Literature Highlights.

Literature Highlights is a digest of notable papers recently published in the leading respiratory journals, allowing our readers to stay up-to-date with research advances. Coverage in this issue includes time to smear and culture conversion during TB treatment; probability of diagnosing ventilator-associated pneumonia in intensive care and use of antimicrobials; optimising computer-aided chest X-ray to diagnose intra-thoracic TB in children; and clinical standards for asthma in low- and middle-income countries.

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.

Adapting active case-finding for TB during the COVID-19 pandemic in Yogyakarta, Indonesia.

The COVID-19 pandemic and response measures, including lockdowns and the reorientation of health services, have disrupted essential health services for other diseases, including TB, HIV and malaria. For TB, reductions in case detection due to the COVID-19 pandemic are projected to result in increased TB transmission, morbidity and mortality. Active case-finding (ACF) for TB using community-based approaches is a potential strategy to offset reductions in TB detection by obviating the need for patients to seek care at a health facility. A number of approaches can be used to conduct TB ACF safely and screen designated target populations while managing the risks of SARS-CoV-2 transmission for staff, individuals and the community. We present a framework of options for and experience of adapting TB ACF services in response to the challenges of COVID-19 in our programme in Yogyakarta, Indonesia. Key changes have included revised prioritisation of target populations focusing on household contacts, reducing case-finding throughput, implementation of additional infection control measures and precautions, and integration of COVID-19 screening among those being screened for TB. Our approach could inform other programmes seeking to adapt TB ACF services to mitigate the negative impact of COVID-19 on TB case detection.

La pandémie de COVID-19 et les mesures de riposte incluant des confinements et une réorientation des services de santé ont perturbé les services de santé essentiels destinés aux autres maladies comme la TB, le VIH et le paludisme. En ce qui concerne la TB, les réductions de la détection des cas dues à la pandémie de COVID-19 devrait entraîner une augmentation de la transmission, morbidité et mortalité de la TB. La recherche active des cas (ACF) de TB grâce à des approches communautaires est une stratégie potentielle visant à compenser pour les réductions de détection de la TB en écartant le besoin pour les patients de solliciter des soins dans un structure de santé. Plusieurs approches peuvent être utilisées pour réaliser l'ACF TB de façon sûre et de dépister des populations cibles désignées tout en gérant les risques de transmission du SARS-CoV-2 pour le personnel, les individus et la communauté. Nous présentons un cadre d'options et d'expériences d'adaptation des services TB ACF en réponse aux défis du COVID-19 dans notre programme à Yogyakarta, Indonésie. Les changements majeurs ont inclus une révision des priorités des populations cibles focalisée sur les contacts domiciliaires ; une réduction de la cadence de la recherche de cas ; la mise en œuvre de mesures supplémentaires de lutte contre l'infection et de précautions ; et l'intégration du dépistage de COVID-19 parmi ceux dépistés pour la TB. Notre approche pourrait informer d'autres programmes voulant adapter les services TB ACF afin d'atténuer l'impact négatif du COVID-19 sur la détection des cas de TB.

TB contact tracing for young children: an Australian cascade of care review.

OBJECTIVE: To evaluate care cascades for programmatic active case finding and latent TB infection (LTBI) management in young child TB contacts (aged <5 years) in Victoria, Australia. DESIGN: This was a retrospective review of public health surveillance data to identify contacts of all pulmonary TB cases notified from 2016 to 2019. RESULTS: Contact tracing identified 574 young child contacts of 251 pulmonary TB cases. Active TB was found in 28 (4.9%) contacts, none of whom had previously received bacille Calmette-Guérin vaccination, and 529 were tested for TB infection using the tuberculin skin test (TST). The overall TST positivity was 15.3% (95% CI 0.1-0.2). Among the 574 children, 150 (26.1%) were close contacts of sputum smear-positive cases and 25 (16.7%) of these were not referred to TB clinics. Of the 125 referred, 81 were considered to have LTBI, 79 agreed to commence TB preventive treatment (TPT) and 71 (89.9%) completed TPT. Following completion of TPT, no child was subsequently diagnosed with active TB. CONCLUSION: There was a high yield from active case finding and uptake of TPT. Notable losses in the cascade of care occurred around referral to tertiary clinics, but high treatment completion rates and good outcomes were found in those prescribed treatment.

OBJECTIF: Evaluer les cascades de soins pour la recherche active programmatique des cas et la prise en charge de l'infection tuberculeuse latente (ITL) chez les contacts de jeunes patients atteints de TB âgés de <5 ans dans l'état de Victoria, Australie. SCHÉMA: Revue rétrospective de données de surveillance de santé publique afin d'identifier les contacts de tous les cas de TB pulmonaire notifiés de 2016 à 2019. RÉSULTATS: Le traçage des contacts a identifié 574 jeunes enfants tous contacts de 251 cas de TB pulmonaire. Une TB active a été trouvée chez 28 enfants contacts (4,9%), aucun n'ayant reçu le vaccin bacille Calmette-Guérin, et 529 ont été testés à la recherche d'infection TB avec un test cutané à la tuberculine (TCT). La positivité d'ensemble du TCT a été de 15,3% (IC 95% 0,1­0,2). Parmi les 574 enfants, 150 (26,1%) étaient des contacts étroits de cas à frottis de crachats positifs et 25 (16,7%) d'entre eux n'ont pas été référés dans des structures TB. Sur les 125 enfants référés, 81 ont été considérés comme ayant une ITL, 79 ont accepté de débuter un traitement préventif (TPT) et 71 (89,9%) l'ont terminé. Aucun enfant n'a ensuite eu de diagnostic de TB active. CONCLUSION: La recherche active de cas et la couverture TPT ont eu un rendement élevé. Des pertes notables dans la cascade de soins sont survenues lors de référence aux structures tertiaires, mais ceux qui ont reçu un traitement ont eu un taux élevé d'achèvement et de bons résultats.

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.

Tuberculosis contact investigation and short-course preventive therapy among young children in Africa.

SETTING: The largest cities in Benin, Burkina Faso, Cameroon and Central African Republic.OBJECTIVE: To demonstrate the feasibility and document the effectiveness of household contact investigation and preventive therapy in resource-limited settings.DESIGN: Children under 5 years living at home with adults with bacteriologically confirmed pulmonary tuberculosis (TB) were screened using questionnaire, clinical examination, tuberculin skin test and chest X-ray. Children free of active TB were offered preventive treatment with a 3-month rifampicin-isoniazid (3RH) or 6-month isoniazid (6H) regimen in Benin. Children were followed-up monthly during treatment, then quarterly over 1 year. Costs of transportation, phone contacts and chest X-rays were covered.RESULTS: A total of 1965 children were enrolled, of whom 56 (2.8%) had prevalent TB at inclusion. Among the 1909 children free of TB, 1745 (91%) started preventive therapy, 1642 (94%) of whom completed treatment. Mild adverse reactions, mostly gastrointestinal, were reported in 2% of children. One case of incident TB, possibly due to a late TB infection, was reported after completing the 3RH regimen.CONCLUSION: Contact investigation and preventive therapy were successfully implemented in these resource-limited urban settings in programmatic conditions with few additional resources. The 3RH regimen is a valuable alternative to 6H for preventing TB.

Drug-resistant tuberculosis diagnosis since Xpert® MTB/RIF introduction in Papua New Guinea, 2012-2017.

SETTING: Xpert® MTB/RIF was introduced in Papua New Guinea in 2012 for the diagnosis of tuberculosis (TB) and of rifampicin-resistant TB (RR-TB), a marker of multi-drug-resistant TB (MDR-TB). OBJECTIVE: To assess the concordance of Xpert with phenotypic drug susceptibility testing (DST) performed at the supranational reference laboratory and to describe the patterns of drug-resistant TB observed. DESIGN: This was a retrospective descriptive study of laboratory data collected from April 2012 to December 2017. RESULTS: In 69 months, 1408 specimens with Xpert results were sent for mycobacterial culture and DST; Mycobacterium tuberculosis was cultured from 63% (884/1408) and DST was completed in 99.4%. The concordance between Xpert and culture for M. tuberculosis detection was 98.6%. Of 760 RR-TB cases, 98.7% were detected using Xpert; 98.5% of 620 MDR-TB cases were identified using phenotypic DST. Phenotypic resistance to second-line drugs was detected in 59.4% (522/879) of specimens tested, including 29 with fluoroquinolone resistance; the majority were from the National Capital District and Daru Island. CONCLUSION: The high concordance between phenotypic DST and Xpert in identifying RR-TB cases supports the scale-up of initial Xpert testing in settings with high rates of drug resistance. However, rapid DST in addition to the detection of RR-TB is required.

Implementation of screening and management of household contacts of tuberculosis cases in Daru, Papua New Guinea.

SETTING: Daru Island, Western Province, Papua New Guinea (PNG). OBJECTIVE: To describe the implementation of a screening programme for household contacts of tuberculosis (TB) cases residing on Daru Island. DESIGN: This was a retrospective descriptive study evaluating two periods of implementation: introduction and expansion of a screening programme for household contacts of drug-resistant TB (DR-TB) cases (March 2016 to September 2017), and inclusion of drug-susceptible TB (DS-TB) cases with provision of preventive therapy for eligible contacts between October 2017 and March 2018. RESULTS: In the first period, the contact screening programme was established and strengthened by increasing coverage over time. There was a large number of contacts (median 8) in each household, and a high uptake of screening. In the second period of evaluation, respectively 412 and 223 contacts of 42 DS-TB and 25 DR-TB index cases were screened. Overall, 156 (24.6%) contacts reported TB-related symptoms and 9 (1.4%) were diagnosed with active TB. All 9 commenced TB treatment: 5 had DS-TB and 4 had DR-TB. Of 82 child contacts of DS-TB cases eligible for preventive therapy, 57 (69.5%) commenced treatment and 45 completed treatment. CONCLUSION: Community-based household contact screening and management was successfully implemented under programme conditions in this high burden TB and DR-TB setting in PNG.

Outcomes in children treated for tuberculosis with the new dispersible fixed-dose combinations in Port Moresby.

SETTING: The new child-friendly fixed dose combinations (FDCs) were introduced at Port Moresby General Hospital, Papua New Guinea, in 2016 for the first-line treatment of children (aged <15 years) with tuberculosis (TB) who weighed <25 kg. OBJECTIVE: To describe the characteristics and outcomes for children treated with the new FDCs, and to identify risk factors for unfavourable treatment outcomes. DESIGN: This was a retrospective cohort study of all children treated for TB with the FDCs from August 2016 to August 2017. RESULTS: Of 713 children included, 488 (68%) were diagnosed with pulmonary TB. Only 6 (0.8%) TB cases were bacteriologically confirmed and human immunodeficiency virus (HIV) status was known in 50%. Treatment outcomes were favourable in 425 (60%) children. Of 288 children with unfavourable outcomes, there were 242 (84%) with loss to follow-up (LTFU) and 25 (8.4%) were known to have died. Children who were severely underweight (weight-for-age Z score <-3) on presentation were at greater risk of LTFU compared to children of normal weight on multivariable analysis (aRR 1.3, 95%CI 1.0-1.6, P < 0.05). CONCLUSION: Alternative models of care to decrease LTFU during treatment are needed, including integration with nutritional support. Improving diagnosis through microbiological confirmation of TB and HIV are major challenges to be addressed.

Challenges in TB diagnosis and treatment: the Kavieng Provincial Hospital experience, Papua New Guinea.

SETTING: The Tuberculosis (TB) Basic Management Unit at Kavieng Provincial Hospital, New Ireland Province, Papua New Guinea. OBJECTIVE: To assess the linkage between laboratory diagnosis and treatment initiation and describe the characteristics and treatment outcomes of TB patients. DESIGN: This was a retrospective cohort study of 1) sputum smear-positive TB patients recorded in the laboratory register, and 2) TB patients recorded in the treatment register in 2015 and 2016. RESULTS: Of the 221 patients registered for TB treatment, 173 (78%) were clinically diagnosed; extrapulmonary TB was common (36% of all patients). Unfavourable treatment outcomes were seen in more than 40% of patients, including death (10%) and loss to follow-up (26%), and were significantly more common in smear-negative vs. smear-positive pulmonary TB patients (RR 1.69 [95%CI 1.02-2.80]). Only 4 (<2%) TB patients had undergone testing for HIV. Twelve (21%) of 58 sputum smear-positive TB patients were not registered as undergoing treatment for TB. CONCLUSION: This study identifies diagnostic and treatment gaps in the TB treatment cascade at the Kavieng Basic Management Unit. The TB programme requires strengthening to address the high proportions of clinically diagnosed TB, of patients not tested for HIV and of loss to follow-up.

Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

Adjustment to acute or early HIV-1 infection diagnosis to prompt linkage to care and ART initiation: qualitative insights from coastal Kenya.

Diagnosing and treating patients with acute or early HIV-1 infection (AEHI) is an important strategy to prevent HIV-1 transmission. We used qualitative methods to understand factors that facilitate adjustment to AEHI diagnosis, prompt linkage to care and initiation of antiretroviral treatment (ART). Twenty-three AEHI patients (12 women, 11 men) included 18 participants identified at health facilities, and 5 participants identified in a sex worker cohort. Of these, 17 participants (9 women, 8 men) participated in qualitative interviews about their AEHI status 2 weeks after diagnosis. Thirteen participants (7 women, 6 men) returned for a second interview 12 weeks after diagnosis. Interviews explored participants' experiences at the time of and following their diagnosis, and examined perceptions about ART initiation and behavior change recommendations, including disclosure and partner notification. A grounded theory framework was used for analysis, eliciting three important needs that should be addressed for AEHI patients: 1) the need to better understand AEHI and accept one's status; 2) the need to develop healthy strategies and adjust to the reality of AEHI status; and 3) the need to protect self and others through ART initiation, adherence, safer sex, and disclosure. A preliminary conceptual framework to guide further intervention and research with AEHI populations is proposed.

Decentralisation of child tuberculosis services increases case finding and uptake of preventive therapy in Uganda.

BACKGROUND: A lack of capacity to diagnose tuberculosis (TB) in children at peripheral health facilities and limited contact screening and management contribute to low case finding in TB-endemic settings. OBJECTIVE: To evaluate the implementation of a pilot project that strengthened diagnosis, treatment and prevention of child TB at peripheral health facilities in Uganda. METHODS: In June 2015, health care workers at peripheral health facilities were trained to diagnose and treat child TB. Community health care workers were trained to screen household TB contacts. Before-and-after analysis as well as comparisons with non-intervention districts were used to evaluate impact on caseload and treatment outcomes. RESULTS: By December 2016, the average number of children (age < 15 years) diagnosed with TB increased from 45 to 108 per quarter. The proportion of child TB among all TB cases increased from 8.8% to 15%, and the proportion completing treatment increased from 65% to 82%. Of 2270 child TB contacts screened, 55 (2.4%) were diagnosed with TB. Of 910 eligible child contacts, 670 (74%) started preventive therapy, 569 (85%) of whom completed therapy. CONCLUSION: The strengthening of child TB services at peripheral health facilities in Uganda was associated with increased case finding, improved treatment outcomes and the successful implementation of contact screening and management.

Tuberculosis in adolescents and young adults: epidemiology and treatment outcomes in the Western Cape.

SETTING: Western Cape Province, South Africa. OBJECTIVES: To characterise tuberculosis (TB) epidemiology, disease presentation and treatment outcomes among adolescents (age 10-19 years) and young adults (age 20-24 years) in the Western Cape. DESIGN: A retrospective, cross-sectional review of routine patient-level data from the Electronic TB Register (ETR.Net) for 2013. Site of TB disease, human immunodeficiency virus (HIV) status and TB treatment outcomes were analysed by 5-year age groups (<5, 5-9, 10-14, 15-19, 20-24 and 25 years of age). TB notification rates were calculated using census data. RESULTS: Adolescents and young adults comprised 18.0% of all new TB notifications in 2013. The notification rate was 141 TB cases/100 000 person-years (py) among 10-14 year olds, 418/100 000 py among 15-19 year olds and 627/100 000 py among 20-24 year olds. HIV prevalence among TB patients was 10.9% in 10-14 year olds, 8.8% in 15-19 year olds and 27.2% in 20-24 year olds. Older adolescents (age 15-19 years) and young adults (age 20-24 years) with HIV co-infection had poor treatment outcomes: 15.6% discontinued treatment prematurely and 4.0% died. CONCLUSIONS: Young people in the Western Cape suffer a substantial burden of TB, and those with TB-HIV co-infection are at high risk of treatment discontinuation.

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.