Supportive care and antibiotics for severe pneumonia among hospitalized children: A pragmatic randomised controlled trial
Lead Research Organisation:
University of Oxford
Department Name: Tropical Medicine
Abstract
Pneumonia, an infection of the lungs, is the leading cause of deaths among young children. The World Health Organization (WHO) have developed recommendations for the diagnosis and treatment of pneumonia in low and middle income countries using simple clinical features and low cost, widely available antibiotics. The recommend treatment for children at the highest risk of death (severe pneumonia) is injectable benzylpenicillin or ampicillin and gentamicin. Following the introduction of vaccines against the main causes of pneumonia to national immunization programmes in many low-income countries, there has been growing debate over the appropriateness of the currently recommended treatments. Many clinicians already believe that the recommended treatment is ineffective and frequently opt to use other antibiotics such as amoxicillin-clavulanic acid and ceftriaxone instead. The first key question in this study seeks to compare two antibiotics against the current recommended treatment. We will investigate is whether either (i) intravenous amoxicillin-clavulanic acid or (ii) ceftriaxone is superior to benzylpenicillin plus gentamicin (standard care) for the treatment of children admitted to hospital with severe pneumonia.
Some authorities advise against feeding through a tube inserted into the stomach through the nose in severely ill children. The main reason for this is are the potential for compromising the ability to breath in a patient already experiencing difficulty breathing and an increased risk of choking on feeds given through the tube. However, the alternative, providing fluids through an intravenous drip requires careful monitoring by a nurse to ensure the fluid is given at a safe rate over the desired duration. This a common challenge in many low resource settings where a limited number of nursing staff are required to attend to several duties. Fluids provided through a drip are also lack the necessary nutrients to match the increased demands of the body during a serious illness. The second key question for this study is therefore whether feeding through a tube inserted into the stomach through the nose is superior to providing fluids through an intravenous drip for the management of children with severe pneumonia.
We will recruit 4392 children at 12 hospitals in Kenya. Children who meet the criteria for recruitment will be allocated to the study treatment groups through a balanced process pre-determined process that ensures each participant has a fair chance of receiving any given study treatments. Each of the two questions will be studied in the same set of patients. Thus, a child recruited in the study will receive any one of the three antibiotic treatments and either of the two fluid treatments. For each of the study questions, we will compare the percentage of children who die within the first five day of recruitment in the alternative treatment groups. We will also compare the length of hospitalisation, and the percentage of children who die within 30 days of recruitment in the alternative treatment groups. Chest X-rays and blood samples will be collected in a smaller group of patients to examine possible explanations for differences in responses to the treatments. Finally, we will compare the costs of receiving the alternative study treatments against the outcomes we observe among children assigned to the respective study groups and explore the social perceptions of caregivers and health workers towards the treatments.
Some authorities advise against feeding through a tube inserted into the stomach through the nose in severely ill children. The main reason for this is are the potential for compromising the ability to breath in a patient already experiencing difficulty breathing and an increased risk of choking on feeds given through the tube. However, the alternative, providing fluids through an intravenous drip requires careful monitoring by a nurse to ensure the fluid is given at a safe rate over the desired duration. This a common challenge in many low resource settings where a limited number of nursing staff are required to attend to several duties. Fluids provided through a drip are also lack the necessary nutrients to match the increased demands of the body during a serious illness. The second key question for this study is therefore whether feeding through a tube inserted into the stomach through the nose is superior to providing fluids through an intravenous drip for the management of children with severe pneumonia.
We will recruit 4392 children at 12 hospitals in Kenya. Children who meet the criteria for recruitment will be allocated to the study treatment groups through a balanced process pre-determined process that ensures each participant has a fair chance of receiving any given study treatments. Each of the two questions will be studied in the same set of patients. Thus, a child recruited in the study will receive any one of the three antibiotic treatments and either of the two fluid treatments. For each of the study questions, we will compare the percentage of children who die within the first five day of recruitment in the alternative treatment groups. We will also compare the length of hospitalisation, and the percentage of children who die within 30 days of recruitment in the alternative treatment groups. Chest X-rays and blood samples will be collected in a smaller group of patients to examine possible explanations for differences in responses to the treatments. Finally, we will compare the costs of receiving the alternative study treatments against the outcomes we observe among children assigned to the respective study groups and explore the social perceptions of caregivers and health workers towards the treatments.
Technical Summary
Pneumonia is the leading cause of deaths among young children, with inpatient mortality exceeding 10% for the most severe form of the syndrome (severe pneumonia). WHO pneumonia case management guidelines recommend empirical treatment with injectable benzylpenicillin or ampicillin and gentamicin for children at the highest risk of mortality (severe pneumonia). Following the introduction of vaccines against the dominant causes of pneumonia to national immunization programmes in many low-income countries, there has been growing debate over the appropriateness of the current recommendations for empirical treatments. The first key question is whether either intravenous amoxicillin-clavulanic acid or ceftriaxone is superior to benzylpenicillin plus gentamicin (standard care) for the treatment of children hospitalized with severe pneumonia.
Some authorities, including the British Thoracic Society, advise against nasogastric hydration in severely ill children, citing concerns of compromised respiratory status and increased risk of aspiration with nasogastric feeding. However, administration of intravenous fluids demands careful monitoring - a common challenge in many low resource settings. Intravenous fluids are also deficient in nutritive value to match the raised metabolic demands associated with acute illness. The second key question is therefore whether nasogastric feeding is superior to intravenous fluid therapy for supportive management of children with severe pneumonia.
This 3x2 factorial pragmatic trial will enrol 4392 children at 12 hospitals in Kenya. The primary endpoint will be mortality at Day 5 post-enrolment. Secondary outcomes will be length of hospitalisation, and mortality at Day 30. Chest radiographs and blood cultures will be performed on a representative sample of patients to provide data on aetiology. We will assess cost effectiveness of the interventions as well as social perceptions of caregivers and health workers towards the study treatments.
Some authorities, including the British Thoracic Society, advise against nasogastric hydration in severely ill children, citing concerns of compromised respiratory status and increased risk of aspiration with nasogastric feeding. However, administration of intravenous fluids demands careful monitoring - a common challenge in many low resource settings. Intravenous fluids are also deficient in nutritive value to match the raised metabolic demands associated with acute illness. The second key question is therefore whether nasogastric feeding is superior to intravenous fluid therapy for supportive management of children with severe pneumonia.
This 3x2 factorial pragmatic trial will enrol 4392 children at 12 hospitals in Kenya. The primary endpoint will be mortality at Day 5 post-enrolment. Secondary outcomes will be length of hospitalisation, and mortality at Day 30. Chest radiographs and blood cultures will be performed on a representative sample of patients to provide data on aetiology. We will assess cost effectiveness of the interventions as well as social perceptions of caregivers and health workers towards the study treatments.
Planned Impact
We will seek to maximise economic and societal impact of the proposed study through targeting three interrelated audiences.
1. Policy makers
The investigators are active members of national and international technical panels supporting the development policy recommendations in child health. Locally, the PI sits on a national technical working group (TWG) convened by the Ministry of Health to specifically tackle childhood pneumonia. We will use this channel of communication to convene quarterly meetings to share study-related updates as well as coordinate public engagement activities on child health focusing on pneumonia. These meetings will also provide an opportunity for the investigators to receive feedback from the members of the TWG on opportunities that the study team may use to complement the wider Ministry of Health communication strategy. Ultimately, the stakeholders represented on this TWG will play an important role in the dissemination of the study findings and their incorporation into local, regional and global evidence-based clinical practice guidelines for implementation.
2. Health workers
Since 2013, KWTRP has maintained a collaboration with the Ministry of Health in 14 public hospitals to help develop approaches to optimise use of routine hospital data to improve quality of clinical documentation and clinical care. This ongoing project, supported by funding awarded to the Prof. Mike English (Co-PI) involves all 12 of the proposed study sites. Clinical staff at the proposed study hospitals have been directly engaged in the development of the study protocol. We will continue to engage the hospital teams by supporting regular meetings (three annual visits at each site during patient recruitment) at the study hospitals. Such meetings will seek to develop capacity for conducting high quality, ethical research at site level through providing training for clinical staff on areas including basic research methods and GCP. These meetings will also provide the investigators useful feedback on the local experiences of those involved in the study. We will also convene three meetings each year with the hospital paediatricians (site principal investigators) to share study-related updates, and where possible, support further development of their research skills including protocol development for study questions of their own and ultimately, facilitate their involvement in the writing of manuscripts for the trial.
3. General public
Engagement with the wider community will be integrated with the activities of KWTRP's Community Liaison Group. Currently, information on the research activities of KEMRI is given to the community through the activities of the programme's Community Liaison Group, including regular meetings with the KEMRI-Community Representatives, and meeting with County Health Management Teams, hospital and peripheral health staff and local administrative leaders.
Building on experience gained from activities undertaken with support of an advocacy grant awarded to the PI during a previous clinical trial, we will host annual activities on World Pneumonia Day (12th November) at the study sites. Here, caregivers, particularly those of study participants will be provided an opportunity to interact with the study investigators to share their experiences and understanding of the study and the wider implications of research on public health. The information gathered from these events will inform future approaches to designing and conducting similar future studies.
Material communicating lay information on pneumonia and the importance of this and other studies to the general public will be printed on flyers and posters for distribution to the study hospitals. We will also develop briefs for radio and print media stations. A regularly updated interactive public web page hosted by KWTRP will provide additional information on the study while allowing readers to share their views with the study team.
1. Policy makers
The investigators are active members of national and international technical panels supporting the development policy recommendations in child health. Locally, the PI sits on a national technical working group (TWG) convened by the Ministry of Health to specifically tackle childhood pneumonia. We will use this channel of communication to convene quarterly meetings to share study-related updates as well as coordinate public engagement activities on child health focusing on pneumonia. These meetings will also provide an opportunity for the investigators to receive feedback from the members of the TWG on opportunities that the study team may use to complement the wider Ministry of Health communication strategy. Ultimately, the stakeholders represented on this TWG will play an important role in the dissemination of the study findings and their incorporation into local, regional and global evidence-based clinical practice guidelines for implementation.
2. Health workers
Since 2013, KWTRP has maintained a collaboration with the Ministry of Health in 14 public hospitals to help develop approaches to optimise use of routine hospital data to improve quality of clinical documentation and clinical care. This ongoing project, supported by funding awarded to the Prof. Mike English (Co-PI) involves all 12 of the proposed study sites. Clinical staff at the proposed study hospitals have been directly engaged in the development of the study protocol. We will continue to engage the hospital teams by supporting regular meetings (three annual visits at each site during patient recruitment) at the study hospitals. Such meetings will seek to develop capacity for conducting high quality, ethical research at site level through providing training for clinical staff on areas including basic research methods and GCP. These meetings will also provide the investigators useful feedback on the local experiences of those involved in the study. We will also convene three meetings each year with the hospital paediatricians (site principal investigators) to share study-related updates, and where possible, support further development of their research skills including protocol development for study questions of their own and ultimately, facilitate their involvement in the writing of manuscripts for the trial.
3. General public
Engagement with the wider community will be integrated with the activities of KWTRP's Community Liaison Group. Currently, information on the research activities of KEMRI is given to the community through the activities of the programme's Community Liaison Group, including regular meetings with the KEMRI-Community Representatives, and meeting with County Health Management Teams, hospital and peripheral health staff and local administrative leaders.
Building on experience gained from activities undertaken with support of an advocacy grant awarded to the PI during a previous clinical trial, we will host annual activities on World Pneumonia Day (12th November) at the study sites. Here, caregivers, particularly those of study participants will be provided an opportunity to interact with the study investigators to share their experiences and understanding of the study and the wider implications of research on public health. The information gathered from these events will inform future approaches to designing and conducting similar future studies.
Material communicating lay information on pneumonia and the importance of this and other studies to the general public will be printed on flyers and posters for distribution to the study hospitals. We will also develop briefs for radio and print media stations. A regularly updated interactive public web page hosted by KWTRP will provide additional information on the study while allowing readers to share their views with the study team.
Publications
Adetifa IMO
(2021)
Temporal trends of SARS-CoV-2 seroprevalence during the first wave of the COVID-19 epidemic in Kenya.
in Nature communications
Agweyu A
(2020)
Extending the measurement of quality beyond service delivery indicators.
in BMJ global health
Kamau A
(2022)
Malaria hospitalisation in East Africa: age, phenotype and transmission intensity.
in BMC medicine
Lucinde R
(2022)
A pragmatic randomized controlled trial of standard care versus steroids plus standard care for treatment of pneumonia in adults admitted to Kenyan hospitals (SONIA)
in Wellcome Open Research
Macpherson L
(2019)
Risk factors for death among children aged 5-14 years hospitalised with pneumonia: a retrospective cohort study in Kenya.
in BMJ global health
Ogero M
(2020)
Examining which clinicians provide admission hospital care in a high mortality setting and their adherence to guidelines: an observational study in 13 hospitals.
in Archives of disease in childhood
Ogero M
(2020)
Methodological rigor of prognostic models for predicting in-hospital paediatric mortality in low- and middle-income countries: a systematic review protocol.
in Wellcome open research
Ojal J
(2021)
Revealing the extent of the first wave of the COVID-19 pandemic in Kenya based on serological and PCR-test data.
in Wellcome open research
Ojal J
(2022)
Revealing the extent of the first wave of the COVID-19 pandemic in Kenya based on serological and PCR-test data
in Wellcome Open Research
Description | Co-chair of WHO/UNICEF Technical Advisory Group on Measurement for Child Health |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://www.who.int/data/maternal-newborn-child-adolescent-ageing/advisory-groups/chat |
Description | Nominated to national expert panel on integrated community case managment of childhood illnesses in Kenya |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Impact | Participated in a national expert panel constituted by the Ministry of Health to adopt policy recommendations that would permit the use of oral antibiotics by community health workers. Pneumonia remains the leading infectious cause of death in Kenya causing more than 11,000 child deaths annually. A major reason for this is inadequate access to care. The new policy is expected to expand equitable access to life-saving treatment for children with pneumonia in Kenya. As an extension of this engagement since 2020, currently involved in policy consultation towards the adaptation of WHO recommendations for community case management for malaria and severe acute malnutrition. |
Description | Developing a Clinical Learning Network to Maintain and Improve Essential Health Services in Kenyan Health Facilities |
Amount | $838,717 (USD) |
Organisation | World Bank Group |
Sector | Public |
Country | United States |
Start | 01/2021 |
End | 12/2021 |
Description | Development of smartphone application to help diagnose pneumonia in children |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-applicant on a pilot study to determine the feasibility of using videos recorded on smartphones to train machine learning algorithms to identify breathing patterns associated with pneumonia, severe pneumonia or alternative diagnoses such as malaria-induced acidosis or asthma. Leading protocol development and primary data collection and supporting analysis and reporting. |
Collaborator Contribution | Leading the training of machine learning algorithms, validation analysis and reporting. |
Impact | No outcomes yet. |
Start Year | 2019 |
Description | Saving Childrens Lives |
Organisation | Cornell University |
Department | Weill Cornell Medicine |
Country | United States |
Sector | Academic/University |
PI Contribution | Leading expansion of a multi-site intervention to integrate methods for high-quality routine paediatric clinical data collection into the Bugando Medical Centre - American Heart Association, Stanford University and Cornell University's Saving Children's Lives Program in Mwanza, Tanzania. |
Collaborator Contribution | Support for local stakeholder engagement and financial contribution towards setting up data collection, analysis and reporting platform, including costs to support data management activities |
Impact | Two stakeholder meetings held at Bugando Medical Centre in Mwanza, Tanzania. Senior leadership endorsed the proposed collaboration and approved the integration of the data collection tools into routine hospital health information system. |
Start Year | 2018 |
Description | Saving Childrens Lives |
Organisation | Stanford Medicine |
Country | United States |
Sector | Hospitals |
PI Contribution | Leading expansion of a multi-site intervention to integrate methods for high-quality routine paediatric clinical data collection into the Bugando Medical Centre - American Heart Association, Stanford University and Cornell University's Saving Children's Lives Program in Mwanza, Tanzania. |
Collaborator Contribution | Support for local stakeholder engagement and financial contribution towards setting up data collection, analysis and reporting platform, including costs to support data management activities |
Impact | Two stakeholder meetings held at Bugando Medical Centre in Mwanza, Tanzania. Senior leadership endorsed the proposed collaboration and approved the integration of the data collection tools into routine hospital health information system. |
Start Year | 2018 |
Description | BBC Radio Interview World Pneumonia Day 2018 |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Raised public awareness on pneumonia and child health in a radio interview with BBC News (Swahili Service). |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.facebook.com/BBCnewsSwahili/videos/303044896966893/?t=0 |
Description | Commemorating World Pneumonia Day 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | An audience of approximately 60 health professionals, students, policymakers and government implementing partners attended an evening event to commemorate World Pneumonia Day. Delivered a 30-minute presentation on the current implementation of the childhood pneumonia case management recommendations and recent technical updates. This was followed by an interactive question and answer session |
Year(s) Of Engagement Activity | 2018 |
URL | https://twitter.com/Kenyapaeds/status/1060798954802200576 |
Description | Interview for newspaper article |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Engaged in an interview with a leading media house on the burden of pneumonia in children and effective interventions for control. Article published in a local daily newspaper with nationwide circulation and international reach online. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.businessdailyafrica.com/datahub/Children-bear-brunt-of-elusive-pneumonia/3815418-5311622... |
Description | Led PneumoLight Campaign to mark World Pneumonia Day in Kenya |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Coordinated efforts in Kenya to illuminate one of more than 300 monuments across more than countries worldwide, increasing visibility about pneumonia and sharing educational material about the diagnosis and prevention of the disease. |
Year(s) Of Engagement Activity | 2023 |
URL | https://twitter.com/JustACTIONS/status/1594698931832864768 |
Description | Led policy dialogue on pneumonia with national stakeholders in Kenya |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Led a policy dialogue with national stakeholders in Kenya to mark World Pneumonia Day 2019. More than 30 participants contributed actively to a panel discussion and devised individual advocacy actions to stimulate commitment for increased investment in pneumonia prevention, control and treatment interventions. |
Year(s) Of Engagement Activity | 2019 |
URL | https://twitter.com/ProfMikeEnglish/status/1194988234683670528 |
Description | Nominated advisor on Lancet Global Health Commission on Medical Oxygen Security |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | The Lancet Global Health Commission on Medical Oxygen Security will shed light onto the burden of hypoxemia, how to define and measure oxygen access, which oxygen solutions work best in different settings, and how to generate the financing and political will to achieve transformational change. It will address all levels of care from home to hospital, all age groups from neonates to the elderly, all health conditions where hypoxemia is a risk, and all the ways in which access to oxygen can contribute to health system strengthening. Governments and global health and development agencies urgently need this information as they pivot from pandemic response to preparing for the next crisis and returning to the job of achieving the Sustainable Development Goals. |
Year(s) Of Engagement Activity | 2022,2023 |
URL | https://stoppneumonia.org/latest/lancet-global-health-oxygen-commission/ |
Description | Organised engagement activities at 10 study sites (Kenya) to commemorate World Pneumonia Day 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Held engagement activities at 10 study hospitals across Kenya to mark World Pneumonia Day. The event targeted caregivers of hospitalised children and staff working at the hospitals. More than 300 individuals participated and feedback indicated heightened awareness on pneumonia and the key interventions for prevention, control and treatment |
Year(s) Of Engagement Activity | 2019,2020 |
URL | https://twitter.com/KEMRI_Wellcome/status/1194224868537094146 |
Description | Standard Newspaper article on childhood pneumonia |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Raised public awareness on pneumonia and child health through an interview with a reporter from Standard Media Group Limited - one of the leading media houses in Kenya. The article was published in a newspaper article on 12 November 2018. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.standardmedia.co.ke/article/2001302358/kenya-still-struggling-with-killer-pneumonia-desp... |