Applying lessons learnt from research of child pneumonia management in Vietnam.

Pneumonia is the leading cause of paediatric hospitalisation in Vietnam, placing a huge burden on the health care system. Pneumonia is also the main reason for antibiotic use in children. Unfortunately many hospital admissions for child pneumonia in Vietnam are unnecessary and inappropriate use of antibiotics is common, as in the rest of Asia, with little awareness of its adverse effects. We explored the value of an alternative approach that, instead of focusing on the identification of children with severe bacterial pneumonia, focuses on the identification of children with 'unlikely bacterial pneumonia' to improve patient care and rational antibiotic use. Implementing improved models of care require pragmatic management algorithms that are well validated, but it is ultimately dependent on financial structures, management support and evidence-based training of healthcare providers at all relevant levels. Apart from better case management, sustained reductions in the pneumonia disease burden also require increased emphasis on primary prevention.

Disease spectrum and management of children admitted with acute respiratory infection in Viet Nam.

OBJECTIVE: To assess the acute respiratory infection (ARI) disease spectrum, duration of hospitalisation and outcome in children hospitalised with an ARI in Viet Nam. METHODS: We conducted a retrospective descriptive study of ARI admissions to primary (Hoa Vang District Hospital), secondary (Da Nang Hospital for Women and Children) and tertiary (National Hospital of Paediatrics in Ha Noi) level hospitals in Viet Nam over 12 months (01/09/2015 to 31/08/2016). RESULTS: Acute respiratory infections accounted for 27.9% (37 436/134 061) of all paediatric admissions; nearly half (47.6%) of all children admitted to Hoa Vang District Hospital. Most (64.6%) of children hospitalised with an ARI were <2 years of age. Influenza/pneumonia accounted for 69.4% of admissions; tuberculosis for only 0.3%. Overall 284 (0.8%) children died; most deaths (269/284; 94.7%) occurred at the tertiary referral hospital. The average duration of hospitalisation was 7.6 days (median 7 days). The average direct hospitalisation cost per ARI admission was 157.5 USD in Da Nang Provincial Hospital. In total, 62.6% of admissions were covered by health insurance. CONCLUSION: Acute respiratory infection is a major cause of paediatric hospitalisation in Viet Nam, characterised by prolonged hospitalisation for relatively mild disease. There is huge potential to reduce unnecessary hospital admission and cost.

Child pneumonia - focus on the Western Pacific Region.

Worldwide, pneumonia is the leading cause of death in infants and young children (aged <5 years). We provide an overview of the global pneumonia disease burden, as well as the aetiology and management practices in different parts of the world, with a specific focus on the WHO Western Pacific Region. In 2011, the Western Pacific region had an estimated 0.11 pneumonia episodes per child-year with 61,900 pneumonia-related deaths in children less than 5 years of age. The majority (>75%) of pneumonia deaths occurred in six countries; Cambodia, China, Laos, Papua New Guinea, the Philippines and Viet Nam. Historically Streptococcus pneumoniae and Haemophilus influenzae were the commonest causes of severe pneumonia and pneumonia-related deaths in young children, but this is changing with the introduction of highly effective conjugate vaccines and socio-economic development. The relative contribution of viruses and atypical bacteria appear to be increasing and traditional case management approaches may require revision to accommodate increased uptake of conjugated vaccines in the Western Pacific region. Careful consideration should be given to risk reduction strategies, enhanced vaccination coverage, improved management of hypoxaemia and antibiotic stewardship.

Risk factors for child pneumonia - focus on the Western Pacific Region.

Pneumonia is a major cause of disease and death in infants and young children (aged <5 years) globally, as it is in the World Health Organization Western Pacific region. A better understanding of the underlying risk factors associated with child pneumonia is important, since pragmatic primary prevention strategies are likely to achieve major reductions in pneumonia-associated morbidity and mortality in children. This review focuses on risk factors with high relevance to the Western Pacific region, including a lack of exclusive breastfeeding, cigarette smoke and air pollution exposure, malnutrition and conditions of poverty, as well as common co-morbidities. Case management and vaccination coverage have been considered elsewhere.

The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis.

PURPOSE: Cerebrospinal fluid (CSF) hypoglycorrhachia and elevated protein is well-described in bacterial meningitis, but evidence for its differential diagnostic value in tuberculous meningitis (TBM) is lacking. We aimed to assess the diagnostic utility of CSF glucose, CSF to serum glucose ratio and CSF protein in children with suspected TBM. METHODS: We describe CSF glucose and protein values as well as CSF to serum glucose ratios in a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa, from January 1985 to January 2014. RESULTS: Of 615 TBM suspects, 88 (14%) had microbiologically confirmed TBM, 381 (62%) 'probable' TBM and 146 (24%) 'non-TBM'. Mean absolute CSF glucose concentration was significantly lower in the microbiologically confirmed (1.87 ± 1.15 mmol/L) and 'probable' TBM (1.82 ± 1.19 mmol/L) groups compared to non-TBM (3.66 ± 0.88 mmol/L). A CSF glucose concentration of <2.2 mmol/L diagnosed TBM with sensitivity 0.68 and specificity 0.96. Sensitivity using a CSF to serum glucose ratio of <0.5 was 0.90. Mean CSF protein was significantly elevated in the microbiologically confirmed TBM (1.91 ± 1.44 g/L) and 'probable' TBM (2.01 ± 1.49 g/L) groups compared to the non-TBM (0.31 ± 0.31 g/L). A CSF protein >1 g/L diagnosed TBM with sensitivity 0.78 and specificity 0.94. CONCLUSION: Absolute CSF glucose values of <2.2 mmol/L and protein values of >1 g/L differentiated between TBM and non-bacterial meningitis with good specificity, although sensitivity was poor. A CSF to serum glucose ratio is more informative than the absolute value.

Key lessons from the COVID-19 public health response in Australia.

Australia avoided the worst effects of the COVID-19 pandemic, but still experienced many negative impacts. Reflecting on lessons from Australia's public health response, an Australian expert panel composed of relevant discipline experts identified the following key lessons: 1) movement restrictions were effective, but their implementation requires careful consideration of adverse impacts, 2) disease modelling was valuable, but its limitations should be acknowledged, 3) the absence of timely national data requires re-assessment of national surveillance structures, 4) the utility of advanced pathogen genomics and novel vaccine technology was clearly demonstrated, 5) decision-making that is evidence informed and consultative is essential to maintain trust, 6) major system weaknesses in the residential aged-care sector require fixing, 7) adequate infection prevention and control frameworks are critically important, 8) the interests and needs of young people should not be compromised, 9) epidemics should be recognised as a 'standing threat', 10) regional and global solidarity is important. It should be acknowledged that we were unable to capture all relevant nuances and context specific differences. However, the intent of this review of Australia's public health response is to critically reflect on key lessons learnt and to encourage constructive national discussion in countries across the Western Pacific Region.

Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Clinical standards for the dosing and management of TB drugs.

BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

TB and HIV in children - advances in prevention and management.

The human immunodeficiency virus (HIV) epidemic has had a major impact on the age and gender profile of adult tuberculosis (TB) patients, resulting in increased exposure of HIV-infected and uninfected children at a very young age. Young and/or HIV-infected children are extremely vulnerable to develop severe forms of TB following recent exposure and infection. There is an urgent need to implement safe and pragmatic strategies to prevent TB in children, especially in TB endemic areas where they suffer the greatest burden of disease. The management of TB in HIV-infected children poses multiple challenges, but recent advances in the implementation of prevention of mother to child transmission (PMTCT) strategies and HIV care of infants offer hope. These include HIV testing and access to PMTCT for all pregnant women, routine testing of all HIV exposed infants and rapid initiation of antiretroviral treatment irrespective of clinical or immunological disease staging. In addition, careful scrutiny for TB exposure should occur at every health care visit, with provision of isoniazid preventive therapy (IPT) following each documented exposure event. Knowing the HIV infection status of child TB suspects is essential to optimize case management. Although multiple difficulties remain, recent advances demonstrate that the management of children with TB and/or HIV can be vastly improved by well focused interventions using readily available resources.

Opportunities for chemoprophylaxis in children with culture-confirmed tuberculosis.

BACKGROUND AND OBJECTIVES: Chemoprophylaxis is an effective strategy to prevent progression of tuberculosis (TB) in vulnerable children who have had contact with an infectious source of TB. However, many operational gaps prevent implementation of routine chemoprophylaxis in high-burden settings. The TB exposure status and disease spectrum in children diagnosed with culture-confirmed TB are described and missed opportunities for chemoprophylaxis are highlighted. METHODS: All children <13 years of age diagnosed with culture-confirmed TB at a tertiary referral hospital between March 2003 and February 2007 were included. Clinical data were collected from retrospective review of files. TB was classified as pulmonary and extra-pulmonary; disseminated TB included miliary disease and TB meningitis. RESULTS: During the study period, 614 children (327, 53·3% boys, median age 32 months) were diagnosed with culture-confirmed TB. Contact with an infectious adult source case was documented in 333 (54·2%), 237 (71·2%) of whom were <5 years of age, and 24 (7·2%) were HIV-infected and ≥5 years of age. Of those eligible for chemoprophylaxis, missed opportunities were identified in 156/221 (70·6%) children; 127 (81·4%) were <3 years of age, 39 (25%) had disseminated TB and 8 (5·1%) died. The TB source case was the mother or father in 74/156 (47·4%) children. CONCLUSION: Opportunities for initiation of chemoprophylaxis in vulnerable children following TB exposure are often missed. Awareness should be increased among health-care workers and in the community at large regarding the importance of chemoprophylaxis in young and HIV-infected children. Health system strengthening is required to improve delivery of chemoprophylaxis to vulnerable children in close contact with newly diagnosed infectious TB cases.

A case of congenital measles during the 2010 South African epidemic.

Congenital measles is a well recognised but uncommon transplacental infection in the post-vaccine era. A 4-day-old infant is described who presented with uncomplicated congenital measles during the 2010 South African measles outbreak. Clinicians working in regions affected by measles outbreaks should be mindful of waning vaccine-induced measles immunity where infections among pregnant women may result in a resurgence of congenital measles.

Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

Pathways to COVID-19 'community protection'.

To date, no country has reached a natural COVID-19 epidemic peak and observed peaks essentially reflect the effectiveness of 'lockdown' measures. The major challenge is finding a responsible way out of 'lockdown', given that SARS- CoV-2 is now an established global pathogen. Acknowledging limitations in our knowledge regarding the sufficiency and durability of immune responses following natural SARS Cov-2 infection, we discuss three pathways to 'community protection'. Uncontrolled epidemic spread (route 1; R0>2) has been associated with overwhelmed health care systems and high death rates, especially in the vulnerable. Controlled epidemic spread (route 2; effective R0 1-2) can be achieved with limited or strict control of social mixing; strict control will be necessary to ensure that only low-risk individuals become infected, without spill-over to vulnerable groups during their period of infectiousness. It has been demonstrated that local epidemic elimination (route 3; effective R0<1) can be achieved through prolonged 'lock down', supplemented by early active case finding with quarantine of close contacts to ensure rapid termination of transmission chains within the community. Although universal availability of a safe and effective vaccine remains the preferred 'exit strategy', this may be hard to achieve and alternative options must be considered with careful consideration of all adverse outcomes - including health, social and economic consequences.

Highly discordant T cell responses in individuals with recent exposure to household tuberculosis.

BACKGROUND: There are limited data comparing interferon-gamma release assays (IGRAs) for the detection of Mycobacterium tuberculosis infection in highly endemic settings. METHODS: A cross-sectional household contact study was conducted to measure the agreement of two IGRAs in relation to the tuberculin skin test (TST) to detect M tuberculosis infection and to assess the influence of M tuberculosis exposure and age. RESULTS: In 82 individuals in household contact, 93% of children and 42% of adults had a high M tuberculosis contact score. The TST was positive in 78% of adults and 54% of children, the T-SPOT.TB was positive in 89% of children and 66% of adults and the QuantiFERON TB Gold (QTF) was positive in a similar proportion of adults and children (38.1% and 39.6%). In children there was poor agreement between the TST and T-SPOT.TB (kappa = -0.15) and the T-SPOT.TB and the QTF (kappa = -0.03), but good agreement between the TST and the QTF (kappa = 0.78) using 10 mm cut-off. In adults there was fair to moderate agreement between the TST and T-SPOT.TB (kappa = 0.38), the TST and QTF (kappa = 0.34) and T-SPOT.TB and QTF (kappa = -0.50). High levels of exposure to M tuberculosis were associated with at least a sevenfold odds of being T-SPOT.TB positive (95% CI 7.67 to 508.69) and a threefold odds of being QTF positive (95% CI 3.02 to 30.54). There was a significant difference in the magnitude of T-SPOT.TB early secretory antigenic target (ESAT)-6 and culture filtrate protein 10 kD (CFP-10) spot counts between adults and children. CONCLUSIONS: The T-SPOT.TB may be more sensitive than the TST or QTF for detecting recent M tuberculosis infection in children. Differences between assays and the predictive utility of these findings for subsequent disease development should be prospectively assessed.

Mycobacterium tuberculosis transmission is not related to household genotype in a setting of high endemicity.

Among the different strains of Mycobacterium tuberculosis, Beijing has been identified as an emerging genotype. Enhanced transmissibility provides a potential mechanism for genotype selection. This study evaluated whether the Beijing genotype is more readily transmitted than other prevalent genotypes to children in contact with an adult tuberculosis (TB) index case in the child's household. We conducted a prospective, community-based study at two primary health care clinics in Cape Town, South Africa, from January 2003 through December 2004. Bacteriologically confirmed new adult pulmonary TB cases were genotyped by IS6110 DNA fingerprinting; household contacts less than 5 years were traced and screened for M. tuberculosis infection and/or disease. A total of 187 adult index cases were identified from 174 households with children aged less than 5 years. Of 261 child contacts aged 0 to 5 years, 219 (83.9%) were completely evaluated and the isolate from the index case was successfully genotyped. M. tuberculosis infection (induration of >or=10 mm by Mantoux tuberculin skin test) was documented in 118/219 (53.9%) children; 34 (15.5%) had radiographic signs suggestive of active TB. There was no significant difference in the ratio of infected children among those exposed to the Beijing genotype (51/89; 57.3%) and those exposed to non-Beijing genotypes (55/115; 47.8%) (odds ratio, 1.5; 95% confidence interval, 0.8 to 2.7). Genotyping was successful for six children diagnosed with active TB; the isolates from only two children had IS6110 fingerprints that were identical to the IS6110 fingerprint of the isolate from the presumed index case. We found no significant association between the M. tuberculosis genotype and transmissibility within the household. However, undocumented M. tuberculosis exposure may have been a major confounding factor in this setting with a high burden of TB.

Improvement in mycobacterial yield and reduced time to detection in pediatric samples by use of a nutrient broth growth supplement.

There is an urgent need to improve the methods used for the bacteriological diagnosis of childhood mycobacterial disease. This study compared the mycobacterial yields and the times to detection (in days) of mycobacteria in pediatric clinical specimens by using Mycobacterial Growth Indicator Tubes (MGITs) and solid Löwenstein-Jensen (LJ) slants with and without a nutrient broth supplement. A total of 801 specimens from 493 patients were processed: 82.8% were gastric aspirate specimens, 15.6% were sputum specimens, and 1.6% were fine-needle-aspiration biopsy specimens. The mycobacterial yield obtained with MGITs (with and without nutrient broth) was 11.0%, and that obtained with LJ slants was 1.6% (P < 0.001). Of the 88 positive cultures, 62 were detected in MGITs and 73 were detected in MGITs supplemented with nutrient broth (P = 0.11). The mean time to detection in MGITs (without nutrient broth) was 18.5 days, whereas it was 12.4 days in MGITs with nutrient broth (P < 0.001). Supplementation of standard MGITs improved the mycobacterial yield and significantly reduced the time to detection of mycobacteria in pediatric samples.

Disseminated bacille Calmette-Guérin disease in HIV-infected South African infants.

OBJECTIVE: To determine the population-based incidence of disseminated bacille Calmette-Guérin (BCG) disease in HIV-infected infants (aged