A double blind randomized community-based trial of amoxicillin versus placebo for non-severe pneumonia in children aged 2-59 months in Pakistan
Lead Research Organisation:
Aga Khan University
Department Name: Paediatrics
Abstract
Pneumonia is a major cause of illness and death in children in low-income countries. With a view to decreasing death from pneumonia, the World Health Organization and UNICEF developed the the Integrated Management of Childhood Illness (IMCI) algorithm which simplifies management of common childhood illnesses such as pneumonia and diarrhoea into different levels of severity for determining the most appropriate case management by primary healthcare providers. Many pneumonia cases are categorized as non-severe pneumonia (defined as fast breathing above the specified age cut-off for respiratory rates). As there is incomplete information regarding the cause of this type of "pneumonia" from primary care settings, treatment guidelines by WHO are dictated by culture information from hospital pneumonia cases which are different in severity and cause. Current WHO guidelines advocate the use of oral antibiotics for non-severe pneumonia. However, it is postulated that most non severe pneumonia not requiring hospitalization is of viral aetiology, thus does not require antibiotic treatment. The cost of antibiotic treatment for all children with pneumonia is high; an estimated US$ 200 million in South Asia & sub Saharan Africa alone. Since more than 60% of pneumonia is classified as non-severe, this puts a strain on already under-sourced programmes in low-income countries. Giving antibiotics where they confer no benefit also puts the child at risk of side effects and increases the risk of antimicrobial resistance in the community. This uncertainty forms the basis of the proposed study. We propose to show in a clinical trial that the outcome of children diagnosed with WHO defined non severe pneumonia is similar regardless of whether they receive antibiotics or not. This study will be conducted in five primary health care centres located in low income communities of Karachi, Pakistan, with extensive trial experience. Children identified to have fast breathing without any danger signs will be randomized to receive either three days of the WHO recommended oral antibiotic (Amoxicillin 45mg/kg/day divided twice daily) or matching placebo (a drug that will taste and look like the amoxicillin but will not have an active ingredient) by a study physician working at the primary health centre. The assignment of the antibiotic amoxicillin or placebo to a child will be done using a computer generated randomization list in a manner that at the end of the trial, there are equal numbers of children in both arms of the trial. Based on the statistical calculations for sample size, we will need to assign 521 children to receive amoxicillin and the same number of children to receive placebo. All children will receive the antibiotic or placebo under supervision of the primary health care physician in the morning. Evening doses will be delivered by locally hired Community Health Workers (CHWs) visiting the children at their home. All children will be assessed again on day 3 by a study physician to see if the child's presenting sign of high respiratory rate has resolved or not. All children with persistently high respiratory rate and/or development of a new clinical sign indicating illness progression will be labelled a treatment failure. There will invariably be some children with treatment failure in both the treatment arms; we hypothesize that there will be equal number of treatment failures in both the groups i.e. around 7%. If we are able to show with the help of this trial that there is no added advantage of prescribing antibiotics to children with non-severe pneumonia we will develop an evidence base to revise the current WHO guidelines and thus reduce the financial burden on an already resource constrained health system and also decrease out of pocket expenses for families. In the long term this will have implications for decreasing global antimicrobial resistance to antibiotics.
Technical Summary
The WHO IMCI algorithm is designed for use in primary healthcare facilities in low-income countries to improve case management of common childhood illnesses, including pneumonia. It defines non-severe pneumonia as follows- a respiratory rate of 50 breaths/ min or more in infants, or respiratory rate of 40 breaths/ min or more in children 12-59 months irrespective of presence of wheeze and without any danger signs present. The current treatment guidance in low HIV-endemic areas is of a three day course of oral amoxicillin. This recommendation for empiric antibiotic use in non-severe lower respiratory tract illness, which is usually viral, has been questioned in the context of the poor specificity of pneumonia diagnosis in IMCI and the increasing use of vaccines against common bacterial respiratory pathogens. The main objective of the trial is to evaluate if amoxicillin therapy in children aged 2-59 months with non-severe pneumonia at primary health centres, is equivalent to placebo. We also aim to evaluate predictors of treatment failure and the association with particular aetiologies. We will conduct a two arm double blinded randomised trial in which children in reference arm will receive oral Amoxicillin 45 mg/kg/day in two divided doses for three days while children in the comparison arm will receive an inert placebo. Those at greater risk of bacterial pneumonia and asthmatics will be excluded. Both groups will be followed for treatment failure up to day 3 (primary outcome). Per protocol analysis (to avoid a beta error) of outcomes will be undertaken to compare proportional hazards of treatment failure by allocation group. If equivalence (a difference in failure rates of < 5% between groups) is proven, a basis for revision of the current guidelines can be proposed, thus reducing financial burden on both an already resource constrained health system and poor caregivers. In longer term this will have implications for decreasing antimicrobial resistance.
Planned Impact
The proposed study is projected to have both academic and societal/economic impact.
Direct Beneficiaries: The local population will be direct beneficiaries of this research. These include locally resident community health workers. Employment of these women will improve their common knowledge regarding identification of childhood illnesses and their management which will help inculcate awareness among the community in general. It will also add to their monetary well-being. With economic prosperity they will be able to contribute meaningfully to their societies thus adding to their own social welfare. These benefits can be realized in a very short term but will also have long term impact with regards to welfare and empowerment of the locally hired Community Health Workers and enable them to contribute to the health and well-being of their community.
The primary health care physicians will be trained in the management of children in conformity with the World Health Organization's Integrated Management of Childhood Illnesses (IMCI). This will result in wider implementation of these WHO guidelines and will systematically address the most important causes of death and illness among children in these communities. In addition to focus on treatment of pneumonia, it will also provide an opportunity for, and emphasize important preventive interventions such as immunization and improve infant and child nutrition, including breastfeeding.
The results of this trial will help to rationalize the use of antibiotics and thus decrease the out of pocket expenses for the caregivers of these children. The children will also be saved from the undesirable side effects of the antibiotics including the long-term deleterious effects on the native gut micro-biota that may impair growth and nutrition subsequently resulting in altered immune processing that precipitates a vicious cycle of recurrent infections.
The communities in the study area will also benefit from the research as awareness will be fostered regarding signs of disease in children and their prevention and care.
Indirect beneficiaries: This study will help to fill the knowledge gap that exists regarding the usefulness of antibiotics for management of non-severe pneumonia in children two months to five year old, which is postulated to have a viral aetiology in majority of the cases. Rationalizing antibiotic use will reduce the burden on the health care system. It becomes even more important in the context of low income developing countries which have limited and scarce resources with competing priorities. There will be significant economic implications and consequences for the global problem of emerging antibiotic resistance. The results of this study can be used to inform a revision of the policy of empiric antibiotic use for children with isolated fast breathing, classified as non-severe pneumonia by World Health Organization (WHO), residing in HIV non endemic countries. This will increase the effectiveness of the public health care system in the developing countries. These benefits can be realized in a very short duration after the successful implementation of the policy at local, regional and international level. The use of naso-pharyngeal aspirates to detect aetiology of non-severe pneumonia within a trial and their relation with treatment outcomes will provide new insights into the role of organisms especially common viruses in the outcomes of non-severe pneumonia.
Direct Beneficiaries: The local population will be direct beneficiaries of this research. These include locally resident community health workers. Employment of these women will improve their common knowledge regarding identification of childhood illnesses and their management which will help inculcate awareness among the community in general. It will also add to their monetary well-being. With economic prosperity they will be able to contribute meaningfully to their societies thus adding to their own social welfare. These benefits can be realized in a very short term but will also have long term impact with regards to welfare and empowerment of the locally hired Community Health Workers and enable them to contribute to the health and well-being of their community.
The primary health care physicians will be trained in the management of children in conformity with the World Health Organization's Integrated Management of Childhood Illnesses (IMCI). This will result in wider implementation of these WHO guidelines and will systematically address the most important causes of death and illness among children in these communities. In addition to focus on treatment of pneumonia, it will also provide an opportunity for, and emphasize important preventive interventions such as immunization and improve infant and child nutrition, including breastfeeding.
The results of this trial will help to rationalize the use of antibiotics and thus decrease the out of pocket expenses for the caregivers of these children. The children will also be saved from the undesirable side effects of the antibiotics including the long-term deleterious effects on the native gut micro-biota that may impair growth and nutrition subsequently resulting in altered immune processing that precipitates a vicious cycle of recurrent infections.
The communities in the study area will also benefit from the research as awareness will be fostered regarding signs of disease in children and their prevention and care.
Indirect beneficiaries: This study will help to fill the knowledge gap that exists regarding the usefulness of antibiotics for management of non-severe pneumonia in children two months to five year old, which is postulated to have a viral aetiology in majority of the cases. Rationalizing antibiotic use will reduce the burden on the health care system. It becomes even more important in the context of low income developing countries which have limited and scarce resources with competing priorities. There will be significant economic implications and consequences for the global problem of emerging antibiotic resistance. The results of this study can be used to inform a revision of the policy of empiric antibiotic use for children with isolated fast breathing, classified as non-severe pneumonia by World Health Organization (WHO), residing in HIV non endemic countries. This will increase the effectiveness of the public health care system in the developing countries. These benefits can be realized in a very short duration after the successful implementation of the policy at local, regional and international level. The use of naso-pharyngeal aspirates to detect aetiology of non-severe pneumonia within a trial and their relation with treatment outcomes will provide new insights into the role of organisms especially common viruses in the outcomes of non-severe pneumonia.
Organisations
- Aga Khan University (Lead Research Organisation)
- World Health Organization (WHO) (Collaboration)
- Karolinska Institute (Collaboration)
- Bill & Melinda Gates Foundation (Collaboration)
- PATH (Collaboration)
- Malaria Consortium (Collaboration)
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) (Collaboration)
- JustActions (Collaboration)
Publications
Ginsburg AS
(2021)
Lung ultrasound patterns in paediatric pneumonia in Mozambique and Pakistan.
in ERJ open research
Ginsburg AS
(2021)
Serial lung ultrasounds in pediatric pneumonia in Mozambique and Pakistan.
in Scientific reports
Ginsburg AS
(2021)
Performance of lung ultrasound in the diagnosis of pediatric pneumonia in Mozambique and Pakistan.
in Pediatric pulmonology
Jehan F
(2020)
Randomized Trial of Amoxicillin for Pneumonia in Pakistan.
in The New England journal of medicine
Jehan F
(2019)
Should fast breathing pneumonia cases be treated with antibiotics? The scientific rationale for revisiting management in Low and Middle income countries.
in International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
Jehan F
(2016)
A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP).
in BMC infectious diseases
Kerai S
(2019)
A Community-Based Survey on Health-Care Utilization for Pneumonia in Children in Peri-Urban Slums of Karachi, Pakistan.
in The American journal of tropical medicine and hygiene
Lenahan JL
(2018)
Multicentre pilot study evaluation of lung ultrasound for the management of paediatric pneumonia in low-resource settings: a study protocol.
in BMJ open respiratory research
Title | Video recording of clinical signs of illness in children under 5 years of age |
Description | Signs of illnesses as observed by physicians e.g. fast respiratory rate, chest indrawing etc are recorded on film. An archive has been created of about 500 videos. This a rich bank for teaching and training. |
Type Of Art | Film/Video/Animation |
Year Produced | 2014 |
Impact | Improved patient care and teaching. |
Description | Exploratory meeting to review new evidence for Integrated Management of Childhood Illness (IMCI) danger signs |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Publication: Exploratory meeting to review new evidence for Integrated Management of Childhood Illness (IMCI) danger signs |
URL | https://www.who.int/maternal_child_adolescent/documents/imci-meeting-report-new-evidence/en/ |
Description | Guideline Development for WHO : Provision of azithromycin to infants or young children without diagnosed infections, as a means to promote child survival |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
URL | https://www.who.int/maternal_child_adolescent/guidelines/development/provision-of-azithromycin-to-in... |
Description | IMCI Refresher Training |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | IMCI Refresher Training-2017 |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Refresher/training on the Integrated Management of Childhood Illness |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | 30 primary healthcare physicians practising in 5 peri-urban slums of Karachi, Pakistan were given training and refresher training on the Integrated Management of Childhood Illnesses. This has led to improved clinical services to a catchment population of approximately 28,000 children under 5 years of age. |
Description | Technical Advisory Group |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Impact | WHO-UNICEF technical specifications and guidance for oxygen therapy devices |
URL | https://www.who.int/medical_devices/publications/tech_specs_oxygen_therapy_devices/en/ |
Description | Evaluation of impact of lung ultrasound (LUS) on management of pneumonia in low-resource settings, and feasibility, usability and acceptability of this technology: A pilot study |
Amount | $500,000 (USD) |
Funding ID | OPP1157370 |
Organisation | Bill and Melinda Gates Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start |
Description | Randomized Equivalence trial of Amoxicillin Versus Placebo in Pneumonia |
Amount | $440,719 (USD) |
Funding ID | OPP1158281 |
Organisation | Bill and Melinda Gates Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 03/2017 |
End | 05/2018 |
Description | Additional sample collection for the trial |
Organisation | Bill and Melinda Gates Foundation |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | as above |
Collaborator Contribution | As above |
Impact | We received a grant for enrolling additional samples for this trial. |
Start Year | 2017 |
Description | Global Forum on Childhood Pneumonia |
Organisation | JustActions |
Sector | Charity/Non Profit |
PI Contribution | Participated at the forum as a member of the global coalition to reignite the agenda for reducing pneumonia deaths. |
Collaborator Contribution | RETAPP was presented at the forum, leading to discusssion around challenges in diagnosis of pneumonia. |
Impact | 1.Invited commentary in CHEST journal for world pneumonia day |
Start Year | 2020 |
Description | HBGDki |
Organisation | Bill and Melinda Gates Foundation |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Shared data on key variables with Healthy Birth Growth and Development Knowledge Integration group. The objective is to pool data with other pneumonia studies to allow risk prediction of treatment failure in pneumonia. |
Collaborator Contribution | Shared the workflow |
Impact | 1, Signing of agreement 2. In person meeting |
Start Year | 2018 |
Description | Harmonization of RETAPP with ITIP ( Innovative Treatments in Pneumonia ) |
Organisation | PATH |
Country | Global |
Sector | Charity/Non Profit |
PI Contribution | PATH had been funded by BMGF for ITIP trial whereby they will be conducting a trial of fast breathing pneumonia very similar to ours in rural Malawai, Africa The group was interested in armonization of methods and outcomes i order to have comparable results that can better impact policy. WE have helped PATH in shaping their study standard operating procedures by sharing our inclusion/exclusion signs and study outcome. We also have a few shared members on the DSMB. |
Collaborator Contribution | PATH has also hamonized their standard operating procedures with ours which will greatly improve the value of our study as the analysis can also be pooled. |
Impact | Standard Operating procedures of RETAPP and ITIP harmonized |
Start Year | 2014 |
Description | Peer review on a proposal |
Organisation | Bill and Melinda Gates Foundation |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Peer review on a proposal |
Collaborator Contribution | I reviewed a proposal for a trial submitted by WHO. |
Impact | I reviewed a proposal for a trial submitted by WHO. |
Start Year | 2017 |
Description | Pneumonia research priorities expert review panel |
Organisation | International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) |
Country | Bangladesh |
Sector | Public |
PI Contribution | research prioritisation process for paediatric pneumonia |
Collaborator Contribution | Same |
Impact | Ranking of research priorities and discussed the way forwards to disseminate - attract donors and publication |
Start Year | 2020 |
Description | Pneumonia research priorities expert review panel |
Organisation | Karolinska Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | research prioritisation process for paediatric pneumonia |
Collaborator Contribution | Same |
Impact | Ranking of research priorities and discussed the way forwards to disseminate - attract donors and publication |
Start Year | 2020 |
Description | Pneumonia research priorities expert review panel |
Organisation | Malaria Consortium |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | research prioritisation process for paediatric pneumonia |
Collaborator Contribution | Same |
Impact | Ranking of research priorities and discussed the way forwards to disseminate - attract donors and publication |
Start Year | 2020 |
Description | Respiratory rate cutoffs for fast breathing pneumonia |
Organisation | World Health Organization (WHO) |
Country | Global |
Sector | Public |
PI Contribution | Attended a meeting to discuss the above. |
Collaborator Contribution | This is work in progress. We hope to identify new cutoffs for defining fast breathing pneumonia. |
Impact | We will be participating in a systematic review. |
Start Year | 2017 |
Description | Awareness related to vaccination |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Imparted by physicians at all sites for field workers in December 2016 and January 2017 and subsequent quiz was taken to assess their knowledge |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Blog in Newspaper |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | "Flu cases and deaths are on the rise in Pakistan-but should we be alarmed?" |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.dawn.com/news/1383308/flu-cases-and-deaths-are-on-the-rise-in-pakistanbut-should-we-be-a... |
Description | ISID Conference Hyderabad |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The research manager of RETAPP visited Hyderabad, India and presented three posters on RETAPP at the 17th International Congress on Infectious Disease (ICID), Hyderabad India 2-5 March 2016 1. Randomized equivalence trial of amoxicillin versus placebo for fast breathing pneumonia (RETAPP) S. Kerai, I. Nisar , B. Balouch , F. Aziz , F. Jehan 2. Seasonal drivers of WHO defined fast breathing pneumonia - impact of viral activity in the nasopharyngeal niche' B. Baloch, S. Kerai, I. Nisar, N. Brown, F. Aziz, F. Jehan 3. Microbead array based technology for detection and quantitation of viral respiratory pathogens associated with pneumonia among children F. Aziz, S. Kerai, S. Qureshi, I. Nisar, N. Brown, F. Jehan |
Year(s) Of Engagement Activity | 2012,2016 |
URL | http://www.isid.org/icid/Downloads/17thICID_Poster.pdf |
Description | Interview |
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 | Public/other audiences |
Results and Impact | Featured guest on BBC program "Sairbeen" on vaccination |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.facebook.com/AKUPakistan/posts/immunisation-is-not-just-the-governments-job-but-a-shared... |
Description | Interview |
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 | Invited guest to speak on childhood vaccination in Mukamal Clinic at FM107 |
Year(s) Of Engagement Activity | 2018 |
Description | Interview in news paper |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Urdu Newspaper Interview on Vaccines |
Year(s) Of Engagement Activity | 2019 |
Description | Oped |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Vaccine Concerns |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.dawn.com/news/1400928/vaccine-concerns |
Description | Pneumonia awareness week |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | • Pneumonia awareness week was celebrated in last week of November 2015 • Pneumonia awareness was spread through posters and pictorials message in local language. - The idea was to create awareness regarding prevention of pneumonia and its danger sign among community heath workers • Posters were pasted at each study site where RETAPP study is being conducted for 2 weeks. • Quiz was taken to assess knowledge. • Gifts were given to winners. |
Year(s) Of Engagement Activity | 2015 |
Description | Pneumonia day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | Chart competition among CHWs in month of November2016. 41 Field workers participated of them 12 received prize for outstanding work. |
Year(s) Of Engagement Activity | 2016 |
Description | Press Briefing |
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 | press conference at the Karachi Press Club organised by the Medical Microbiology and Infectious Diseases Society of Pakistan (MMIDSP), |
Year(s) Of Engagement Activity | 2019 |
Description | Seminar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Deep Breaths: Childhood Pneumonia arranged in collaboration with PPA and MMIDSP |
Year(s) Of Engagement Activity | 2019 |
Description | Seminar |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Speaker at Seminar Arranged by Patients Helping Hands on Pneumonia prevention |
Year(s) Of Engagement Activity | 2017 |
Description | Training on danger signs for pneumonia |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Imparted by physicians at all sites for field workers for awareness and recognition of danger signs. At the end of the training community health workers made posters and did a presentation on their understanding of danger signs and were assessed by physicians. |
Year(s) Of Engagement Activity | 2017 |