Stefan Unger

Effect of Oxygen Supplementation on Length of Stay for Infants Hospitalized With Acute Viral Bronchiolitis

OBJECTIVE. The goal was to establish the final supportive therapy determinants of hospital length of stay for bronchiolitis. METHODS. A retrospective case study of a randomly selected 25% of subjects <1 year of age who were hospitalized with bronchiolitis between April 1, 2003, and June 15, 2005 (n = 129), was performed. Records of 102 admissions to the general wards were reviewed (77 respiratory syncytial virus positive). Length of stay, pulse oxygen saturation profile, oxygen supplementation, feeding support, and nasal suction were determined. Infants admitted to the PICU (27 admissions) were excluded. RESULTS. The majority of patients presented with feeding difficulties (82% at admission). Oxygen supplementation was not indicated initially for the majority of infants (22% with mean pulse oxygen saturation of 94%). However, oxygen treatment was required by 70% of infants by 6 hours, whereas the mean pulse oxygen saturation decreased by an average of only 2%. Feeding problems were resolved for 98% of infants by 96 hours, followed by oxygen supplementation resolving with an average lag of 66 hours. The mean pulse oxygen saturation at discharge was 95%. There was no significant correlation between pulse oxygen saturation at arrival at the emergency department and subsequent oxygen requirements or length of stay. CONCLUSIONS. Oxygen supplementation is the prime determinant of the length of hospitalization for infants with bronchiolitis. Infants remaining in the hospital for oxygen supplementation once feeding difficulties had resolved did not experience deterioration to the extent of needing PICU support.

Cohort Profile: The Kiang West Longitudinal Population Study (KWLPS)—a platform for integrated research and health care provision in rural Gambia

Cohort Profile: The Kiang West Longitudinal Population Study (KWLPS)—a platform for integrated research and health care provision in rural Gambia Branwen J Hennig, Stefan A Unger, Bai Lamin Dondeh, Jahid Hassan, Sophie Hawkesworth, Landing Jarjou, Kerry S Jones, Sophie E Moore, Helen M Nabwera, Mohammed Ngum, Ann Prentice, Bakary Sonko, Andrew M Prentice* and Anthony J Fulford MRC International Nutrition Group at MRC Unit The Gambia, Banjul, The Gambia, MRC International Nutrition Group, London School of Hygiene & Tropical Medicine, London, UK, University of Edinburgh, Department of Child Life and Health, Edinburgh, UK, MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, UK and Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, UK These authors contributed equally to this work. *Corresponding author. MRC International Nutrition Group at LSHTM, UK & MRC Unit, The Gambia, Keppel Street, London WC1E 7HT, UK. E-mail: Andrew.prentice@lshtm.ac.uk

The Human Immune Response to Respiratory Syncytial Virus Infection

SUMMARY Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

Factors Affecting Access to Healthcare: An Observational Study of Children under 5 Years of Age Presenting to a Rural Gambian Primary Healthcare Centre.

Main Objective Prompt access to primary healthcare before onset of severe illness is vital to improve morbidity and mortality rates. The Gambia has high rates of child mortality and research is needed to investigate contributing factors further. This study aimed to identify factors affecting access to primary healthcare for children <5 years (y) in rural Gambia focusing on delayed presentation and severe illness at presentation as indicators in a setting where primary healthcare is delivered free of charge. Methods Data were extracted from an electronic medical records system at a rural primary healthcare clinic in The Gambia for children (0–5y) between 2009 and 2012. First clinic attendances with malaria, lower respiratory tract infections (LRTI) and diarrhoeal disease, the main contributors to mortality in this setting, were identified and categorized as delayed/non-delayed and severe/non-severe representing our two main outcome measures. Potential explanatory variables, identified through a comprehensive literature review were obtained from an ongoing demographic surveillance system for this population. Variables associated with either delayed/non-delayed and/or with severe/non-severe presentations identified by univariate analysis (p<0.1) were assessed in multivariate models using logistic regression (p<0.05). Results Out of 6554 clinic attendances, 571 relevant attendances were identified. Delayed presentation was common (45% of all presentations) and there was a significantly reduced risk associated with being from villages with free regular access to transport (OR 0.502, 95%CI[0.310, 0.814], p = 0.005). Children from villages with free regular transport were also less likely to present with severe illness (OR 0.557, 95%CI[0.325, 0.954], p = 0.033). Conclusions Transport availability rather than distance to health clinic is an important barrier to accessing healthcare for children in The Gambia, and public health interventions should aim to reduce this barrier.

Growth monitoring and the prognosis of mortality in low-income settings

UNICEF’s 2014 progress report, “Committing to Child Survival: A Promise Renewed,” paints a picture of remarkable progress in combatting child mortality since the turn of the century (1). Yet, there is so much still to be achieved. Every day an estimated 16,000 children <5 y of age die, amassing to a total of 5.9 million deaths annually, the vast majority of which could and should have been avoided. There are numerous proximal and distal causes of these deaths, and many players in the global health community are contributing their expertise to tackle the residual burden from every angle. Nutritionists can play a vital role given that almost half of all child deaths can be attributed, either directly or indirectly, to undernutrition (2). In this issue of the Journal, Schwinger et al. (3) contribute to this endeavor by showing that assessment of a child’s recent growth trajectory provides a more accurate prognosis of likely death than the use of static measures of nutritional status. With the use of a historical cohort in the Democratic Republic of Congo (1989–1991) with data for regular anthropometric measurements in 5657 children ,5 y of age, they compared the antecedent nutritional status of the 264 children who died with that of those who survived. They found that a weight or length velocity score of, 23 predicted death within the next 3 mo with RRs of 7.9 and 11.8, respectively. Receiver operating characteristic analysis showed that weight and length velocity z scores had better predictive abilities (AUCs: 0.67 and 0.69) than the static measures of weight-for-age (AUC: 0.57) and length-for-age (AUC: 0.52) z scores. Among wasted children (weight-for-height z score ,22), the AUC of weight velocity z scores was 0.87. Absolute midupper arm circumference (MUAC) performed best among the attained indexes (AUC: 0.63), but longitudinal assessment of MUAC-based indexes did not increase the predictive value. The authors acknowledge several limitations of their study, but these are not likely to undermine the main conclusion and hence our discussion concentrates on the field implications of the results: How could we use these insights to further reduce child mortality in sub-Saharan Africa and South Asia where the burden is greatest? An AUC of,0.7 would not generally be considered sufficiently robust to warrant the development of a diagnostic or screening tool. The authors argue that their positive predictive value may have been limited by the relatively low mortality rate in the sample, but lower mortality rates are thankfully becoming the norm. They further argue that their results might underestimate the true value of velocity monitoring in other settings because 43% of the deaths were due to malaria and acute respiratory infections, which are not as strongly related to nutrition as, for example, diarrhea. This contention, however, is not supported by other studies in which casefatality rates for malaria and pneumonia are strongly predicted by height and (less so for malaria) by weight z scores (2, 4). Nonetheless, the central observation, that a deterioration in a child’s nutritional status provides an important pointer to ongoing pathology (be it of clinical or social origin) and flags a child as being at heightened risk of death, provides a welcome reinforcement of messages that have been taught to medical students and ancillary health staff for generations. A report by the United Nation’s Subcommittee on Nutrition in 1990 (5) reiterated the long-held view that “Concern is not with whether a child is on a given centile at one point in time, but whether its pattern of growth falls along the same centile band as age increases. This pattern provides more important information than the actual weight at any particular time.” The committee recommended that an assessment of the relative performance, under field conditions, of growth monitoring and onetime screening should be undertaken (5). This is what Schwinger et al. have helpfully provided. However, we need to examine the extent to which these academic insights can be translated to actionable change in the field. On this point we are not optimistic. Even if the velocity scores had yielded exceptional sensitivity and specificity, the task of implementation would be daunting for several reasons. First, it is a sad fact that there are very few examples in low-income settings in which nutritional status is regularly monitored and diligently recorded on children’s road-to-health charts. The barriers relate to the supply, maintenance, and calibration of equipment; the detailed training required

Nebulised hypertonic saline in bronchiolitis: take it with a pinch of salt

Nebulised hypertonic saline is attractive as a therapy for acute viral bronchiolitis. Thick and sticky secretions in oedematous airways induce breathlessness and poor feeding as a hallmark of the disease. Loosening secretions with this simple therapy could prevent admission to hospital, or speed recovery and discharge. In a condition with no current acute therapeutic options, this would be welcome indeed.1 ,2 Hypertonic saline changes mucous rheology, and when used in cystic fibrosis, has good—if modest—effect.3 In bronchiolitis, hypertonic saline has had a promising start. Early trials demonstrated appealing benefits with reduction in length of stay by up to 25%.4 A Cochrane review, last updated in 2013, concludes with a recommendation to use hypertonic saline in bronchiolitis to reduce length of stay in hospitalised patients.5 Hypertonic Saline in acute Bronchiolitis RCT and Economic evaluation (SABRE), printed in this issue,6 is the largest reported study for the use of nebulised hypertonic saline infants hospitalised with bronchiolitis. Importantly, the study protocol challenges head on the difficulties with using a placebo control when testing a nebulised intervention. As it cannot be assumed that nebulised normal saline (0.9%) will have no clinical effect, the non-intervention arm in SABRE was the current standard of care in the UK— i.e., no regular use of epinephrine, salbutamol or 0.9% saline that were nebulised in all previous studies testing hypertonic saline in bronchiolitis. By necessity, that made the trial open label, which leaves a study open to criticism of potential confounding bias. In this case, however, the weight of evidence to date in favour of hypertonic saline and the desperate need for something to work in bronchiolitis, might suggest any anticipated bias would have been in favour of the intervention. Yet, the open label design did not favour the intervention: nebulised hypertonic saline …

The respiratory microbiome and respiratory infections

Despite advances over the past ten years lower respiratory tract infections still comprise around a fifth of all deaths worldwide in children under five years of age with the majority in low- and middle-income countries. Known risk factors for severe respiratory infections and poor chronic respiratory health do not fully explain why some children become sick and others do not. The respiratory tract hosts bacteria that can cause respiratory infections but also normal commensal bacteria. Together, this microbial population is called the microbiome. The composition of the respiratory microbiome in the first few months of life is likely influenced by external factors such as environment, mode of delivery and infant feeding practices, which are also associated with susceptibility to respiratory infections and wheezing illness/asthma. Recently, multiple studies have shown that respiratory microbiota profiles early in life are associated with an increased risk and frequency of subsequent respiratory infections, disease severity and occurrence of wheeze in later childhood. Early interactions between infectious agents such as viruses and the respiratory microbiome have shown to modulate host immune responses potentially affecting the course of the disease and future respiratory health. Deeper understanding of these interactions will help the development of new therapeutic agents or preventive measures that may modify respiratory health outcomes and help us to stratify at risk populations to better target our current interventional approaches.

A Case of “Abnormally Abnormal” Hypoxic Ventilatory Responses: A Novel NPARM PHOX 2B Gene Mutation

ABSTRACT Congenital central hypoventilation syndrome (CCHS) is a rare disorder associated with dysregulation of the autonomic ventilatory response to hypoxia and hypercarbia usually caused by polyalanine repeat expansion mutations in the PHOX 2B gene. Non-polyalanine repeat mutations (NPARM) represent approximately 10% of cases, and usually require continuous ventilation during sleep, although our knowledge of disease progression is limited. Here we present a case with a novel NPARM CCHS mutation associated with a premature stop codon for the PHOX 2B protein. Despite the type of the mutation, patient management with supplementary oxygen has been sufficient. Experience from our case may help when counseling parents.

G431 Three oxygen saturation targets for discharge in children with wheeze – an observational study

Aims Assessing the potential effect of three discharge oxygen saturation (SpO2) targets ( 90%, 94% and 94%) on length of hospital admission in children with wheeze. Methods and patients: Children (1 16 years (y)) admitted with wheeze and oxygen requirement for SpO2 (£92%), had SpO2 in air assessed 4 hourly. Time from admission for SpO2 to become stable for at least 4 hours (h) at 90%, 92% and 94% was recorded. Results 243 children were admitted with wheeze (n=14 excluded due to inadequate demographic data or observation). Fourty eight children did not require oxygen and 39 children reached discharge criteria prior to the specified time ( 4 hour) at SpO2 targets. The median time to discharge was 23 hour (IQR 17 39) for all children admitted with wheeze (n=229), 27 hour (17 40) for children requiring supplemental oxygen (n=181) and 30 hour (IQR 17 40) for children requiring oxygen supplementation and a full data set (n=142). Data on the latter patients (median age 2.8y) were further assessed. Five children were admitted to high dependency. Seventy percent (99/142) had a viral or bacterial agent identified. Time from admission to a stable SpO2 for 4 hour was 8 hour (IQR 5 20) for SpO2 90% in air, 17 hour (IQR 7 30) for SpO2 target of 92%, and 21 hour (IQR 21 30) for SpO2 target of 94%. A time lag was observed in 61 (43%) children between SpO2 targets of 90% and 92% and in 75 (53%) children between targets of 90% and 94%. Presence of any infective agent was not associated with time to stable oxygen at any threshold, except for RSV. RSV was statistically significantly (p<0.001) associated with a more prolonged time to stable oxygen saturation at all thresholds independent of age. Conclusions Reducing SpO2 target levels to 90% in children with acute wheeze could potentially reduce length of stay. This target level has been shown to be safe in infants with bronchiolitis, while it can be postulated that the same would be true for older children with wheeze, a randomised control trial to assess the safety and effect on clinical status is warranted.

G489 Blood gas analysis in acute bronchiolitis – who and when?

Aims The utilisation of blood gas analysis (BGA) in acute bronchiolitis is common with wide variation between hospitals. Guidelines recommend its use only in those with severe respiratory distress and who are tiring but evidence for such practice is sparse. This study investigated clinical indicators that demarcate clinically important rise in carbon dioxide (CO2). Methods We undertook a prospective observational study of children admitted from the emergency department (ED) to a tertiary care university hospital with a diagnosis of bronchiolitis (October 2014–January 2015). Data was obtained from hospital charts and electronic patient information and analysed using STATA/IC 12.1 for Mac. Univariate analysis examined the correlation between blood gas CO2 and oxygen requirement, SpO2 in air, vital signs, feeding support requirement, gender, age, co-morbidities and history of prematurity. Statistically significant variables were entered into a logistic regression model. Results 220 patients with bronchiolitis were admitted (mean age of 0.57 years (95% CI:0.05,0.64)). 113 (51%) had at least one BGA done. Those with more than three BGAs (32/113 (28%)) were significantly younger and more likely to be premature. 14% (30/220) were admitted to intensive/high dependency care (ITU/HDU). In ED a CO2 >7kPA was associated with an admission to HDU/ITU (OR 3.75(95% CI:1.13,12.47), p = 0.031); prematurity and young age also independently predicted ITU/HDU (IRR1.53(95% CI:1.21,1.93), p < 0.0001 and IRR0.68(95% CI:0.53,0.86), p = 0.001 respectively). All but one patient with CO2 >7kPa in ED were < 3m and/or premature. Length of stay (LOS) was also significantly longer in this patient group. For BGA taken during the admission, only oxygen requirement and age (particularly <3months (m)) were significantly associated with CO2 >7kPa in the regression model (OR 2.46(95% CI:1.42,4.26), p = 0.001 and OR 0.08(95% CI:0.03,0.17), p < 0.001; respectively). There was no association between amount of oxygen supplied and level of CO2 measured. Overall, LOS was significantly higher in those who had BGA during admission (4.0 days (d) (95% CI 3.5,4.5) versus 2.3d (95% CI:2.0,2.6)). Conclusion Age under 3 months, history of prematurity and CO2 >7kPa done in ED identify those with prolonged LOS and/or HDU/ITU admission. Significantly raised CO2 is not seen in bronchiolitis without oxygen requirement. Further work will look to elucidate when BGA may be helpful in the management of bronchiolitis.