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TWO ON CAUSES OF CHILDHOOD PNEUMONIA

Sunday, 11th of March 2012

•  TWO ON CAUSES OF CHILDHOOD PNEUMONIA IN AFRICA

Public release date: 8-Mar-2012

Contact: Julie Younkin
jbuss@jhsph.edu
410-340-9784
International Vaccine Access Center

7-country study examining the causes of childhood pneumonia outlined

New insight and understanding into 1 of the largest studies ever conducted on the causes of pneumonia among children in the developing world

(BALTIMORE, MD.) – The scientific journal Clinical Infectious Diseases has released its March Special Supplement focusing entirely on the research design of and pilot data from the Pneumonia Etiology Research for Child Health (PERCH) Project, which seeks to identify the causes of pneumonia among the world's most vulnerable populations. PERCH, led by the International Vaccine Access Center (IVAC) at the Johns Hopkins Bloomberg School of Public Health in collaboration with 7 research centers worldwide, is the largest and most comprehensive study of the etiology of childhood pneumonia conducted in more than 20 years. Pneumonia is the leading cause of death among children under age five, but while the disease is easy to recognize, the causes of pneumonia, which claims the lives of approximately 1.6 million children each year, are not.

"This supplement provides a unique opportunity to share our rigorous, deliberative and inclusive process in designing the PERCH study. We hope that our work can benefit other researchers and result in a greater degree of standardization in child pneumonia research," said Orin Levine, lead investigator on the study and professor of International Health at Johns Hopkins Bloomberg School of Public Health. "In learning more about the causes of pneumonia, we can design better treatments, diagnostics and vaccines to save children's lives."

PERCH, which is made possible by a grant from the Bill & Melinda Gates Foundation, will enroll up to 6,000 children 1-59 months old with severe or very severe pneumonia and a similar number of healthy children from seven selected study sites in order to understand the interplay between risk factors and infection by deadly viruses and bacteria. The seven study sites represent diverse geographic areas and disease ecologies that are expected to face the highest pneumonia disease burden in the coming decades and include Thailand, Bangladesh, The Gambia, Kenya, Mali, South Africa and Zambia.

PERCH was designed with the consultation of 16 external pneumonia experts over the course of 18 months. These experts informed the epidemiologic, clinical, laboratory and statistical design components of the study. Investigators from the seven study sites also contributed to the study design, and in addition ensured local relevance and feasibility.

The timing of PERCH is crucial as the pneumonia landscape has changed significantly since the last major multi-site research studies were conducted by the Board of Science and Technology for International Development (BOSTID) in the 1980s. Bacterial pathogens, especially Haemophilus influenzae and Streptococcus pneumoniae, were recognized to be the major etiologies of pneumonia mortality. Consequently, treatment and prevention strategies have focused primarily on targeting these agents. Since the BOSTID studies, the world has experienced the HIV pandemic, increased malaria control and a scaled up effort to introduce pneumococcal and Hib conjugate vaccines, as well as advancements in scientific technologies. The results of the PERCH study, strategically designed to reflect the expected epidemiological situation in 2015 and beyond, will provide important evidence to guide the next generation of pneumonia prevention and treatment approaches.

"As the world's epidemiologic settings change, we must stay ahead of the next challenge so we do not lose ground in the fight to reduce child mortality," said Dr. Katherine O'Brien, co-principal investigator of PERCH, and professor of International Health at Johns Hopkins. "PERCH will study and evaluate pneumonia and its causes using previously unavailable innovative and more sensitive diagnostic tools."

The Clinical Infectious Diseases supplement will include 15 articles providing the project's scope and methodology, while addressing the rationale behind the approaches to and design components of PERCH. In addition, the supplement provides results from two PERCH pilot projects in Kilifi, Kenya and Noumea, New Caledonia, which helped to inform the design of the larger study. Also included in the supplement is a review of previous and other ongoing pneumonia etiology studies (88 studies published from 2000 to June 2010 plus 65 unpublished studies), which reinforced the need for standardization of methods and analyses for present and future etiology studies in order to optimize their cumulative potential.

Results of the PERCH project are expected to become available in 2014. The study protocol, case report forms and standard operating procedures are available online at http://www.jhsph.edu/ivac/perch.html.

PERCH Collaborators

Collaborating institutions include: the University of Witwatersrand, Johannesburg and the National Institute for Communicable Diseases, Sandrigham, in South Africa; Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Programme in Kilifi, Kenya; Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA; Centre pour le Développement des Vaccins, Mali (CVD-Mali) in Bamako, Mali; the Thailand Ministry of Public Health; Centers for Disease Control and Prevention, Atlanta, Georgia, USA; Thailand Ministry of Public Health (MOPH) - U.S. Centers for Disease Control and Prevention (CDC) Collaboration in Nonthaburi, Thailand; Boston University Center for Global Health and Development, Boston, MA, USA; Boston University at the University Teaching Hospital of Lusaka, Zambia; the Medical Research Council Gambian Unit, Fajara and Basse, The Gambia; the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) in Dhaka, Bangladesh; the University of Otago and Canterbury Health Laboratories in Christchurch, New Zealand.

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The International Vaccine Access Center (IVAC) has as its mission to accelerate global access to life-saving vaccines through development and implementation of evidence-based policies. Drawing upon expertise and faculty from the Johns Hopkins Bloomberg School of Public Health, IVAC works to strengthen the evidence base for vaccine introduction including undertaking targeted, policy-focused research in areas such as disease burden, cost-effectiveness, vaccine policy, demand forecasting and disease epidemiology. For more information, please visit www.jhsph.edu/ivac.

 

 

Expert Review of Respiratory Medicine

December 2011, Vol. 5, No. 6, Pages 731-733 , DOI 10.1586/ers.11.74

(doi:10.1586/ers.11.74)

Rationale and expectations of the Pneumonia Etiology Research for Child Health (PERCH) study

Richard A Adegbola^† & Orin S Levine

† Author for correspondence

 

The Pneumonia Etiology Research for Child Health (PERCH) project is an ambitious attempt at improving our understanding of the changing etiology of pneumonia given increasing access to effective vaccine utilization against the two major bacterial pathogens of pneumonia in children and recent advances in general child survival strategies [1].

Pneumonia is the leading global killer of children under the age of 5 years, with an estimate of 1.575 million deaths in 2008 [2], accounting for one in five deaths in children under 5 years of age. More than 155 million new episodes of clinical pneumonia occur in children under 5 years of age annually with 97% of these in the developing world [3]. Childhood pneumonia deaths are declining since the last decade [2,4] following intensified global efforts to increase access to effective vaccination and treatment management, but pneumonia is still an important cause of serious pediatric illness and will remain so in the nearest future.

Pneumonia has remained the ‘forgotten killer of children’ for several decades owing to its apparent lack of attention and funding [5]. Reducing the burden of pneumonia mortality is essential to reaching the Millennium Development Goals (MDGs), and the Bill & Melinda Gates Foundation is pursuing a number of initiatives aimed at reducing childhood mortality and morbidity due to pneumonia, from diagnostics to vaccines and epidemiology to economics, and evaluation of innovative antimicrobial treatment options.

Pneumonia is a syndrome but it is yet unclear what pathogens are responsible for a large fraction of pneumonia deaths, which creates an important knowledge gap. The leading risk factors contributing to pneumonia incidence are lack of exclusive breastfeeding, undernutrition, exposure to indoor air pollution, low birth weight, crowding and absence of immunization. In countries with weak health systems and limited access to care, far too many of the cases of severe pneumonia progress to death. In order to achieve the MDG 4 child health target of reducing pneumonia mortality by two-thirds between 1990 and 2015, it will be essential to scale-up the use of the available tools for prevention and treatment, as directed by the 2010 World Health Assembly resolution calling for more concerted efforts toward protecting children from pneumonia [6].

Early etiology studies identified Streptococcus pneumoniae and Haemophilus influenzae type B (Hib) as the main bacterial pathogens associated with severe and/or fatal childhood pneumonia [7,8]. A more representative epidemiology study covering Asia, Africa and Latin America initiated by the Board of Science and Technology for International Development (BOSTID) at the US National Academy of Sciences in the early 1980s also identified pneumococcus and Hib as major bacterial causes of childhood deaths due to pneumonia [9]. These studies made important contributions to the development and implementation of prophylactic vaccines and treatment strategies for these agents. Despite their success, there were certain limitations to the BOSTID studies, including the lack of standardization of case definitions, insensitive diagnostics and the challenges with ascertaining pneumonia causality.

Several important changes have also occurred since those studies. Hib and pneumococcal conjugate vaccines, which can protect against pneumonia caused by these pathogens, have been developed and are showing promising effects [10,11]. With funding from the GAVI Alliance, access to these new vaccines is being accelerated for resource-poor countries and this is expected to lead to dramatic reductions in Hib and pneumococcal pneumonia, consequently changing the etiology of pneumonia [12,13]. HIV-infection has become widespread and this increases the frequency of pneumonia and modifies the distribution of pneumonia pathogens [14]. Moreover, substantial changes in nutrition, living conditions (e.g., urbanization) and access to care are likely to modify transmission of agents and the natural history of infection.

On the diagnostic side, there are new molecular platforms with increased sensitivity of pathogen detection [15] that can now be deployed. It is crucial that the advances in molecular tools are explored to monitor the evolving etiology of pneumonia and improve our efforts to develop new approaches and algorithms for preventing, diagnosing and treating childhood pneumonia.

Studying pneumonia etiology is complicated by various epidemiologic and microbiologic factors:

	• Pneumonia, an infection of the lung tissue, ranges in severity and outcome;
	• The pathogens causing pneumonia and the distribution of those pathogens vary according to severity of the episode. The distribution of pathogens causing mild cases of pneumonia is not the same as that causing cases resulting in death;
	• Obtaining biologic samples for etiologic testing from the site of infection, the lung, is generally not possible;
	• Many pathogens causing pneumonia are commonly identified in humans who do not have pneumonia;
	• Cases of pneumonia are commonly associated with infection by more than one infectious agent.

Thus, identification of a pathogen in a case of pneumonia does not necessarily mean that it is the cause of the illness and, conversely, failure to identify a pathogen does not mean it is absent. The result is the need to establish an etiologic diagnosis by considering multiple possible etiologies (exposures) as the cause of the pneumonia episode.

PERCH is a large, multicenter, case–control study to determine the etiology of pneumonia among children of less than 5 years of age. It is a 5-year study covering seven countries – five in Africa and two in Asia – that is designed to address some of the major limitations of past studies and to anticipate the prevailing epidemiologic patterns of the future. Seven research sites have been selected based on technical capacity, local epidemiology, demographics and status of Hib and pneumococcal conjugate vaccine immunization.

The PERCH project is sponsored by a grant from the Bill & Melinda Gates Foundation to the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health. The study will be carried out using standardized methods, collecting novel or uncommon specimens (e.g., induced sputum and post-mortem lung tissue) and applying advanced diagnostic techniques to address the potential for multiple possible etiologies. PERCH is primarily a hospital-based study because of the need to focus on severe and potentially fatal pneumonia and because this is the setting in which the most important diagnostic procedures can be performed and specimens can be collected (e.g., blood, lung aspirates, induced sputum and post-mortem tissue). Five sites will also link cases with population denominators, providing pathogen-specific pneumonia incidence estimates as well.

The clinical protocol and study methods for PERCH study have been finalized, based on expert input and results from two pilot sites and are available to the research community on the internet at [101]. Multiplex PCR assays were systematically evaluated in the laboratory and ultimately a final platform from FastTrack Diagnostics (Luxembourg) was selected based on a careful evaluation of costs, logistics and provision of service support. Enrollment in PERCH began in August 2011 and participants are expected to be enrolled for 2 full years.

PERCH will provide etiology data that can be overlaid with incidence figures to produce an estimate of the incidence, by etiology, of pneumonia for each country, and permit the estimation of mortality rates by pathogen. These estimates will be valuable to a wide range of public health stakeholders. They will provide a firm evidence base for developing countries to take decisions on program priorities, for donors to focus investments in health, for developers of vaccines, drugs and diagnostics to target their efforts on new products, and for clinicians to reform protocols and best practice recommendations on empiric therapy regimens.

While PERCH is undoubtedly the largest multicountry pneumonia etiology study in two decades, it cannot be assumed that the diversity from various epidemiologic settings will be covered in studies undertaken in only seven countries. It is crucial to complement PERCH with results from other ongoing pneumonia studies or from those that have been recently concluded in several other developed and developing country settings. The challenges with this effort will include the use of a variety of clinical and laboratory methods, thus making comparability of results from these studies difficult for drawing more generalizable conclusions. Ultimately, the entire research community benefits when pneumonia etiology studies have acceptable and understandable levels of comparability in their methods. Thus, further efforts to harmonize the methods used in pneumonia etiology studies is an important next step and one that the whole community needs to participate in undertaking.

Financial & competing interests disclosure

RA Adegbola is an employee of the Bill & Melinda Gates Foundation. He is the senior project officer for the PERCH project; OS Levine is the project’s principal investigator. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

 

References

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1	WHO, UNICEF, the Hib Initiative, PneumoADIP. Global Action Plan for Prevention and Control of Pneumonia (GAPP). WHO Press, Geneva, Switzerland, 1–28 (2009).
2	Black​‌ RE, Cousens S, Johnson HL et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet375,1969–1987 (2010). [CrossRef] [Medline]
3	Rudan​‌ I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull. World Health Organ.86,408–416 (2008). [CrossRef] [Medline]
4	Lozano​‌ R, Wang H, Foreman KJ. Progress towards Millennium Development Goals 4 and 5 on maternal and child mortality: an updated systematic analysis. Lancet378(9797),1139–1165 (2011). [CrossRef] [Medline]
5	UNICEF, WHO. Pneumonia: the Forgotten Killer of Children. WHO Press, Geneva, Switzerland, 1–44 (2006).
6	World Health Assembly 63.24. Accelerated progress towards achievement of millennium development goal 4 to reduce child mortality: prevention and treatment of pneumonia. Presented at: 63rd World Health Assembly. Geneva, Switzerland, 17–21 May 2010.
7	Shann​‌ F. Etiology of severe pneumonia in children in developing countries. Pediatr. Infect. Dis.5,247–252 (1986). [CrossRef] [Medline] [CAS]
8	WHO. Technical bases for the WHO recommendations on the management of pneumonia in children at first-level health facilities. Programme for the control of acute respiratory infections. WHO Press, Geneva, Switzerland, 1–24 (1991).
9	Selwyn​‌ BJ. The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries. Coordinated Data Group of BOSTID Researchers. Rev. Infect. Dis.12(Suppl. 8),S870–S888 (1990). [CrossRef] [Medline]
10	Whitney​‌ CG, Farley MM, Hadler J et al. Decline in invasive pneumococcal disease after the introduction of protein–polysaccharide conjugate vaccine. N. Engl. J. Med.348,1737–1746 (2003). [CrossRef] [Medline]
11	Adegbola​‌ RA, Secka O, Lahai G et al. Elimination of Haemophilus influenzae type b (Hib) disease from The Gambia after the introduction of routine immunisation with a Hib conjugate vaccine: a prospective study. Lancet366,144–150 (2005). [CrossRef] [Medline]
12	Greenwood​‌ BM, Weber MW, Mulholland K. Childhood pneumonia – preventing the world’s biggest killer of children. Bull. World Health Organ.85,502–503 (2007). [CrossRef] [Medline]
13	Scott​‌ JA, English M. What are the implications for childhood pneumonia of successfully introducing Hib and pneumococcal vaccines in developing countries. PLoS Med.5,e86 (2008). [CrossRef] [Medline]
14	McNally​‌ LM, Jeena PM, Gajee K et al. Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study. Lancet369,1440–1451 (2007). [CrossRef] [Medline] [CAS]
15	Azzari​‌ C, Moriondo M, Indolfi G et al. Molecular detection methods and serotyping performed directly on clinical samples improve diagnostic sensitivity and reveal increased incidence of invasive disease by Streptococcus pneumoniae in Italian children. J. Med. Microbiol.57(Pt 10),1205–1212 (2008). [CrossRef] [Medline] [CAS]

Website

101	PERCH: pneumonia etiology research for child health. www.jhsph.edu/ivac/perch.html

Affiliations

Richard A Adegbola

Bill & Melinda Gates Foundation, Seattle, WA, USA. richard.adegbola@gatesfoundation.org

Orin S Levine

International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MA, USA