February 2020 PIN Newsletter


A Comment from the Coordinator


Lots going on in the world of pneumonia.  January 29-31, 2020 stakeholders gathered at CosmoCaixa in Barcelona, Spain to attend the Global Forum on Childhood Pneumonia.  In addition to a declaration to reduce child pneumonia deaths to less than 3 per 1000 live births by 2030, outcomes from the meeting included important commitments from Indonesia (introduction of pneumococcal conjugate vaccine into routine immunization services), Nigeria (introduction of national pneumonia control strategy), and Spain (increased Official Development Assistance support).


In addition, this month in our Deep Breaths Blog, we will hear from PIN Member Michael Mina as he discusses why measles is the master childhood infection.

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Global Forum on Childhood Pneumonia 29-31 January 2020

Every Breath Counts https://stoppneumonia.org/latest/global-forum/

The Global Forum on Childhood Pneumonia is a major opportunity to ensure that pneumonia is at the forefront of national and global health agendas; galvanise national action, and mobilise the donor community to increase awareness of the scale of the pneumonia challenge.


ISGlobal, Save the Children, UNICEF, Every Breath Counts, Bill & Melinda Gates Foundation, ”la Caixa” Foundation, USAID, Unitaid and Gavi have joined forces to address one of the greatest and gravest health challenges facing children around the world.


As the world’s first conference on childhood pneumonia – taking place on 29-31 January 2020 at CosmoCaixa in Barcelona, Spain – the Global Forum sets out to agree practical pathways that governments and their partners can take to meet the Sustainable Development Goal on child survival and the Global Action Plan for Pneumonia and Diarrhea (GAPPD) target of three child pneumonia deaths per 1,000 live births.


This is not a forum for reflection, but a call to action to deliver concrete measures with the potential to save hundreds of thousands of children’s lives.

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Pneumococcal conjugate vaccines decrease community-acquired alveolar pneumonia with and without pleural effusion in children

By Triadou D, Givon-Lavi N, Greenberg D, Ben-Shimol S

Infectious Diseases, November 27, 2019.

Radiographically-proven community-acquired alveolar pneumonia with pleural effusion (PE-CAP) has a less favourable outcome than pneumonia without pleural effusion (NPE-CAP). We assessed PE-CAP and NPE-CAP rate dynamics in children <60 months in southern Israel before and after 7- and 13-valent pneumococcal conjugate vaccine (PCV7/PCV13) implementation (2002–2016).

An ongoing, prospective observational study. Our hospital serves a captive population of ∼75,000 children <60 months, enabling incidence calculation. PCV7/PCV13 were implemented in Israel in July 2009/November 2010, respectively. All chest radiographs (CXRs) were digitalized and analysed according to the WHO Standardization of Interpretation. Annual incidences of PE-CAP and NPE-CAP were calculated, 2002–2016. Incidence-rate ratios (IRRs) comparing PCV13 (2013–2016), PCV7 (2010–2011) and pre-PCV (2002–2008) periods were calculated.

Following PCV7/PCV13 introduction, PE-CAP and NPE-CAP rates substantially declined. However, the rate dynamics were different, with steeper declines observed in PE-CAP rates, possibly deriving from differences in disease aetiology.

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Leave it to Lefamulin: A Pleuromutilin Treatment Option in Community-Acquired Bacterial Pneumonia

By Young Ran Lee, Katy Louise Jacobs.

Drugs, November 8, 2019

Lefamulin (BC-3781) is the first systemic pleuromutilin antibiotic found to be safe and effective in the treatment of community-acquired bacterial pneumonia (CABP) in humans. This novel antibiotic was developed to combat the increasing incidence of bacterial resistance to current therapies. As the first semisynthetic pleuromutilin for systemic use in humans, lefamulin has demonstrated efficacy against the most common bacteria responsible for CABP, including strains exhibiting resistance to macrolides, fluoroquinolones, tetracyclines, vancomycin, and beta-lactams. In vitro studies have demonstrated efficacy against Staphylococcus aureus, beta-hemolytic and viridans group streptococci, coagulase-negative staphylococci, Enterococcus faecium, Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophilia, and Moraxella catarrhalis at MIC values lower than those of currently available therapies. T

wo phase III trials (LEAP-1 and LEAP-2) have demonstrated similar findings, meeting non-inferiority criteria for CABP with a minimal side-effect profile. Pharmacokinetic and pharmacodynamic evaluations have shown sufficient drug levels in plasma, subcutaneous adipose tissue, skeletal muscle, and epithelial lining fluid, warranting further investigation for other clinical uses. Lefamulin was approved by the United States Food and Drug Administration (FDA) on 19 August 2019 for the treatment of CABP.


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Exploratory meeting to review new evidence for Integrated Management of Childhood Illness danger signs


The World Health Organization, August 1, 2019


For children up to 5 years of age with common childhood illnesses, WHO’s IMCI strategy recommends using clinical signs for diagnosis, treatment and place-of-treatment decisions. In order to increase access to pneumonia treatment, in 2014 WHO revised pneumonia management guidance within IMCI. It now recommends that lower chest indrawing, which previously required hospitalization along with other referral clinical signs considered as danger signs for injectable antibiotics, be treated with oral amoxicillin on an outpatient basis in settings with low HIV prevalence. These danger signs include convulsions; unable to drink; unconscious or drowsy; vomiting everything; stiff neck; severe dehydration; stridor in a calm child; oedema on both feet; weight for height (WHZ) Z-score less than - 3 SD or mid-upper arm circumference (MUAC) less than 115 mm; severe palmar pallor; clouding of the cornea in a child with measles, and tender swelling behind the ear in a child with an ear problem.


However, a recent retrospective analysis of data from hospitalized children in Kenya showed that mortality was high among children with mild to moderate palmar pallor, WAZ less than - 3 SD and lower chest indrawing. This finding raised concerns that these children should be treated on an inpatient basis despite the revised guidelines. In order to evaluate the implications of this new evidence and other data and to identify questions for future research, a two-day exploratory meeting of pneumonia research experts, epidemiologists and child health specialists/paediatricians from a range of countries with varying resources was convened in Geneva, Switzerland, on 4–5 September 2018.

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Vaccine Reduces Pneumonia in Kenya

By M.J. Friedrich

JAMA. June 18, 2019


Introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) resulted in sharply reduced pneumonia cases in Kenya, according to a report from an international team of researchers.

In 2011, Kenya was the first African country to add PCV10 to its national childhood immunization schedule. The vaccine protects against 10 common strains of Streptococcus pneumoniae. The schedule called for a 3-dose series administered to infants at 6, 10, and 14 weeks of age, with a catch-up campaign for children younger than 5 years.

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Colonization rate of Streptococcus pneumoniae, its associated factors and antimicrobial susceptibility pattern among children attending kindergarten school in Hawassa, southern Ethiopia.

By Aberash Assefa Haile, Deresse Daka Gidebo, and Musa Mohammed Ali

BMC Research Notes. June 17, 2019


The aim of this study was to determine the colonization rate of Streptococcus pneumoniae, antimicrobial susceptibility pattern and associated risk factors among children attending kindergarten school in Hawassa, Ethiopia.

Out of 317 study participants, 68 (21.5%) were colonized with S. pneumoniae. Colonization rate was significantly associated with factors such as age (3 to 4 years old) (P = 0.01), having a sibling whose age was less than 5 years (P = 0.011), sharing a bed with parents (P = 0.005), cooking within bedroom (P = 0.002), and previous hospitalization (P = 0.004). Forty-four (64.6%), 33 (48.5%), and 2942.6%) of S. pneumoniae isolated were resistant to cotrimoxazole, penicillin, and tetracycline respectively.

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Disease severity and clinical outcomes of community acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicenter prospective registry study from CAP-China Network

By Fei Zhou, Yimin Wang, Yingmei Liu, Xuedong Liu, Li Gu, Xiaoju Zhang, Zenghui Pu, Guoru Yang, Bo Liu, Qingrong Nie, Bing Xue, Jing Feng, Qiang Guo, Jianhua Liu, Hong Fan, Jin Chen, Yongxiang Zhang, Zhenyang Xu, Min Pang, Yu Chen, Xiuhong Nie, Zhigang Cai, Jinfu Xu, Kun Peng, Xiangxin Li, Pingchao Xiang, Zuoqing Zhang, Shujuan Jiang, Xin Su, Jie Zhang, Yanming Li, Xiuhong Jin, Rongmeng Jiang, Jianping Dong, Yuanlin Song, Hong Zhou, Chen Wang, Bin Cao CAP-China network

European Respiratory Journal, June 4, 2019


Although a wide knowledge of influenza viral pneumonia have been established, the significance of non-influenza respiratory viruses in community acquired pneumonia (CAP) and their impact on clinical outcomes remains unclear, especially in non-immunocompromised adult population. Hospitalised immunocompetent patients with CAP were prospectively recruited from 34 hospitals in Mainland China. Respiratory viruses were detected by molecular methods. Comparisons were conducted between influenza and non-influenza viral-infection groups. In total, 915 of 2336 adult patients with viral infection were enrolled in the analysis with influenza virus (28.4%) most frequently detected, followed by respiratory syncytial virus (3.6%), adenovirus (3.3%), human coronavirus (3.0%), parainfluenza virus (2.2%), human rhinovirus (1.8%), and human metapneumovirus (1.5%). Non-influenza viral infections accounted for 27.4% of viral pneumonia. Consolidation was more frequently observed in patients with adenovirus infection. The occurrence of complications such as sepsis (40.1% versus 39.6%, p=0.890) and hypoxemia (40.1% versus 37.2%, p=0.449) during hospitalisation in influenza group didn't differ from that of non-influenza group. Compared with influenza viral infection, the multivariable-adjusted odds ratios and 95% confidence intervals (CIs) of CURB-65 >3, PaO2/FiO2 <200 mmHg, and occurrence of sepsis or hypoxemia for non-influenza viral infection were 0.87 (0.26-2.84), 0.72 (0.26-1.98), 1.00 (1.63-1.58), and 1.05 (0.66-1.65), respectively. The hazard ratio and 95% CI of 90-day mortality was 0.51 (0.13-1.91). The high incidence of complications in non-influenza viral pneumonia and similar impact of non-influenza viruses relative to influenza virus on disease severity and outcomes suggest more attention should be given to CAP caused by non-influenza viruses.

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Predictors of ‘unlikely bacterial pneumonia’ and ‘adverse pneumonia outcome’ in children admitted to hospital in central Vietnam

By Phuong T K Nguyen, Hoang T Tran, Thach S Tran, Dominic A Fitzgerald, Stephen M Graham, Ben J Marais

Clinical Infectious Diseases, May 27, 2019


Prospective enrolment of all children under five admitted with ‘pneumonia’ (per clinician assessment) to the Da Nang Hospital for Women and Children over a one-year period. Children were classified as having ‘likely or ‘unlikely’ bacterial pneumonia and followed for outcome assessment. A Bayesian Model Averaging (BMA) approach was used to identify predictors of ‘unlikely bacterial pneumonia’ and ‘adverse pneumonia outcome’, which guided the development of a pragmatic management algorithm.

Of 3,817 patients assessed, 2,199 (57.6%) met World Health Organisation (WHO) pneumonia criteria. In total, 1594 (41.7%) children were classified as ‘unlikely’ and 129 (3.4%) as ‘likely’ bacterial pneumonia. The remainder (2,399; 62.9%) were considered to have disease of ‘uncertain aetiology’. Factors predictive of ‘unlikely bacterial pneumonia’ were ‘no fever’, ‘no consolidation on chest radiograph’ and ‘absolute neutrophil count <5x109/L’ at presentation, which had a negative predictive value (NPV) for ‘likely bacterial pneumonia’ of 99.0%. Among those meeting WHO pneumonia criteria 8.6% (189/2,199) experienced an adverse outcome. Not having ‘any WHO danger sign’ or ‘consolidation on chest radiograph’ had a NPV of 96.8% for ‘adverse pneumonia outcome’.

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Atypical and Typical Bacteria in Children with Community Acquired Pneumonia

Jama-Kmiecik A, Frej-Mądrzak M, Sarowska J, Teryks-Wołyniec D, Skiba A, Choroszy-Król  


Part of the Advances in Experimental Medicine and Biology book series, April 2019


This seeks to determine the pathogens in respiratory specimens and blood serum obtained from children who present with community acquired pneumonia (CAP) diagnosed on the basis of clinical and radiological evidence. The study group consisted of 46 hospitalized children aged 1–11 years. The material for research consisted of pharyngeal swabs and samples of blood serum. One hundred and thirty eight pharyngeal swabs were examined for the presence of C. pneumoniae antigen, C. pneumoniae DNA, and for typical pathogens. C. pneumoniae DNA was detected in pharyngeal swabs with nested PCR. Classical microbiological culture was used for detection of typical bacteria. ELISA test were used for detection anti-C. pneumoniae and anti-M. pneumoniae antibodies in the serum. C. pneumoniae DNA was identified in 10.9% of children. Positive culture for typical pathogens was observed in 8.7% of children. Specific anti-C. pneumoniae IgM antibodies were found in 8.7% of children, and IgG and IgA antibodies in 1 child each. Specific anti-M. pneumoniae IgG antibodies were found in 13.1% of children and IgM antibodies in 1 child. We conclude that the underlying bacterial etiology of CAP is rather rarely conclusively confirmed in children. Nonetheless, determining the etiology of CAP is essential for the choice of treatment to optimize the use and effectiveness of antimicrobials and to avoid adverse effect. Due to considerable variations in the power of detection of the type of atypical bacteria causing CAP, the search for the optimum diagnostic methods continues.

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Association between urinary community-acquired fluoroquinolone-resistant Escherichia coli and neighbourhood antibiotic consumption: a population-based case-control study

by Marcelo Low, MPH; Ami Neuberger, MD; Prof Thomas M Hooton, MD; Prof Manfred S Green, MBChB; Prof Raul Raz, MD; Prof Ran D Balicer, MD; et al.

Published in The Lancet Infectious Diseases, 01 April 2019. 



It is unknown whether increased use of antibiotics in a community increases the risk of acquiring antibiotic resistance by individuals living in that community, regardless of prior individual antibiotic consumption and other risk factors for antibiotic resistance. Researchers used a hierarchical multivariate logistic regression approach to evaluate the association between neighbourhood fluoroquinolone consumption and individual risk of colonisation or infection of the urinary tract with fluoroquinolone-resistant Escherichia coli. A population-based case-control study of adults (aged ≥22 years) living in 1733 predefined geographical statistical areas (neighbourhoods) in Israel was performed. A multilevel study design was used to analyse data derived from electronic medical records of patients enrolled in the Clalit state-mandated health service. 300,105 events with E coli growth and 1 899 168 cultures with no growth were identified from medical records and included in the analysis. 45 427 (16·8%) of 270 190 women and 8835 (29·5%) of 29 915 men had fluoroquinolone-resistant E coli events. The study team found an independent association between residence in a neighbourhood with higher antibiotic consumption and an increased risk of bacteriuria caused by fluoroquinolone-resistant E coli. Odds ratios (ORs) for the quintiles with higher neighbourhood consumption (compared with the lowest quintile) were 1·15 (95% CI 1·06–1·24), 1·31 (1·20–1·43), 1·41 (1·29–1·54), and 1·51 (1·38–1·65) for women, and 1·17 (1·02–1·35), 1·24 (1·06–1·45), 1·35 (1·15–1·59), and 1·50 (1·26–1·77) for men. Results remained significant when the analysis was restricted to patients who had not consumed fluoroquinolones themselves. These data suggest that increased use of antibiotics in specific geographical areas is associated with an increased personal risk of acquiring antibiotic-resistant bacteria, independent of personal history of antibiotic consumption and other known risk factors for antimicrobial resistance.  Article access can be found here.   
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Maternal pertussis vaccination and its effects on the immune response of infants aged up to 12 months in the Netherlands: an open-label, parallel, randomised controlled trial

by Daan Barug, MD; Inge Pronk, BSc; Marlies A van Houten, MD; Florens G A Versteegh, PhD; Mirjam J Knol, PhD; Jan van de Kassteele, PhD; et al.

Published in The Lancet Infectious Diseases, 01 April 2019.


Maternal tetanus, diphtheria, and acellular pertussis (Tdap) vaccination offers protection for neonates against clinical pertussis until primary vaccinations, but maternal antibodies also interfere with infants' immune responses to primary vaccinations. Researchers investigated the effect of maternal Tdap vaccination on the pertussis antibody responses of infants starting primary vaccinations at age 3 months. In an open-label, parallel, randomised, controlled trial, pregnant women aged 18–40 years with a low risk of pregnancy complications were recruited through independent midwives at 36 midwife clinics in the Netherlands and received Tdap vaccination either at 30–32 weeks of pregnancy (maternal Tdap group) or within 48 h after delivery (control group). All term-born infants were vaccinated with the diphtheria, tetanus, and pertussis-inactivated poliomyelitis- Haemophilus influenzae type B-hepatitis B six-in-one vaccine and a ten-valent pneumococcal vaccine at 3 months, 5 months, and 11 months. Randomisation was done using a number generator in a 1:1 ratio and with sealed envelopes. Participants and clinical trial staff were not masked, but laboratory technicians were unaware of study group assignments. The primary endpoint was serum IgG pertussis toxin antibody concentrations at age 3 months. Cord blood and infant blood samples were collected at age 2 months, 3 months, 6 months, 11 months, and 12 months. Analysis was done by modified intention to treat with all randomly assigned participants in case a laboratory result was available. This trial is registered with ClinicaltTrialsRegister.eu (EudraCT 2012-004006-9) and trialregister.nl (NTR number NTR4314). The trial is now closed to new participants. Between Jan 16, 2014, and March 4, 2016, 118 pregnant women were enrolled into our study, with 58 in the maternal Tdap group and 60 in the control group. The geometric mean concentration (GMC) of pertussis toxin antibodies were higher in infants in the maternal Tdap group than in the control group infants at age 3 months (GMC ratio 16.6, 95% CI 10.9–25.2) and also significantly higher compared with control infants at age 2 months. After primary vaccinations, antibody concentrations for pertussis toxin, filamentous haemagglutinin, and pertactin were significantly lower at all time points in infants of the maternal Tdap group than in infants in the control group. No safety issues after maternal Tdap vaccination were encountered. In view of the high pertussis toxin antibody concentrations at age 3 months, maternal vaccination supports a delay of the first pertussis vaccination in infants until at least age 3 months. Maternal antibody interference affects antibody concentrations after primary and booster vaccinations. The clinical consequences of this interference remain to be established.  Article access can be found here.    
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Longitudinally evaluating the lung function of children in low- and middle-income countries: it's about time

by Eric D McCollum

Published in Clinical Infectious Diseases, 28 March 2019. 


Article access can be found here. 


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Impact of 13-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in children under 15 years old in Madrid, Spain, 2007 to 2016: The HERACLES clinical surveillance study

by Picazo JJ, Ruiz-Contreras J, Casado-Flores J, Negreira S, Baquero-Artigao F, Hernández-Sampelayo T, Otheo E, Amo MD, Méndez C; Heracles Study Group

Published in Vaccine, 19 March 2019.



Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Using the data from the HERACLES clinical surveillance study (2007-2016), researchers describe the population impact of the 13-valent pneumococcal conjugate vaccine (PVC13) on invasive pneumococcal disease (IPD) in children <15 years of age in the Community of Madrid, Spain.

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Ongoing Exposure of U.K. Infants to Vaccine Serotype Pneumococci

by Mary Slack, FRCPATH; Andrew Vyse, PhD; Harish Madhava, MD; Ralf-Rene Reinert, MD; Gillian Ellsbury, MD; Carole Czudek, PhD; Bradford Gessner, MD

Published in The Pediatric Infectious Disease Journal, April 2019. doi: 10.1097/INF.0000000000002184  "To the editors: 

We read with interest the article by Makwana et al. The authors note that most childhood invasive pneumococcal disease (IPD) cases are now due to non-13 valent pneumococcal conjugate vaccine (PCV13) serotypes though PCV13 serotypes remain in circulation with serotypes 3 and 19A listed among the top 10 that caused IPD in children in 2015/16. Of the 25 cases with PCV13-type IPD in 2015/16, 11 (44%) were due to serotype 19A.


Key insight is given into the IPD burden in infants 3–11 months of age, which over the 6-year study period accounted for a substantial proportion (508/1255, 40%) of the total in children <5 years of age. Additionally, meningitis was most prevalent in infants (209/456 cases, 45.8%) and was associated with the highest case fatality (9.6%). The most recent data from 2015/16 showed 103/271 (38%) of IPD cases occurred in infants 3–11 months of age, with 5 (4.8%) attributed to PCV13 serotypes. This reflects an increase in infant IPD compared with 2014/15 and slightly exceeds the number of cases in this age group in 2010/11 when PCV13 was first introduced illustrating a continuing and substantial burden of infant IPD. ..."


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Respiratory syncytial virus (RSV) and child pneumonia


Above, photo submitted by Keith Klugman, The Bill & Melinda Gates Foundation


Talks by:


Ting Shi, University of Edinburgh: ”Global disease burden estimate of RSV in young children”


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Influenza and child pneumonia


Above, photo submitted by Kawsar Talaat, Johns Hopkins Bloomberg School of Public Health



Talks by:

Tim Uyeki (Influenza Division, Centers for Disease Control and Prevention): “Influenza and Influenza-associated Pneumonia in Children”


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Epidemiological characteristics of nasopharyngeal Streptococcus pneumoniae strains among children with pneumonia in Chongqing, China

by YY Yu, XH Xie, Y Deng, Y Gao, Y Zhang, H Li, J Luo, ZX Luo, and EM Liu

Published in Scientific Reports, 01 March. 2019. doi: 10.1038/s41598-019-40088-6



Streptococcus pneumoniae (pneumococcus) is the most common respiratory pathogen worldwide. Nasopharyngeal carriage with S. pneumoniae is the major source of lower respiratory tract infection and horizontal spread among children. Investigating nasopharyngeal S. pneumoniae is crucial for clinicians to control pneumococcus disease. Researchers retrospectively analyzed clinical information of 5,960 hospitalized children, focusing on pneumonia children less than five years with positive nasopharyngeal pneumococcal cultures. Nasopharyngeal aspirates (NPAs) were collected between June 2009 and December 2016, which were outside the pneumococcal conjugate vaccine (PCV) period. NPAs were subjected to common bacterial culture and antibiotic susceptibility tests, and serotypes were identified by both multiplex PCR and DNA sequencing. Results clearly revealed that clinical manifestations of the children whose NPAs were S. pneumoniae culture positive were serious, especially in those less than twelve months old. Fifteen different serotypes of nasopharyngeal S. pneumoniae were detected, the most common ones being 19F (35.2%), 6A/B (23.8%), 19A (11.4%), 15B/C (9.3%) and 23F (7.8%). Eight serotypes, accounting for 85.5% of the isolates, corresponded to the PCV13 serotypes. Approximately one-third of all S. pneumoniae strains were susceptible to penicillin. Overall, researchers consider nasopharyngeal S. pneumoniae culture as beneficial in assessing the situations of pneumonia children. Moreover, PCV13 could be useful in preventing pneumococcal disease in Chongqing, China.

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Burden of hospital admissions caused by respiratory syncytial virus (RSV) in infants in England: a data linkage modelling study

by RM Reeves, P Hardelid, N Panagiotopoulos, M Minaji, F Warburton, and R Pebody

Published in The Journal of Infection, 25 February 2019. doi: 10.1016/j.jinf.2019.02.012



Current national estimates of respiratory syncytial virus (RSV)-associated hospital admissions are insufficiently detailed to determine optimal vaccination strategies for RSV. Researchers employed novel methodology to estimate the burden of RSV-associated hospital admissions in infants in England, with detailed stratification by patient and clinical characteristics.

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Smartphone-enabled video-observed versus directly observed treatment for tuberculosis: a multicentre, analyst-blinded, randomised, controlled superiority trial

by Alistair Story, PhD; Robert W Aldridge, PhD; Catherine M Smith, PhD; Elizabeth Garber, MSc; Joe Hall, MSc; Gloria Ferenando, MSc; et al.

Published in The Lancet, 21 February 2019. DOI: https://doi.org/10.1016/S0140-6736(18)32993-3



Directly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s, but it is inconvenient for patients and service providers. Video-observed therapy (VOT) has been conditionally recommended by WHO as an alternative to DOT. Researchers tested whether levels of treatment observation were improved with VOT.

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