data did not include information on the recovery process and mechanisms. Also not covered in the article was the extent to which CA contributed to birth asphyxia and whether CA alone had the same outcome as CA plus asphyxia.

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J Pediatr 2020; 225: 132-7

Pediatrics 2017; 139: e20163781

Semin Fetal Neonatal Med 2006; 11: 343-53.

The year 2000 marked a turning point in global efforts to control malaria, a leading cause of death among children under 5 in Africa. Since then, malaria prevalence in sub-Saharan Africa has halved. Globally 19 countries have eliminated malaria and another 20 are on the verge of elimination. This progress has been fuelled by the deployment of malaria prevention and treatment technologies that together with unprecedented global malaria funding, have facilitated dramatic increases in the scale of malaria control efforts. Despite this, the burden of malaria remains high with >200 million cases and around 400,000 deaths per year. Evidence suggests that progress has slowed in recent years. Some countries are seeing increases in malaria transmission and the World Health Organization (WHO) and other global leaders in malaria control policy have called for a renewed focus on reducing the malaria burden. Reductions in malaria morbidity and mortality will require new insights into gaps in the effectiveness of malaria control programs, including evidence on health system performance in the management of paediatric malaria. Most of the global malaria mortality burden is among young children in sub-Saharan Africa who are infected with Plasmodium falciparum that requires prompt and appropriate anti-malarial treatment in order to prevent progression to severe morbidity or death. Because symptoms of malaria overlap with common viral and bacterial diseases, laboratory confirmation of the disease through microscopy or rapid test is strongly recommended. WHO guidelines include blood test confirmation of malaria prior to treatment because testing can ensure better management of non-malarial illness, reduce wasted resources on unnecessary anti-malarial prescriptions, and improve health system surveillance. WHO and country-level guidelines have evolved substantially in this century, including the introduction of Artemisinin Combination Therapies (ACTs) as first-line treatment for uncomplicated malaria. Unfortunately first-line caregivers often do not seek formal facility-based care for children with malaria symptoms, instead using over-the-counter medications, informal care, or no care at all. More unfortunate is that even children seen by a formal healthcare provider may not receive appropriate care. In an analysis carried out by US and Swiss-based researchers, clinical observation data covering 12 years and ±25,000 sick-child visits across 6,400 health facilities in 9 sub-Saharan African countries the focus was on the extent to which children with a malaria diagnosis received a confirmatory blood test result and appropriate anti-malarial treatment. Data from the Service Provision Assessment (SPA) survey was used. SPAs are nationally representative facility surveys capturing quality of sick-child care, facility readiness, and provider and patient characteristics. The nine countries were Uganda, Rwanda, Namibia, Kenya, Malawi, Senegal, Ethiopia, Tanzania and Democratic Republic of the Congo. Children observed were on average 20.5 months old and were most commonly diagnosed with respiratory infection (47.7%), malaria (29.7%), and/or gastrointestinal infection (19.7%). Among the 7,340 children with a malaria diagnosis only 32.5% received both a blood-test–based diagnosis and an appropriate anti-malarial. The range for care according to guidelines ranged from 3.4% to 57.1% across countries. Roughly 20% of children diagnosed with malaria received no anti-malarial at all, and nearly 10% received oral artemisinin monotherapy, which is not recommended because of concerns regarding parasite resistance. Confirmatory blood test diagnosis and appropriate anti-malarial treatment was positively correlated with being seen at a facility with diagnostic equipment in stock (adjusted OR 3.67; 95% CI: 2.72–4.95), and being seen at a facility with ACTs in stock. However, even if all children diagnosed with malaria were seen by a trained provider at a facility with diagnostics and medicines in stock, only a predicted 37.2% (95% CI: 34.2%–40.1%) would have received a blood test and appropriate anti-malarial. This improved slightly to 44.4% if only the later years were analysed. Thus a majority of children diagnosed with malaria across 9 sub-Saharan African countries did not receive recommended care. Important quality gaps remain in the countries studied. Similar analysis is required for South Africa.

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PLoS Med 17: 2020: e1003254. https://doi.org/10.1371/journal.pmed.1003254

World Health Organization. 2010 Guidelines for the treatment of malaria. 2nd ed. Geneva, Switzerland

BMC Med. 2020; 18: 17. https://doi.org/10.1186/s12916-019-1483-6

Preterm infants have different DNA methylation (DNAm) patterns vs. term infants and some of these differences appear to persist into adulthood. Specifically, alterations in DNAm have been associated with conditions such as sepsis and pain-related stress (which may subsequently affect serotonergic tone, temperament and neurobehavioral responses). Thus, variations in neonatal DNAm may serve to link preterm birth, complications that these infants may experience, and persistent developmental impairments. Clinically it is well known that bronchopulmonary dysplasia (BPD), severe brain injury (SBI), and severe retinopathy of prematurity (ROP) are independently associated with poor 18-month outcomes e.g. cerebral palsy, cognitive delay, hearing loss, blindness and death, and the combination of these morbidities is an even stronger predictor of impairment or death. For example, preterm infants with severe BPD are more likely to have severe ROP compared to infants without BPD, and both of these complications may involve altered regulation of angiogenic and/or angiostatic factors. To further explore the relationship between DNAm and severe neonatal complications, American researchers hypothesized that these neonatal morbidities may be encoded and expressed as DNAm which is an epigenetic mechanism for regulating gene expression, typically occurring at cytosine-phosphate-guanine (CpG) motifs/sites. The study examined the relationships between the cumulative impact of serious neonatal morbidities experienced during NICU stay (BPD, SBI, infections (INF) and ROP) and DNAm measured at the time of NICU discharge. This Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study was conducted at nine university-affiliated NICUs from April 2014 through June 2016. All participants were born at < 30 weeks gestational. Infants with major congenital anomalies were excluded. Overall, 704 infants were enrolled and at the time of discharge buccal cells were collected on 624 of these infants for epigenomic (DNAm) screening. Epithelial cells made up 95.7% of the cells in 95% of the buccal samples while immune cells made up the majority of the remaining cell types. In 532 infants in which DNAm data and composite neonatal morbidity risk scores were available there was a 60% chance of experiencing at least one of the four neonatal morbidities (BPD, SBI, INF, or ROP), while a small subset experienced three or more of these morbidities (n = 28, 5.3%). The most common health complication was BPD (273, 51%), with severe ROP being least common (34, 6.4%). Each unit increase in the composite morbidity risk score resulted in a 1–4% increase in DNAm result, and the cumulative neonatal morbidity scores were strongly associated with increasing DNAm at eight CpGs and decreasing DNAm at two CpGs i.e. within 10 identified genes. These relationships largely followed dose–response patterns. Among the four complications included in the neonatal morbidity risk score, BPD appeared to be the primary driver of the epigenetic responses, but SBI, INF, and/or ROP were also associated with differential methylation at all of the genome-wide significant CpG sites. These epigenetic differences may be related to common processes within the identified genes, possibly interacting with and influencing important mediators and processesd such as fibroblast growth factor receptor (FGFR), angiogenic processes, cellular proliferation, cell cycle regulation and neuronal signalling. It is not clear if buccal cell DNAm patterns at these genes are reflective of DNAm patterns at these same genes in neuronal, respiratory, and immune cells. However the data suggest that cellular process related to fibroblast growth factor activities, cellular proliferation and invasion, and neural development and signalling may be sensitive to severe neonatal morbidities in infants that are born very preterm. Some CpGs associated with preterm birth have been shown to be methylated in adult blood, suggesting that DNAm could potentially mediate some of the long-term health consequences that are associated with prematurity. Overall the findings support evidence that neonatal DNAm in preterm infants with severe complications may inform future health outcomes by identifying epigenetic variation associated with neonatal morbidities. Future research should investigate whether these differences in DNAm persist, amplify, or attenuate as the children age.

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Clin Epigenet 2020; 12:151 https://doi.org/10.1186/s13148-020-00942-1

Sci Rep. 2019; 9: 6322

Genome Med. 2013; 5: 96

Lactic acidosis (LA) is a known complication of status asthmaticus in adults but data are lacking for children. The LA may be a side-effect of β₂-agonists used in acute asthma treatment, potentially complicating interpretation of hyperventilation due to hypoxaemia and/or stimulation of pulmonary mechanoreceptors. These stimuli may result in respiratory alkalosis, the most frequent acid-base disturbance observed in acute asthma. If not recognised, the latter may lead to progressive respiratory insufficiency, hypercapnia and respiratory acidosis. Further complicating the situation is that hyperventilation related to β₂-stimulated LA may also be regarded as a sign of impending respiratory failure, potentially resulting in inappropriate escalation of bronchodilator therapy. To gain greater insight into the prevalence and risks of LA in asthmatic children and adolescents, Swiss researchers studied patients treated with salbutamol for moderate or severe acute asthma between May 2017 and April 2019 in a tertiary care hospital. Subjects were 2 to 17 years of age requiring inhaled β₂-agonists at least 2-hourly and with a qualifying asthma PRAM (Pediatric Respiratory Assessment Measure) score. Basic data included age; body mass index; sex; initial degree of asthma severity; dose and type of salbutamol, steroids and ipratropium bromide; and type of maintenance intravenous fluid. Salbutamol was administered via a metered dose inhaler (pMDI) or nebuliser. Capillary blood was drawn four hours after the first administration of salbutamol and with any evidence of tachypnoea or worsening of the respiratory status. Hyperglycaemia was defined as glucose >11 mmol/l. The primary outcome was the prevalence of LA. Of 627 eligible patients 154 were ultimately entered into the study. Two-thirds of the 154 were between 2 and 6 years. Forty-three percent of episodes were categorised as severe (PRAM > 8) and 57% as moderate (PRAM 4–8). Salbutamol was administered by pMDI alone in 30% of cases and by nebuliser (alone or associated with pMDI administration) in 70%. Mean overall dose of salbutamol during the first 4 hours was similar in subjects above and below 6 years of age. Those with severe asthma received higher doses of salbutamol (19±10mg) compared to patients with moderate asthma (6.7±5.7mg), p < 0.0005. When delivered by nebulisation the mean salbutamol dose was 16±9mg vs. 2.4±1.2mg when delivered by inhaler (p < 0.0005). Almost all patients (95%) received (mainly oral) corticosteroids at a mean dose of 1.85±0.75 mg/kg, and 15% received ipratropium bromide. Secondary appearance of tachypnoea or worsening of the respiratory status required a second blood gas in 13 patients. Overall 87% of patients had hyperlactatemia (lactate >2.2 mmol/l). Lactic acidosis (lactate >5 mmol/l and anion gap ≥16 mmol/l) was observed in 26%. Thirty-four (22%) showed compensated LA (lactate >5mmol/l, pH ≥7.35, pCO2 <35mmHg). Only 6 (4%) had pH <7.35. None had hypercapnia (pCO2 > 40 mmHg). In multivariate analysis, age >6 years (OR=2.8; 95% CI 1.2–6.6), glycaemia >11mmol/l (OR=3.2; 95% CI 1.4–7.4), and salbutamol administered by nebuliser (OR=10; 95% CI 2.7–47) were identified as risk factors for LA. Lactic acidosis involves one of two mechanisms: Type A is associated with impaired oxygen delivery and/or hypotension. Type B implies underlying disease (e.g. diabetes, renal disease), drugs (such as β₂-agonists), or inborn errors of metabolism. Exposure to high doses of drugs such as salbutamol induces a hyper-adrenergic state, leading to increased lactate production. There is glycogenolysis, gluconeogenesis and glycolysis and transformation of glucose to glucose 6-phosphate and then to pyruvate. Furthermore, β₂-agonists enhance lipolysis. Free fatty acids inhibit pyruvate dehydrogenase, which allows pyruvate to enter the Krebs cycle. In this way, pyruvate to lactate formation is promoted. Types A and B can be distinguished by the L/P ratio (L/P< 25/1 vs. L/P>25/1). Studies have shown that LA is Type B in asthma but it is self-limiting and no fatal case has been described in children. In this study the greater risk of LA when salbutamol was administered by nebulisation was probably related to the higher dose delivered via this delivery system. Concurrent use of corticosteroids may also elevate blood glucose level and in this study 36% of patients receiving steroids had glucose >11mmol/l. So what are the bottom lines? LA is a frequent and early complication of asthma in children treated with high doses of bronchodilators but it is self-limiting. Levels of LA are higher in subjects >6 years of age, when salbutamol is administered by nebuliser, and if there is concurrent hyperglycaemia. It is important to recognise LA to avoid unnecessary and harmful therapeutic intensification.

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Europ J Pediatr 2020; https://doi.org/10.1007/s00431-020-03834-x

S Afr Med J 2013; 103: 199-207

Pediatr Crit Care Med 2007; 8: 519–523.

Globally pneumonia is the leading cause of mortality in children aged <5 years and accounts for 16% of deaths in that age category. The aetiology of pneumonia is rarely established in clinical practice, commonly leading to empirical antibiotic treatment. Up to 60% of cases are associated with viral infections, so antibiotic treatment is often unnecessary. This is a serious issue in the era of drug-resistance and antibiotic stewardship. Therefore, whenever possible, viral and bacterial pneumonia should be differentiated. Several studies suggest that bacterial pneumonia can often not be distinguished from non‐bacterial pneumonia on the basis of chest X-ray (CXR), and apart from C‐reactive protein (CRP) levels, routine blood tests have limited practical value. Rapid viral antigen testing for viral pneumonia can yield results within 30 minutes, but applying this test in all patients is neither practical nor cost‐effective. Lung ultrasound (LUS) has the potential to differentiate between bacterial and viral pneumonia with high inter-observer reliability. Using portable or hand‐held machines it is easy to perform at a child's bedside, requiring only 5 to 10 minutes in skilled hands. The technique was utilised by clinicians from India in a study of 200 children over an 18-month period during 2017-8. Around 46% were assessed in the emergency department and the remainder as in-patients. Children (excluding neonates) presenting with a clinical suspicion of pneumonia and requiring a clinically-indicated CXR were eligible for the study. LUS and CXR diagnoses were recorded as bacterial, viral, or mixed type of pneumonia and children were followed up until recovery. A final diagnosis was made using a combination of clinical profile, laboratory tests and CXR findings. This clinical-radiological diagnosis was then used as the reference standard. LUS was suggestive of bacterial/alveolar pneumonia in the presence of lung consolidation i.e. echo-poor/hypoechoic areas with or without air bronchograms, a ‘shred sign,’ or ‘hepatisation’ of the lung. Children with LUS suggestive of interstitial pneumonia were diagnosed as viral pneumonia, as indicated by multiple (>3) focal B lines in any one field of view, confluent B lines, pleural abnormalities (irregularity, thickening, or coarse pleural surface) and small sub-pleural consolidation <0.5cm. Small subpleural consolidations (typically 0.25 to 0.5cm in depth) containing no sonographic air bronchograms, associated with an interruption in the pleural line, and typically having a trailing ‘comet tail’ are also associated with viral infection. The children in whom features of both alveolar and interstitial pneumonia on LUS were present were diagnosed as mixed pneumonia. The LUS diagnosis was compared with the clinical-radiological diagnosis i.e. the reference standard. Since mixed pneumonia also required administration of antibiotics, the children diagnosed as mixed on LUS were combined with bacterial pneumonia at the time of comparison with the reference standard. The accuracy of LUS in diagnosing bacterial and viral pneumonia was then calculated in terms of sensitivity, specificity, positive predictive value, and negative predictive value. The mean age of the study sample was 2 years 1 month. Tachycardia was present on examination in 99%, tachypnoea in 76% and crepitations and/or wheeze in 45%. Fifty-seven percent had leucocytosis while blood culture was positive in only 3 subjects. Of the 200 children, predominantly alveolar pattern was seen in 28%, predominantly interstitial pattern in 41.5% and a combination of alveolar and interstitial (i.e. mixed pattern) in 23% of the patients. In 15 children LUS did not reveal any abnormality. Lung consolidation and air bronchograms were the dominant findings in children diagnosed as bacterial pneumonia on LUS, while pleural irregularity was the dominant sign in viral pneumonias (90,4%), followed by coalescent and multiple focal B-lines (70-77%). The sensitivity of LUS in diagnosing bacterial pneumonia was 91%, specificity 91.3%, positive predictive value 91.9%, and negative predictive value 90.3%. The sensitivity of LUS in diagnosing viral pneumonia was 78.4%, specificity 90.4%, positive predictive value 87.3%, and negative predictive value 91.3%. The time taken to conduct LUS examination ranged from 4 to 15 minutes with an average of 9 minutes 36 seconds. The authors conclude that LUS has a high accuracy in differentiating between bacterial and viral pneumonia in children and can avoid unnecessary antibiotic therapy. Perhaps once one has the required skills to perform LUS the reasonable next step would be a focus on the ±50% in which there was either no LUS diagnosis or a diagnosis of viral pneumonia. Those with an LUS diagnosis of bacterial pneumonia would be treated with antibiotics, while the remainder would be X-rayed and further investigated. Only those in which viral pneumonia remained questionable would receive antibiotics - a significant step towards good stewardship.

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J Clin Ultrasound 2020; doi:10.1002/jcu.22951

Int J Contemp Pediatr 2016; 3:1026

Pediatr Pulmonol 2013; 48: 1195-1200

Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition in neonates. It is mainly seen in term and post-term infants, with an incidence of around 2 per1000 live births. While often idiopathic, chronic foetal hypoxia may affect pulmonary vasculature. Significant ventilation-perfusion mismatches occur postnatally with or without accompanying alveolar disease such as meconium aspiration syndrome. Symptoms include respiratory distress in the first hours after birth with low arterial oxygen saturations that are not responsive to supplemental oxygen but may be responsive to assisted hyperventilation. Pulmonary artery resistance and pulmonary artery pressure (PAP) are typically both increased. Mortality in developing countries is estimated to be around 10–20%, often due to lack of access to the current gold standard i.e. inhaled nitric oxide, a gas that vasodilates by increasing cyclic GMP in pulmonary smooth muscle cells. In the past clinicians relied on support from vasoactive drugs such as tolazoline and nitroprusside as well as dopamine and dobutamine, all of which have effects that go beyond the pulmonary vasculature. More recently attention has been given to phosphodiesterase inhibitors such as milrinone and sildenafil. Milrinone increases cardiac output by decreasing afterload, and induces pulmonary artery vasodilatation with resultant reduction in pulmonary artery pressure through its effects on cyclic AMP and GMP. However, at higher doses, it increases systemic blood pressure. Sildenafil dilates the pulmonary vasculature by increasing intracellular cyclic GMP, decreases PAP, but as with other vasoactive drugs has effects beyond the lungs and may cause complications. Enter bosentan, an antagonist of the endothelin A and B receptors. Several studies have shown that it is effective in the treatment of pulmonary arterial hypertension and appears to be more specific for the pulmonary vasculature. To compare sildenafil and bosentan, researchers in Iran conducted a double-blind study in neonates suffering from PPHN. Echocardiographic findings, duration of oxygen dependency, invasive ventilatiory support requirement and duration of medication were compared between the two groups. After randomisation and subsequent withdrawal of 10 subjects, 40 remained in the study, 15 in the bosentan and 25 in the sildenafil group. Groups were matched in terms of maternal and neonatal risk factors. Results showed that bosentan was effective in the treatment of PPHN and reduced pulmonary hypertension in a shorter period. Bosentan decreased the PAP, severity of tricuspid valve insufficiency, and improved cardiac output more effectively in a shorter period compared to sildenafil. Oxygen demand and the need for aggressive respiratory support were similar between the groups without any short-term effects such as systemic hypotension.

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J Clin Neonatol 2020; 9:249-54

J Pediatr 2016; 177: 90‑6

S Afr J Child Health. 2008; 2: 4.

Around 80% of the world’s under-five deaths occur in low and middle income countries (LMICs). Most are due to either acute respiratory infection or acute gastroenteritis. Interventions such as exclusive breast feeding, safe complementary feeding and universal vaccination have been introduced to mitigate the risks of these diseases. Childhood pneumonia remains the single largest contributor to global post-neonatal mortality and a recent review estimated an incidence of community-acquired childhood pneumonia in LMICs of 0.22 episodes per child per year. Of these, 11.5% progress to severe episodes. All these statistics translate to an estimate 68 million cases of pneumonia and >650 000 deaths per year. Pneumonia therefore contributes about 15% of the total 5.6 million annual under-five year child deaths, the vast majority in LMICs and in primary care settings where resources are limited and populations more susceptible. Standard treatment includes fluids, antibiotics and oxygen. Micronutrients and their relation to pneumonia have been the subject of research for several years, the consensus being that mass vitamin A preventative supplementation reduces subsequent all-cause mortality, but that adjunctive treatment in acute pneumonia does not alter the disease process. In this regard zinc, another key micronutrient, remains controversial. It has immune-enhancing properties and deficiency is associated with increased susceptibility to infection. In gastroenteritis, zinc supplementation enhances recovery in LMICs and, according to meta-analysis, reduces mortality by an estimated 23%. Population preventative zinc supplementation reduces all-cause mortality and reduces pneumonia incidence if administered regularly. However, the role of adjunctive zinc at the time of presentation with pneumonia remains controversial. Meta-analyses published in 2011, 2012 and 2016 found no effect, while another that included studies up to 2015 and published in 2018 estimated a significant reduction in mortality (risk ratio 0.43, 95% CI 0.22 to 0.83). In an effort to update the data Swedish researchers performed a new meta-analysis involving the efficacy of adjunctive zinc supplementation in children aged 2 to 60 months presenting with pneumonia in LMICs. They identified 11 trials published between 2004 and 2019, 7 from South Asia, 3 from Africa and 1 from South America. Treatment failure was comparable in both zinc and placebo groups when analysed for all patients (OR 0.95 (95% CI 0.80 to 1.14)) and also only for those with severe pneumonia (OR 0.93 (95% CI 0.75 to 1.14)). No difference was seen in mortality between zinc and placebo groups (OR 0.64 (95% CI 0.31 to 1.31)). Time to recovery from severe pneumonia did not differ between the treatment and control groups for patients with severe pneumonia (HR 1.01 (95% CI 0.89 to 1.14)). Removal of four studies with high risk of bias made no difference to the conclusions. Their conclusion was that there is no evidence that adjunctive zinc treatment improves recovery from pneumonia in children in LMICs.

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BMJ Paediatr Open 2020;4:e000662. doi:10.1136/bmjpo-2020-000662

Paediatr Respir Rev 2012;13:184–91

Br J Nutr 2016;115:807–16.

Health disparity research across the globe has highlighted the disturbing consequences that racial/ethnic and socioeconomic differences have on health outcomes and the delivery of accessible, high-quality health care. Recent research has drawn attention to kernicterus in the US where black neonates account for more than 25% of kernicterus cases despite representing only 14% of births. Research from the UK and Ireland also showed that hyperbilirubinaemia ≥510µmol/l was more likely in black neonates, suggesting that the disparate risk is not limited to the US. Infants with kernicterus generally experience extreme (≥425µmol/l) or hazardous (≥510µmol/l) total serum bilirubin (TSB) exposures. Peak TSB levels in black neonates with kernicterus range from 475 to 920µmol/l with a median of 670µmol/l. However, in comparison with white infants, black neonates actually have a lower overall incidence of significant (≥290µmol/l) and severe TSB (≥340µmol/l). This paradox of lower overall incidence of severe hyperbilirubinaemia in black neonates but higher incidence of hazardous hyperbilirubinaemia was first highlighted in the Collaborative Perinatal Project (1959-1966) and was confirmed in several investigations, showing a risk ratio of 4.20 (95% CI, 1.33-13.2) vs. white infants. Approximately 1 in every 8000 black neonates showed a TSB level of ≥510µmol/l vs. 1 in every 33 000 white neonates. Both biologic and non-biologic contributors have been explored to explain the apparent paradox. One possible biologic contributor is glucose-6-phosphate dehydrogenase (G6PD) deficiency. This is a prevalent and overrepresented cause of kernicterus worldwide, and with the high prevalence of G6PD deficiency among African Americans may contribute to the black kernicterus health disparity. Approximately 12.2% of African American men and boys and 4.1% of African American women and girls have G6PD deficiency, and together they account for 75% of individuals with G6PD deficiency in the US. In the US Pilot Kernicterus registry, G6PD deficiency accounts for more than 1 in 5 cases, nearly all of which are in black neonates. Notably, with G6PD deficiency the haemolysis is triggered by oxidative stress and the trigger is often unidentified. Consequently the event may occur later in the neonatal course i.e. after discharge from hospital, and laboratory evidence of haemolysis is often absent. Although not as severe as the G6PD Mediterranean variant, the enzymatic deficiency of the G6PD African A- variant is now recognized to pose a risk for haemolysis, hazardous hyperbilirubinaemia and kernicterus. Furthermore there may impairment of bilirubin metabolism as a result of co-expression of uridine-diphosphate-glucuronosyl transferase 1A1 (UGT1A1) genetic sequence variations of Gilbert syndrome which is common among African Americans. Another possible biologic contributor is symptomatic ABO haemolytic disease that is more common in black newborns as a result of elevated titres of anti-B haemolysins in black populations. Among the non-biologic contributors one must consider unreliable clinical assessment of jaundice in infants with darker skin tones. Several studies have confirmed a poor correlation between visual assessments and actual TSB levels, thereby placing black neonates at risk for delayed recognition until hyperbilirubinaemia is pronounced and/or signs of intermediate-to-advanced acute bilirubin encephalopathy develop. One must also consider limited parental health literacy and care-seeking practices that can result in delayed care of babies with hyperbilirubinaemia, particularly for families of lower socioeconomic status. While kernicterus is regarded as an uncommon phenomenon, it would be interesting to establish the extent to which the above factors apply to the South African situation.

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JAMA Pediatr. 2020; 174: 1199-1205

J Pediatr. 2013;162: 1068-1069

Semin Fetal Neonatal Med. 2010; 15: 176-182.

Paediatricians are aware of the rapid changes in human development during the first 3 years of life and development of the gut microbiome is no exception. Breastfeeding, birth mode, geographical location, antibiotics and postnatal home influences (e.g. accelerated microbial diversity in the presence of siblings and furry pets) are all significant early life modifiers of the biome. Both caesarean section and early antibiotics increase the risk of childhood obesity in epidemiological studies, and disturbances in the gut microbiome, so‐called dysbiosis, can be seen in the epidemic of non‐communicable diseases in children such as obesity, allergy, asthma, diabetes, inflammatory bowel disease, coeliac disease and autism spectrum disorders. The microbiome is passed from a mother to child, and interest in the vaginal microbiome during pregnancy has centred around changes in the Lactobacillus species, possible influences on preterm delivery, and the potential for probiotic treatments to restore normal equilibrium. Maternal weight, pregnancy weight gain, and complications of pregnancy such as diabetes and pre‐eclampsia all influence the composition and functional capacity of the gut microbiome, even through the pre‐school years. The breastfed infant has a gut microbiome rich in Bifidobacterium longum species which has strain‐specific genes that metabolise the indigestible human milk oligosaccharides to short‐chain fatty acids in the colon. These short‐chain fatty acid bacterial products regulate host metabolism and immunity. For example, butyrate maintains gut epithelial integrity, supports differentiation of regulatory T cells, and promotes anti‐inflammatory responses, and there is increasing literature on the protective effects of human milk oligosaccharides on the development of childhood allergy and obesity. Understanding how the gut microbiome shapes brain development and behaviour during early life is a new focus in neuroscience since the gut microbiome may communicate bi‐directionally with the brain. Short‐chain fatty acids can cross the blood brain barrier, alter levels of neurotransmitters and neurotrophic factors, and modulate brain development and behaviour in experimental models. In fact a causal link has been shown between a high‐fat diet during pregnancy, dysbiosis in the infant gut microbiome and social behavioural deficits in the autism mouse model. These deficits were reversed by a single commensal strain, Lactobacillus reuteri. Some of the most compelling efficacy data for the use of probiotics has been in the prevention of necrotising enterocolitis (NEC). Multiple Cochrane reviews in this field suggest that probiotics should be standard of care, however the studies in general lack sufficient consistency to compare them directly, making conclusions problematic. Interestingly, even before probiotics were being widely used to treat gastrointestinal conditions, there was an understanding of the potential to modify the development of the immune system early in life. Lactobacillus GG was given prenatally to mothers and then postnatally to infants for 6 months. This preventative treatment reduced atopic eczema in at‐risk infants by 50%. Further studies that largely support these findings suggest that the postnatal component is essential. Type 1 diabetes is an indication of the accumulating data around interventions to modulate the gut microbiome in early life for primary prevention. Finland has the highest incidence in the world of type 1 diabetes, neighbouring Russian Karelia one of the lowest incidences, and Estonia to the south intermediate incidence. As the incidence decreases across these three countries the abundance of B. longum increases. B. longum has strain‐specific genes that metabolise human milk oligosaccharides to short‐chain fatty acids which, by preserving epithelial integrity, may reduce transfer of antigen across the gut to the systemic circulation. Further evidence comes from functional analysis of the gut microbiome. Young children with increased genetic risk who do not develop type 1 diabetes have gut microbiomes that support increased production of short‐chain fatty acids compared with at‐risk children who do develop the disease. These findings raise the potential benefit of short‐chain fatty acid supplements in prebiotics, such as commercially available butyrylated starch preparations, and of probiotics such as B. longum for primary prevention of type 1 diabetes. On the other hand, recent literature cautions that the use of probiotics may interfere with normal reconstitution of the microbiome, for example after a gastrointestinal infection. While these papers rightly lead one to reflect on the potential harm that probiotics may exert, they also highlight that probiotics can colonise and may have both detrimental and beneficial effects on the host. Prevention of allergy and NEC are promising beginnings, but only by fully understanding the composition and function of the microbiome in health at different ages will one be able to progress to the next stage of microbial therapy.

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J Paediatr Child Health 2020; 56: 1735–1738

Nature 2018; 562: 589–94

Gut 2019; 68: 1108–14