Comprehensive care programmes for children with medical complexity.

BACKGROUND: Children with medical complexity (CMC) represent a small, but growing, proportion of all children. Regardless of their underlying diagnosis, by definition, all CMC have similar functional limitations and high healthcare needs. It has been suggested that improving aspects of healthcare delivery for CMC improves health- and quality of life-related outcomes for children and their families and reduces healthcare-related expenditure. As a result, dedicated comprehensive care programmes have been established at many hospitals to meet the needs of CMC; however, it is unclear if such programmes are effective. OBJECTIVES: Our main objective was to assess the effectiveness of comprehensive care programmes that aim to improve care coordination and other aspects of health care for CMC and to assess whether the effectiveness of such programmes differs according to the programme setting and structure. We aimed to assess their effectiveness in relation to child and parent health, functioning, and quality of life, quality of care, number of healthcare encounters, unmet healthcare needs, and total healthcare-related costs. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and CINAHL in May 2023. We also searched reference lists, trial registries, and the grey literature. SELECTION CRITERIA: Randomised and non-randomised trials, controlled before-after studies, and interrupted time series studies were included. Studies that compared enrolment in a comprehensive care programme with non-enrolment in such a programme/treatment as usual were included. Participants were children that met the criteria for the definition of CMC, which is: having (i) a chronic condition, (ii) functional limitations, (iii) increased health and other service needs, and (iv) increased healthcare costs. Studies that included the following types of outcomes were included: health; quality of care; utilisation, coverage and access; resource use and costs; equity; and adverse outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed the risk of bias in each included study, and evaluated the certainty of evidence according to GRADE criteria. Where possible, data were represented in forest plots and pooled. We were unable to undertake a meta-analysis for comparisons and outcomes, so we used a structured synthesis approach. MAIN RESULTS: We included four studies with a total of 912 CMC as participants. All included studies were randomised controlled trials conducted in hospitals in the USA or Canada. Participants varied across the included studies; however, all four studies included children with complex and chronic illness and high healthcare needs. While the primary aim of the intervention was similar across all four studies, the components of the interventions differed: in the four studies, the intervention involved some element of care coordination; in two of the studies, it involved the child receiving care from a multidisciplinary team, while in one study, the intervention was primarily centred on access to an advanced practice nurse care coordinator and another study involved nurse a practitioner-paediatrician dyad partnering with families. The risk of bias in the four studies varied across domains, with issues primarily relating to the lack of blinding of participants, personnel, and outcome assessors, inadequate allocation concealment, and incomplete outcome data. Comprehensive care for CMC compared to usual care may make little to no difference to child health, functioning, and quality of life at 12 or 24 months (three studies with 404 participants) and we assessed the evidence for the outcomes in this category (child health-related quality of life and functional status) as being of low certainty. For CMC, comprehensive care probably makes little or no difference to parent health, functioning, and quality of life compared to usual care at 12 months (one study with 117 participants) and we assessed the evidence for this outcome as being of moderate certainty. Comprehensive care for CMC compared to usual care may slightly improve child and family satisfaction with, and perceptions of, care and service delivery at 12 months (three studies with 453 participants); however, we assessed the evidence for these outcomes as being of low certainty. For CMC, comprehensive care probably makes little or no difference to the number of healthcare encounters (emergency department visits) and the number of hospitalised days (hospital admissions) compared to usual care at 12 months (three studies with 668 participants), and we assessed the evidence for these outcomes as being of moderate certainty. Three of the included studies (668 participants) reported cost outcomes and had conflicting results, with one study reporting significantly lower healthcare costs at 12 months in the intervention group compared to the control group, one reporting no differences between groups, and the other study reporting a greater increase in total healthcare costs in the intervention group compared to the control group. Overall, comprehensive care may make little or no difference to overall healthcare costs in CMC; however, the methods used to measure total healthcare costs varied across studies and the certainty of the evidence relating to this outcome is low. No studies assessed the costs to the family. AUTHORS' CONCLUSIONS: The findings of this review should be treated with caution due to the limited amount and quality of the published research that was available to be included. Overall, the certainty of the evidence for the effectiveness of comprehensive care for CMC ranged from low to moderate across outcomes and there is currently insufficient evidence on which to draw strong conclusions. There is a need for more high-quality randomised trials with consistency of the target population and intervention components, methods of reporting outcomes, and follow-up periods, as well as full cost analyses, taking into account both costs to the family and costs to the healthcare system.

Evaluating an admission avoidance pathway for children in the emergency department: outpatient intravenous antibiotics for moderate/severe cellulitis.

OBJECTIVE: Children with moderate/severe cellulitis requiring intravenous antibiotics are usually admitted to hospital. Admission avoidance is attractive but there are few data in children. We implemented a new pathway for children to be treated with intravenous antibiotics at home and aimed to describe the characteristics of patients treated on this pathway and in hospital and to evaluate the outcomes. METHODS: This is a prospective, observational cohort study of children aged 6 months-18 years attending the ED with uncomplicated moderate/severe cellulitis in March 2014-January 2015. Patients received either intravenous ceftriaxone at home or intravenous flucloxacillin in hospital based on physician discretion. Primary outcome was treatment failure defined as antibiotic change within 48 hours due to inadequate clinical improvement or serious adverse events. Secondary outcomes include duration of intravenous antibiotics and complications. RESULTS: 115 children were included: 47 (41%) in the home group and 68 (59%) in the hospital group (59 hospital-only, 9 transferred home during treatment). The groups had similar clinical features. 2/47 (4%) of the children in the home group compared with 8/59 (14%) in the hospital group had treatment failure (P=0.10). Duration of intravenous antibiotics (median 1.9 vs 1.8 days, P=0.31) and complications (6% vs 10%, P=0.49) were no different between groups. Home treatment costs less, averaging $A1166 (£705) per episode compared with $A2594 (£1570) in hospital. CONCLUSIONS: Children with uncomplicated cellulitis may be able to avoid hospital admission via a home intravenous pathway. This approach has the potential to provide cost and other benefits of home treatment.

Successful treatment of refractory immune thrombocytopenia with rituximab in a 10-week-old infant.

Immune thrombocytopenic purpura (ITP) that is unresponsive to conventional treatment is uncommon. In this situation, additional therapeutic options are limited and management is challenging. We describe the case of a 10-week-old infant that developed life-threatening ITP that was unresponsive to immunoglobulin and corticosteroids that was successfully managed with the monoclonal antibody rituximab. The literature on the use of rituximab in nonresponsive ITP is reviewed.

The influence of bacille Calmette-Guerin vaccine strain on the immune response against tuberculosis: a randomized trial.

RATIONALE: Approximately 100 million doses of bacille Calmette-Guérin (BCG) vaccine are given each year to protect against tuberculosis (TB). More than 20 genetically distinct BCG vaccine strains are in use worldwide. Previous studies suggest that BCG vaccine strain influences the immune response and protection against TB. Current data on which BCG vaccine strain induces the optimal immune response in humans are insufficient. OBJECTIVES: To compare the immune response to three different BCG vaccine strains given to infants at birth. METHODS: Newborn infants in a tertiary women's hospital were immunized at birth with one of three BCG vaccine strains. A stratified randomization according to the mother's region of birth was used. MEASUREMENTS AND MAIN RESULTS: The presence of mycobacterial-specific polyfunctional CD4 T cells measured by flow cytometry 10 weeks after immunization. Of the 209 infants immunized, data from 164 infants were included in the final analysis (BCG-Denmark, n = 54; BCG-Japan, n = 54; BCG-Russia, n = 57). The proportion of polyfunctional CD4 T cells was significantly higher in infants immunized with BCG-Denmark (0.013%) or BCG-Japan (0.016%) than with BCG-Russia (0.007%) (P = 0.018 and P = 0.003, respectively). Infants immunized with BCG-Japan had higher concentrations of secreted Th1 cytokines; infants immunized with BCG-Denmark had higher proportions of CD107-expressing cytotoxic CD4 T cells. CONCLUSIONS: There are significant differences in the immune response induced by different BCG vaccine strains in newborn infants. Immunization with BCG-Denmark or BCG-Japan induced higher frequencies of mycobacterial-specific polyfunctional and cytotoxic T cells and higher concentrations of Th1 cytokines. These findings have potentially important implications for global antituberculosis immunization policies and future tuberculosis vaccine trials.

Advances in the diagnosis of pulmonary tuberculosis in HIV-infected and HIV-uninfected children.

The identification of improved diagnostic tests for tuberculosis has been identified as a global research priority. Over the past decade, there has been renewed interest in the development and validation of novel diagnostic tools for pulmonary tuberculosis that are applicable to resource-poor settings. These techniques are aimed primarily at improving detection of the organism or a specific host immune response. Although most studies have focused on determining the accuracy of novel tests in adults, it is likely they will also have the capacity to significantly improve the diagnosis of childhood tuberculosis. Improving the quality of clinical samples obtained from children with suspected tuberculosis remains an important research priority while awaiting validation of novel diagnostic tests. This review will focus on a number of recent developments for the diagnosis of tuberculosis, with a specific emphasis on the application of these new tests to children in settings where tuberculosis is endemic.

Follow-up and Clinical Outcomes of Human Immunodeficiency Virus (HIV)-Exposed Infants in A Low-Prevalence Setting in A Multidisciplinary Model of Care in Australia: The Children's HIV Exposure Study 1.

BACKGROUND: Prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) is effective, but outcome information beyond the postnatal period in low-prevalence settings is scarce. A multidisciplinary model of care (MOC) was developed to ensure PMTCT. Our aims in this study were to assess how well HIV-exposed infants are followed up through this MOC and to determine infant outcomes to age 18 months. METHODS: This was a multicenter, prospective study of infants exposed to HIV during pregnancy, born 1 September 2009-31 August 2016 in Victoria, Australia. RESULTS: There were 129 live births from 127 pregnancies. There were no episodes of HIV transmission. Sixteen (13%) infants were born prematurely, 15 (12%) had low birthweight, and 6 (5%) had a congenital anomaly. There were 122 (95%) infants with an HIV polymerase chain reaction (PCR) within 2 weeks of birth. The proportion in the MOC reduced from 95% at 2 weeks postnatally to 75% by 18 months. Eighty-eight percent cared for within the MOC had 2 viral PCR tests completed after stopping antiretroviral prophylaxis compared with 22% of those outside of the MOC. By 18 months, 84/126 (67%) children attended follow-up, with higher rates within the MOC than outside (76% vs 6%; odds ratio, 46; 95% confidence interval, 6 to 365; P < .001). CONCLUSIONS: HIV-exposed, uninfected infants in this low-prevalence setting had good prospective follow-up through this MOC to 3 months. The decrease in follow-up by 18 months could be addressed in several ways, including expanding the MOC and providing better links to regional/rural services.

Reversion and conversion of Mycobacterium tuberculosis IFN-gamma ELISpot results during anti-tuberculous treatment in HIV-infected children.

BACKGROUND: Recent interest has focused on the potential use of serial interferon gamma (IFN-gamma) release assay (IGRA) measurements to assess the response to anti-tuberculous (TB) treatment. The kinetics of IFN-gamma responses to Mycobacterium tuberculosis (MTB) antigens in HIV-infected children during treatment have not however been previously investigated. METHODS: IFN-gamma responses to the MTB antigens, ESAT-6, CFP-10 and PPD were measured by an enzyme-linked immunospot assay (IFN-gamma ELISpot) at presentation and at one, two and six months after starting anti-tuberculous treatment in HIV-infected children with definite or probable TB. Responses at different time points were compared using a Mann-Whitney U test with paired data analysed using the Wilcoxon signed rank test. A Fisher's exact or Chi-squared test was used to compare proportions when test results were analysed as dichotomous outcomes. RESULTS: Of 102 children with suspected TB, 22 (21%) had definite TB and 24 (23%) probable TB. At least one follow up IFN-gamma ELISpot assay result was available for 31 (67%) of the 46 children. In children with definite or probable TB in whom the IFN-gamma ELISpot assay result was positive at presentation, anti-tuberculous treatment was accompanied by a significant decrease in both the magnitude of the IFN-gamma response to individual or combined MTB-specific antigens (ESAT-6 median 110 SFCs/106 PBMC (IQR 65-305) at presentation vs. 15 (10-115) at six months, p = 0.04; CFP-10 177 (48-508) vs. 20 (5-165), p = 0.004, ESAT-6 or CFP-10 median 250 SFCs/106 PBMC (IQR 94-508) vs. 25 (10-165), p = 0.004) and in the proportion of children with a positive IFN-gamma ELISpot assay (Fisher's exact test: ESAT-6 15/0 vs 5/11, p = 0.0002, CFP-10 22/0 vs 8/17, p = 0.0001, ESAT-6 or CFP-10 22/0 vs. 9/17, p= 0.002). However almost half of the children had a positive IFN-gamma ELISpot assay after six months of anti-tuberculous treatment. In addition, there was conversion of the IFN-gamma ELISpot assay result during anti-tuberculous therapy in six of 12 children in whom the initial IFN-gamma ELISpot assay was negative. CONCLUSIONS: In HIV-infected children with definite or probable TB, anti-tuberculosis treatment is accompanied by a reduction in the magnitude of the IFN-gamma ELISpot response to MTB-antigens. However, serial IFN-gamma ELISpot measurements appear to have limited clinical utility in assessing a successful response to anti-tuberculous treatment in HIV infected children.

Susceptibility of Mycobacterium bovis BCG vaccine strains to antituberculous antibiotics.

Mycobacterium bovis BCG is one of the most commonly administered vaccines. Complications, including disseminated BCG disease, are rare but increasingly reported in immunodeficient children. There is growing recognition of the importance of differences between BCG vaccine strains. We determined the susceptibilities of five genetically distinct BCG vaccine strains to 12 antituberculous drugs.

Splenic cyst and its management in a 21-month-old boy: a rare complication of invasive meningococcal disease.

Splenic complications of invasive meningococcal disease (IMD) are well recognised, though cyst formation is rare, particularly in paediatric populations. The best approach to their management is not yet established. This case outlines the management of a splenic cyst in a 21-month-old boy following severe IMD. The case took place in the context of an acute emergence of serogroup W prompting significant media attention and subsequent change in vaccination practice at a jurisdictional level in Australia. The patient was critically unwell early in the illness, then later a collection in the left upper quadrant was detected, shown on ultrasound to be a 11.6×7.7 cm splenic cyst. In this case, the cyst was managed by ultrasound-guided drainage tube insertion. The residual collection was small and stable on subsequent imaging.

Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. METHODS: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. FINDINGS: 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). INTERPRETATION: Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. FUNDING: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.

A Comparison of Hospital Versus Outpatient Parenteral Antibiotic Therapy at Home for Pyelonephritis and Meningitis.

BACKGROUND: Despite the benefits of home treatment with outpatient parenteral antimicrobial therapy (OPAT), children with pyelonephritis and meningitis are rarely included. We aimed to compare clinical characteristics and outcomes between hospital and home treatment for these conditions and to identify factors influencing home treatment. METHODS: Children admitted to the hospital with pyelonephritis or proven and presumed bacterial meningitis from January 1, 2012, to December 31, 2013 were identified retrospectively. Patients who received any OPAT (home group) received daily visits via our Hospital-in-the-Home (HITH) program; inpatients (hospital group) received standard care. Clinical and demographic features, length of stay, readmission rate and cost were compared between hospital and home groups. RESULTS: One hundred thirty-nine children with pyelonephritis and 70 with meningitis were identified, of which 127 and 44 were potentially suitable for OPAT, respectively. Of these, 12 (9%) with pyelonephritis received OPAT, contrasting with 29 (66%) with meningitis. Clinical features did not differ between hospital- and home-treated patients for either condition. Patients with meningitis in the hospital group were younger than those transferred to HITH (1 vs. 2 months; P = 0.01). All patients were afebrile before transfer to HITH. Admissions for pyelonephritis were brief with inpatients having a shorter length of stay than home patients (median: 3 vs. 4.5 days; P = 0.002). Unplanned readmission rates were comparable across all groups. Transfer to HITH resulted in a saving of AU$178,180. CONCLUSIONS: Children with pyelonephritis and meningitis can feasibly receive OPAT. Age, treatment duration and fever influence this decision. None of these should be barriers to OPAT, and the cost savings support change in practice.

Comparable CD4 and CD8 T cell responses and cytokine release after at-birth and delayed BCG immunisation in infants born in Australia.

BACKGROUND: More than 120 million doses of BCG vaccine are administered worldwide each year. Most infants are given BCG at birth in accordance with WHO recommendations. However, the effect of the maturing neonatal immune system on the immune response and protection conferred by BCG remains uncertain. Previous studies investigating the influence of age at immunisation on the immune response induced by BCG have reported conflicting results. This study compared BCG given at birth and at two months of age in infants in Australia. METHODS: Infants born in Melbourne were randomly allocated to immunisation with BCG-Denmark at birth or two months of age. Ten weeks after immunisation, anti-mycobacterial immune responses were measured in a whole blood assay using intracellular cytokine assays and xMAP multiplex cytokine analysis. RESULTS: Result from 98 BCG-immunised infants were included in the final analysis. BCG immunisation at birth (n=54) and at 2months of age (n=44) induced comparable proportions of mycobacteria-specific cytokine-producing CD4 and CD8 T cells, as well as comparable proportions of polyfunctional (TNF(+) IL-2(+) IFN-γ(+)) CD4 T cells. Concentrations of cytokines in supernatants were also similar in both groups. CONCLUSIONS: Cellular immunity measured 10weeks after BCG immunisation was similar in infants given BCG at birth and in those given BCG at 2months of age. Although definitive correlates of protection against TB remain uncertain, these results suggest that delaying BCG immunisation does not confer any immunological advantage in cellular immunity.

Congenital Tuberculosis Complicated by Hemophagocytic Lymphohistiocytosis.

We present the case of a male infant with congenital tuberculosis in a nonendemic setting complicated by hemophagocytic lymphohistiocytosis, who was treated successfully with antituberculous therapy and corticosteroids. We review the pediatric literature concerning the unusual association of these 2 rare conditions.