DRAFT: This module has unpublished changes.

Upper Respiratory Infection

Vignette

http://www.rockhopper.tv/programmes/389

In order to gain insight into the context of this problem, please view the above video from Rockhopper TV about pneumonia in the Philippines.

Introduction

Acute respiratory infections (ARIs) are the leading causes of child mortality worldwide, yet they are easily treatable. The number of child deaths across the globe was an estimated 8.8 million in 2008, with pneumonia claiming 1.6 million children’s lives, or 18% of all under 5 mortality (Black, 2010).

Because of their significant contribution to child mortality, ARIs should be a central focus in the discussion surrounding and implementation of maternal and child health programs. The fight against ARIs is not lost; recent research has shown that there is much that can be done to prevent and treat ARIs even in resource limited settings. Advances such as home based care and increased access to vaccines put us in an exciting position to make an impact on the lives of children across our globe.

This chapter addresses the epidemiology of ARI, its signs and symptoms, intervention strategies for prevention and treatment of ARI, and program management issues including monitoring and evaluation.  Finally, new developments and controversies in addressing ARI globally will be discussed.

Epidemiology

Acute respiratory infections (ARIs) continue to be the leading cause of acute illnesses worldwide and remain the most important cause of infant and young children mortality, accounting for about two million deaths each year and ranking first among causes of disability-adjusted life-years (DALYs) lost in developing countries (94.6 millions, 6.3% of total) (WHO, 2009). Early recognition and prompt treatment of pneumonia is life saving (WHO 2008). The following chart, represents the percentages of Global Distribution of cause-specific mortality among children under-five, pneumonia has the highest percentage (19%) among the other causes.

Global distribution of cause-specific mortality among children under-five, 2000-2003

Source: Child Health Epidemiology Resources Group (CHERG), with additional data from UNICEF

In the figure above the first cause of death is neonatal causes, however many neonatal deaths have been attributed to severe infections that have not been taken into account in these models. The exact proportion of pneumonia among these infections has not been clearly established because of the difficulties in distinguishing causes among severe infections in newborns. However, at least another 300 000 deaths caused by pneumonia are likely to occur worldwide during the neonatal period (Lawn 2006).

### Distribution of deaths from pneumonia and other causes in children aged less than 5 years, by WHO region

Source: AFR, African Region; AMR, Americas Region; EMR, Eastern Mediterranean Region; EUR, European Region; SEAR, South-East Asia Region; WPR, Western Pacific Region

Populations affected by ARI

Children under 5 years of age in developing countries are the most susceptible to infection and death from ARI, with the greatest risk of mortality occurring during the neonatal period (HaRP 2010). 20% of childhood deaths under-5 years of age are due to Acute Lower Respiratory Infections (ALRIs - pneumonia, bronchiolitis and bronchitis), of which 90% are due to pneumonia. Over two-thirds of pneumonia mortality occurs in Africa and South and Southeast Asia (USAID HaRP, 2006). Overall, in developing countries, infants and young children have 7-10 episodes of ARI per year, one tenth of which are severe enough to require hospitalization. Although most episodes are self-limiting infections of the upper respiratory tract, such as viral bronchitis and otitis media, they represent a huge economic burden to the public health system and increase the risk of progression to more severe disease (McCracken, 2000).

Etiology

Respiratory infections are caused by viruses or bacteria that manifest in any area of the respiratory tract, including the nose, middle ear, throat, larynx, air passages, and lungs. The main etiological agents responsible for ARI in children are Streptococcus pneumoniae (SP), Haemophilus influenzae (Hi), respiratory syncytial virus (RSV), Para Influenza Virus type 3 (PIV-3), and Group B streptococcus in newborns (WHO 2005). Even though the pathogens vary with the child’s age, their immune condition, and the environment, most ARI episodes are caused by viruses. (Childinfo, 2009). However, the etiology of ARI varies according to certain factors. In developing countries bacterial infection plays a greater role in causing pneumonia than it does in developed countries. Also, the main causative agent of pneumonia in areas where HIV prevalence is high, pneumocystis jiroveci, has a higher proportion of gram-negative bacterial organisms (USAID HaRP 2006). Early recognition of symptoms and the use of affordable antibiotics can prevent 30 to 60% of ARI related deaths (Child Health Research Project)

Transmission and Risk Factors

Pneumonia can be spread in a number of ways. The viruses and bacteria that are commonly found in a child's nose or throat can infect the lungs if they are inhaled. They may also spread via air-borne droplets from a cough or sneeze. In addition, pneumonia may spread through blood, especially during and shortly after birth. More research needs to be done on the different pathogens causing pneumonia and the ways they are transmitted, as this has critical importance for treatment and prevention (WHO, 2010)

The risk of developing an ARI, having a progressive disease and/or death from the disease is increased with the presence of certain risk factors: low birth weight, absence of breast-feeding, malnutrition, measles, vitamin A deficiency, indoor air pollution, smoking and HIV infection, poor hygiene and missing EPI vaccination. In developing countries, nasopharyngeal transmission rates are twice as high as in developed countries due to higher exposure to these risk factors which increases bacterial colonization of the upper airways found early on in nursing infants. This explains the higher frequency of bacterial ARI in poor communities. For example, the incidence of pneumonia in a developing country is 10 times higher than that in the United States (McCracken, 2000) ARI related mortality is higher during infancy and particularly the neonatal period where more than half of the deaths occur (USAID 2008)

Pathophysiology

Pneumonia is an inflammation of the lungs caused by bacteria, viruses, or chemical irritants. It is a serious infection or inflammation in which the air sacs fill with pus or other liquid.

Pulmonary infection occurs when the normal defense mechanisms are overcome and germs from an inhaled contaminant reach the peripheral air passages.  This phenomenon causes edema in the bronchia, bronchioles and alveoli, along with leukocyte infiltration. The congestion acts as culture medium for bacteria to grow and replicate.  This process may stay circumscribed to an area or extend along the lungs.  As consolidation takes place, the respiratory function alters the vital capacity and the distensibility of the airways decreases. The blood flow and ventilation of the involved areas is affected, altering the ventilation/perfusion relationship and resulting in decreased oxygenation and increased respiratory and cardiac workloads. When the effort to inhale increases, retraction of the lower part of the thorax occurs causing a perceptible horizontal extension of the ribs, a reliable sign of a severe restriction of pulmonary function which increases the risk of child death from pneumonia (McCracken, 2000.)

Pneumonia is the leading cause of death among respiratory ailments and nearly 75% of these deaths occur in infants under 1 year of age (USAID 2008).  The devastating impact of ARI is apparent not only due to its high mortality, but its considerable rate of morbidity and co-morbidity as well.  Low birth weight, malnourished and non-breastfed children and those living in overcrowded conditions are at higher risk of getting pneumonia. These children are also at a higher risk of death from pneumonia.  The health research approach shows that every ARI death contributes to 2-3 further deaths.

Pneumonia, for example, considerably worsens the morbidity associated with other diseases such as malnutrition, Vitamin A deficiency, measles, and HIV infections in children. Such co-morbidity has a synergistic effect on mortality. For example, the estimated case fatality rate of children who suffer from ARI and measles is approximately 62%. Excluding measles results in the proportion of death falling to 24% (WHO, 2005) Additionally, in HIV infected children, pneumonia represents the most common deadly initial manifestation of the disease (USAID, HaRP 2006)

The incidence of ARIs in children aged less than 5 years is estimated to be 0.29 and 0.05 episodes per child-year in developing and industrialized countries, respectively, which translates into 151 million and 5 million new episodes each year, respectively (Campbell, 2007)

Clinical presentation signs and symptoms

Because respiratory frequency is the most sensitive and reliable index for evaluating the presence and severity of ARI, it is the current method used by health delivering personnel. Training involves counting the respiratory rate (at rest) and observing the breathing pattern and general state of the infant or child. It is important to note, however, that several diseases can mimic the signs of ARI. For example, respiratory distress can be the presenting feature of up to 45% of malaria cases in areas with high prevalence of the disease, particularly in sub-Saharan Africa (USAID HaRP, 2006). Depending on the symptoms, the WHO  classifies pneumonia in: very severe pneumonia, severe pneumonia, pneumonia, and no pneumonia (WHO 2005).

It is over seven years since the Integrated Management on Child Ilnesess (IMCI) has been introduced. During this period, the Department of Child and Adolescent Health and Development (CAH) and many WHO partners have continued to support work to evaluate the performance and increase the evidence base for the technical guidelines.The technical updates provided in this document reflect the results from this work, coming from new research findings and technical consultations. The updates cover six areas, and the first one is about the diagnosis and treatment of severe and non-severe pneumonia. These guidelines give an organized tool to assess sick children from 2 months to 5 years. The following chart shows the integrated Management tool for pneumonia.

The complete IMCI guidelines can be downloaded in the following link:

Health, economic, and social impact of the problem

Research has shown that prevention and proper treatment of pneumonia could avert one million deaths in children every year. With proper treatment alone, 600 000 deaths could be avoided.

The cost of treating all children with pneumonia in 42 of the world's poorest countries is estimated at around US$600 million per year. Treating pneumonia in South Asia and sub-Saharan Africa – which account for 85% of deaths – would cost a third of this total, at around US$ 200 million. The price includes the antibiotics themselves, as well as the cost of training health workers, which strengthens the health systems as a whole. (WHO,2010)

Program Management

Treatment

The most effective intervention for ARIs is treatment with an appropriate, low-cost antibiotic such as cotrimoxazole, amoxicillin, ampicillin, and procaine penicillin. With antibiotic treatment, about 60% of ARI deaths could be prevented. However, both S. pneumoniae and H. influenzae have shown significant resistance to these standard antimicrobial drugs in the past decade. This poses a serious problem in both industrialized and developing countries (McCracken, 2000). New antibiotics, such as azithromycin, levofloxacin, or cefuroxime, are effective against drug resistant strains but are more costly, making them impractical for routine treatment in the developing world (Merck, 2008).

While treatment with antibiotics is the cornerstone of ARI intervention, it is also important that health workers encourage appropriate health-seeking behavior for caretakers of children. According to UNICEF, only 53% of caretakers seek care for their children with ARI symptoms. This lack of access has several contributing factors, including:

• Local health facilities are not well stocked (Acharya and Cleland, 2000)
• Distance and travel time to a health facility (Simoes et al, 2003)
• Cost, cultural reasons, and lack of child care for other children at home (Peterson et al, 2004)

These problems with referral for pneumonia have led to several recent studies trying to make treatment available at the home for even severe pneumonia. This will be discussed in more detail in the section on controversies.

Prevention

The best prevention of ARI, like many diseases, is vaccination. The vaccines for diphtheria, pertussis, and tetanus, regularly included in immunization programs, are very effective in preventing some infections that can lead to ARI.  Vaccines also exist for H. influenzae serotype b (Hib) and S. pneumoniae (pnuemococcus) infection, and are frequently used in the United States and other developed countries (Dagan, 2010).

photo credit: GAVI Alliance

Studies in the Gambia have demonstrated the efficacy of a pneumococcal conjugate vaccine, substantially improving child survival. The Hib vaccine trial, also conducted in the Gambia, reduced the occurrence of disease caused by Hib despite irregular supply of the vaccine. Nevertheless, these vaccines are still considered too expensive for regular use in developing countries (LaForce and Sogunro, 2001).

Because primary prevention in the form of vaccination remains difficult in developing countries, many prevention efforts focus on reducing the environmental and behavioral factors that can lead to ARIs.  The most commonly targeted factors include:

• Malnutrition
• Vitamin A and zinc deficiency
• Low-birth weight
• Absence of breastfeeding
• Incomplete immunizations
• Poor hygiene
• Low socioeconomic status
• Indoor air pollution (including tobacco smoke and smoke from biomass-burning stoves)

To address dangerous co-morbidities resulting from these factors and others, the WHO introduced the Integrated Management of Childhood Illness (IMCI) (Ghimire et al, 2010). This approach trains health technicians and community health workers to assess and treat several childhood complications at once, and has been shown to reduce child mortality.

Future efforts of the IMCI include working to :

• improve the specificity of the diagnosis of non-severe pneumonia;
• limit unnecessary antibiotic use
• develop alternative antibiotic regimes for the management of severe pneumonia
• determine the appropriateness of fluid restriction in severe pneumonia
• monitor antimicrobial resistance among organisms responsible for pneumonia
• research the management of wheezing and of otitis media (WHO, 2008)

Technical Tools and Issues

In order to implement IMCI strategies, as well as more focused ARI prevention and treatment programs, several technical issues need to be considered. These include potential abuse and resistance to available antibiotics, vaccine development, and availability of oxygen and other essential tools in diagnosing and treating ARIs.

Antibiotic resistance

Within the past two decades, significant resistance to standard antibiotics has emerged for the two main respiratory bacteria, S. pneumonia and H. influenza type b.  Inappropriate use of antibiotics contributes to the development of resistance to standard low cost drugs. Often, health promoters will provide caretakers with antibiotics as a misguided form of prevention or to appease the client’s expectations. IMCI strategies that focus on promoting accurate diagnosis, case management and home treatment of early upper respiratory infections are helping to reduce inappropriate use of antibiotics (LaForce and Sogunro, 2001).

photo credit: The Lancet

Vaccines

More cost-effective ways of administering vaccinations is another technical concern. Apart from the standard DPT/DTaP vaccine against diphtheria, pertussis and tetanus, vaccines against Hib and pneumococcus exist and are very effective in HIV-negative children, but the high cost of procuring and storing these vaccines in resource poor settings has made them unrealistic for use in developing countries (WHO, 2005). The significant reduction in their efficacy among HIV-positive children presents an additional challenge communities with high HIV prevalence (Zar, 2004).

Resources

Other equipment and tools are essential for appropriate diagnosis and treatment. To effectively diagnose and treat ARI, clinics and rural dispensaries require stop watches, weighing scales, calculators, patient registers, and drug stock cards. In addition to receiving antibiotics, children with severe pneumonia and hypoxia may need oxygen therapy to prevent brain damage. However, the availability of oxygen in hospitals in developing countries is limited.

Management Issues

In addition to the above tools, there are a number of management issues surrounding strategies combating ARI, such as IMCI. To be considered properly trained, health workers should be able to use equipment correctly, recognize the signs of pneumonia in children, give correct doses of the oral antibiotic, refer severe cases when feasible, and instruct families on essential supportive measures (McCracken, 2000).  IMCI is designed to assure that health workers are properly trained, and that training is reinforced. Nevertheless, there are some considerable challenges in implementing and expanding IMCI. These include capacity building, structural changes within ministries of health, incorporating IMCI into ongoing district and national efforts to improve child health, and designing effective support and supervisory systems for health workers (Huicho et al, 2005).

Monitoring and Evaluation

Monitoring and evaluating ARI interventions at the individual, district, and national level is key to improved understanding of the changing epidemiology of pneumonia. Because monitoring must take place on several levels, a country-wide health information system is essential. Monitoring of ARI should flow roughly through the steps in the model that follows.

Some key indicators to monitor for improved ARI treatment and prevention include:

• % of caregivers who know that difficult or fast breathing is a sign to seek care immediately
• % of children under five with pneumonia taken to an appropriate health care provider
• % of under 5 deaths due to pneumonia
• % of children under 5 with pneumonia who received antibiotics (UNICEF/WHO, 2006)
• % of children prescribed and treated with an antibiotic of any class
• % prescribed and treated with cotrimoxazole
• % prescribed and treated with amoxicillin
• % treated with an antibiotic obtained over-the-counter
• % treated with a safe home remedy
• % consulting a community health worker
• % consulting a health facility (Holloway, 2009)

New Developments and Controversies

New Developments

In the last 100 years of public health history, vaccines have been by far the most effective tool in preventing communicable disease and death, and ARIs are no exception. Some of the most exciting innovations in ARI prevention surround new vaccine development for both bacterial and viral respiratory infections. For bacterial infections, pnueumocci are the major cause of mortality and morbidity related to ARI.  Currently the licensed pneumococcal conjugate vaccine, a 23-valent polysaccharide vaccine, induces good antibody responses to pneumocci for 60 to 70% of adults (National Center for Immunization and Respiratory Diseases, 2010). However, the response of this vaccine is unreliable in children under 2 years, nor has it been documented that maternal vaccination protects newborn infants against pnuemococcal disease. As such, better antibody levels need to be reached, especially for children less than 2 years old, for this vaccine to be effective in combating childhood ARI.

Other common bacterial causes of severe pneumonia include S. aureus, S. pneumoniae and H. influenzae type b (Hib). Vaccines currently exist for Hib and S. pneumoniae  and have been shown to be cost-effective interventions (Niessen, 2009). Although S. pneumoniae conjugate vaccine, a live attenuated influenza virus vaccine (administered as a intranasal spray) induces a higher level of antibody production in infants, this vaccine does not protect against a few serotypes (1 and 5) of S. pneumoniae that cause severe disease in developing countries.

Viruses, such as RSV and PIV, are another common cause of acute lower respiratory infections in children worldwide. RSV in particular is the most important cause of lower respiratory tract illness in infants and children worldwide (WHO, 2009). Development of RSV and PIV vaccines is ongoing, but has faced many challenges.  In the 1960s candidate vaccines were put into use, but ultimately failed due to negative immune responses in children which led to significant hospitalization and two infant deaths.  Vaccines contributing to more severe disease on subsequent exposure to the virus remains the largest obstacle to the generation of vaccines for viral ARIs (WHO, 2009).

While some effective vaccines are available, barriers to their distribution and use still exist.  Chief among these is the issue of financing the development and production of these often expensive tools.  In the hopes of overcoming financial barriers to vaccines distribution, the Global Alliance for Vaccines and Immunization (GAVI) has begun to support a new approach to funding called Advanced Market Commitments (AMC) for vaccines.  In this approach, donor countries purchase large amounts of vaccines at a given price, which is less expensive than normal market prices.  These vaccines are provided to recipient countries from whom there is demand for protracted periods of time at the agreed upon price.  This guaranteed demand from donor countries provides an incentive for vaccine makers to conduct research and develop vaccines where it might not have otherwise made economic sense for them to do so.  In addition, it allows recipient countries to rely on a guaranteed supply of vaccines for conducting immunization campaigns.  This is an example of a cutting edge approach to financing to meet donor, recipient, and industry needs which is making pneumococcal vaccines available to developing countries 20 years ahead of historical precedent (GAVI, 2007; de Quadros, 2009; WHO, 2008).

Another area of innovation has been micronutrient supplementation.  In particular, zinc and vitamin A have recently been shown to dramatically reduce childhood morbidity and mortality from ARIs (Sazawal and Black, 2003). A randomized controlled trial done by Brooks, et al., in Bangladesh showed that the intake of 70mg of zinc weekly reduces pneumonia and mortality in young children (Brooks et al, 2005). A previous study in Bangladesh found a 40% reduction in the rate of acute lower respiratory infection in malnourished children receiving one dose of 20mg of iron and zinc weekly (Sazawal, 2003). In addition to its proven efficacy, it has also been demonstrated that zinc supplementation is a cost-effective intervention (Niessen, 2009). Further research should be done to assess the optimum dose and length of time of protection offered after zinc supplementation.

New oxygen delivery methods, especially in regions were tanked oxygen is difficult to obtain, are currently being developed and introduced.  The main drawback of oxygen supplementation in developing countries has traditionally been the cost and significant infrastructural needs associated with oxygen therapy.  However, new developments in pulse oximetry and the creation of oxygen concentrators are changing the nature of this issue.  Oxygen concentrators would replace tanked oxygen, and rely only on electricity and ambient air to produce a consistent and low cost supply of oxygen to treat hypoxaemia (Duke, 2008). Recent research has shown that improving oxygen supplies and the detection of hypoxaemia can reduce death rates from childhood pneumonia by 35%, and that they can be cheaper per life saved than other interventions such as the pneumococcal vaccine (Duke, 2010).

Controversies

Over the last five to ten years there has been considerable controversy surrounding the WHO guidelines for treatment of severe pneumonia. In particular, the issue of facility-based versus community-based treatment strategies has been in question.  The work of many researchers, among them BUSPH professor Donald Thea, has been instrumental in creating an evidence base to show that treatment of children with severe pneumonia can succeed at home just as in hospital settings. The research of Dr. Thea was essentially comprised of a series of three studies, each taking a small step toward proving the equivalency, and potentially the superiority, of home based treatment with oral antibiotics.  The first study, whose results were published in 2004, was a multicentre study which showed equivalency between treatment of severe pneumonia with oral amoxicillin and injectable penicillin in controlled settings.  This study also pointed to some of the comparative advantages of oral amoxicillin, such as decreased need for referrals, decreased risk of needle-borne infections, and decreased costs to the family, among others (Addo-Yobo et al., 2004). The next step in this process was to prove that oral amoxicillin could be administered effectively not only in a controlled setting, but also in a home setting. Another randomized equivalency trial was undertaken, which was published in 2008 and demonstrated that “home treatment with high-dose oral amoxicillin is equivalent to currently recommended hospitalization and parenteral ampicillin for treatment of severe pneumonia without underlying complications” (Hazir, 2008).  The final step in Dr. Thea’s group’s efforts to change the model of treatment for children with severe pneumonia was to show that home treatment with oral amoxicillin could not only prove effective, but that community health workers could be primarily responsible for successful diagnosis and treatment.  Analysis has not been completed, but at the time of writing it appears data not only confirm equivalency of home treatment by community health workers, but suggest superiority over treatment in hospitals with parenteral ampicillin.

While these landmark studies were taking place, similar research was ongoing elsewhere.  One non-randomized controlled study in Senegal showed that community health workers treated 97% of cases correctly with an oral antibiotic known as cotrimoxazole (BASICS, 2004). This work and other similar research has led the WHO to change its guidelines regarding the referral of children with severe pneumonia to hospitals, in favor of home treatment when it is possible. While the growing body of research on this subject is very encouraging, it is very important to continue to examine the role of home treatment by community health workers, recognizing that every culture and context presents different challenges that need to be overcome.

Despite the aforementioned research, opposition to home treatment of children with severe pneumonia remains, and primarily comes from two sources. One is a common concern, largely from physicians, that health workers may misuse medicines, resulting in increased antibiotic resistance (D’Allessandro et al, 2005). This notion is gradually carrying less weight in the debate, due to research results to the contrary. Vaccine supporters often point out that increased vaccine use would decrease the need to prescribe antibiotics overall, thereby rendering this and many of the other arguments surrounding antibiotic resistance largely moot (Theodoratou, 2010). The other main concern with community-based treatment relates to a lack of political and infrastructure support. A recent study of national level policy on community case management of pneumonia surveyed 57 countries in Africa and Asia with the highest levels of under 5 mortality about the policy support for these methods, and found that only a third of these countries had policy support for home-based treatment (Marsh et al, 2008).

Another current controversy surrounds the mistrust of vaccines and vaccination programs in many communities in both developed and developing countries. Despite rapid advances in the development of new vaccines, concerns about vaccine safety continue.  These concerns negatively affect vaccination campaigns and efforts globally (BBC, 2008).

Emerging Concerns

HIV presents a unique and important set of concerns related to ARIs.  ARIs are often an opportunistic illness and are continuing to increase and spread among HIV positive children.  The HIV epidemic has led to a dramatic increase in the HIV-related Pneumocystis pneumonia (PCP), which is seen almost exclusively in immunocompromised patients (Aliouat-Denis, 2008). HIV also poses serious problems for the treatment of seropositive children, as many vaccines are not effective or raise safety concerns for immunocompromised children (Zar, 2004).  According to the WHO, the case fatality rate for HIV-infected children with pneumonia in the hospital is almost five times as high as for non-HIV-infected children with pneumonia (WHO, 2008).

Conclusion

As one of the major contributors to childhood mortality, ARIs need to be a part of the forefront of Maternal and Child Health programs. With a sound understanding of how ARIs affect the individual, family, and community we need to work more diligently to implement already proven effective treatment plans to populations in need. We should also be continuing development of prevention methods and our understanding of social, economic, and political constraints that prevent people from seeking appropriate health care. As work continues in this field, we hope to eliminate childhood deaths due to an easily treatable disease.

References

Acharya L.B., Cleland J. (2000). Maternal and child health services in rural Nepal:
does access or quality matter more? Health Policy Plann., 15, 223-229.

Addo-Yobo, E., N. Chisaka, M. Hassan, P. Hibberd, J. Lozano, P. Jeena, W. Macleod, I. Maulen, A. Patel, and S. Qazi. "Oral Amoxicillin versus Injectable Penicillin for Severe Pneumonia in Children Aged 3 to 59 Months: a Randomised Multicentre Equivalency Study." The Lancet 364.9440 (2004): 1141-148. Print.

Aliouat-Denis, C, et al. (2008). Pneumocystis species, co-evolution and pathogenic power. Infection, Genetics, and Evolution8, 708-726.

BBC News - news.bbc.co.uk... Nigeria seeks Asian Polio Vaccine. Accessed 18 September 2008.

Benguigui, Y. (1999). Technical guidelines for the prevention, diagnosis, treatment and control of ARI at the primary care level. In Respiratory Infections in Children. PAHO: Washington, D.C.

Bhutta, Z. (2010). Countdown to 2015 decade report (2000-10): taking stock of maternal, newborn, and child survival. Lancet, 375, 2032-2044.

Black RE.,  Morris SS.,  Bryce J.  (2003) Where and why are 10 million children dying every year?  The Lancet, 361, 2226-34.

Black, R.E. (2010). Global, regional, and national causes of child mortality in 2008: a systematic analysis. The Lancet375(9730), 1969-1987.

Brooks A., Sanotoshyam M., et al.  (2005)  Effect of weekly zinc supplements on incidence of pneumonia and diarrhea in children younger than 2 years in urban, low-income population in Bangladesh: randomized controlled trial.  Lancet

Child Health Research Project -Acute respiratory infections. Accessed 18 September 2008. www.childhealthresearch.org...

“CHWs in Senegal can appropriately treat pneumonia with cotrimoxazole.” Published by the Basic Support for Institutionalizing Child Survival Project (BASICS II) for the United States agency for International Development, Republique du Senegal Ministere de la Sante de l’Hygience et de la Prevention, and UNICEF. September 2004.

Controversial funding mechanism to fight pneumonia. Bulletin of the World Health Organization, 2008 May; 86(5): 325–326.

D’Allessando U, Talisuna A, Boelart M. Editorial: should artemisnin-based combination treatement be used in the home-based management of malaria? Trop Med Int Health 2005;10:1-2. PMID:15655007 doi:10.1111/j.1365-3156.2004.01375.x

Dagan, R., Poland, G. World Pneumonia Day: Fighting pneumonia with safe and affordable vaccines. Vaccine. 2010 October.

Duke, T. (2008). Improved oxygen systems for childhood pneumonia: a multihospital effectiveness study in papua new guinea. Lancet, 372(9646), 1328-33.

Duke, T. (2010). Oxygen concentrators: a practical guide for clinicians and technicians in developing countries. Annals of Tropical Paedriatics: International Child Health, 30(2), 87-101.

GAVI. (2007). What is an AMC?. Retrieved from www.vaccineamc.org...

Ghimire, M., Pradhan, Y.V., Maskey, M.K. (2010). Community-based interventions for
diarrhoeal diseases and acute respiratory infections in Nepal. Bull World Health
Organ, 88
, 216-221.

Harp: Focus Area - ARI. Available at: www.harpnet.org... [Accessed September 16, 2010].

Hazir, T, Fox LM, Fox M, Ashraf, Y, MacLeod, WB, et al. Ambulatory short-course high-dose oral amoxicillin for treatment of sever pneumonia in children: a randomized equivalency trial. Lancet 2008; 371:49-56.

Holloway, K.A., Karkee, S.B., Tamang, A., Gurun, Y.B., Kafle, K.K., Pradhan, R., Reeves, B.C. (2009). Community intervention to promote rational treatment of acute respiratory infection in rural Nepal. Tropical Medicine and International Health (14):1, 101-110.

Huicho, L, Davila, M., Campos, M., Drasbek, C., Bryce, J., Victoria, C. (2005). Scaling
up Integrated Management of Childhood Illness to the national level: achievements   and challenges in Peru. Health Policy and Planning, 20 (1), 14-24.

Jones G., et al. (2003). How many child deaths can we prevent this year? The Lancet  362, 65-71.

LaForce M.,  Sogunro R. (2001). Reducing death due to Acute Respiratory Infections. A Better Future for Children: Progress Toward World Summit Goals for Health and
Nutrition USAID
.

Marsh, D, Gilroy K, Van de Weerdt R, Wansi, E, Qazi, S. Community case management of pneumonia: at a tipping point? Bull World Health Organ 2008;86: 381-389.

McCracken GH Jr.  (2000). Etiology and treatment of pneumonia. Pediatric Infectious
Disease, 19,
373-7.

The Merck Manual Sec. 5, Ch. 52, Pneumonia. Accessed 18
September 2008.

Metlay., et al.  (2002)  Tensions in antibiotic prescribing: pitting social concerns against the interest of individual patients.  JGIM  17(2),  pp. 87-94.

Nantanda, R. (2008). Bacterial aetiology and outcome in children with severe pneumonia in Uganda. Annals of Tropical Paedriatics: International Child Health, 28(4), 253-260.

National Center for Immunization and Respiratory Diseases. (2010, September 9). Pneumococcal vaccination. Retrieved from www.cdc.gov

Niessen, L. Comparative impact assessment of child pneumonia interventions. Bulletin of the World Health Organization, 2009 June; 87(6): 472–480.

Peterson S., Nsungwa-Sabiiti J., Were W. et al. (2004). Coping with pediatric referral—Ugandan patients experience. Lancet, 363, 1955-1956.

de Quadros, A. (2009). Pneumonia prevention gets a fresh opportunity. International Journal of Tuberculosis and Lung Disease, 13(11), 1318.

Rasmussen Z.,  Pio A., Enarson P. (2000). Case management of childhood pneumonia in developing countries: recent relevant research and current initiatives. International Journal of Tuberculosis & Lung Disease, 4(9), 807-26.

Roth, D.E., Caulfield, L.E., Essati, M., Black, R.E. (2008). Acute lower respiratory infections in childhood: opportunities for reducing the global burden through nutritional interventions. Bull World Health Organ, 86 (5), 356-364.

Sazawal S.,  Black RE.  (2003)  Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials.  The Lancet Infectious Diseases  3(9),  pp.  547-56.

Simoes EAF, Peterson S, Gamatie Y, et al. (2003). Management of severely ill children at first level health facilities in sub-Saharan Africa when referral is difficult. Bull World Health Organ, 81, 522-531.

Theodoratou, E, et al. (2010). The effect of Haemophilus influenzae type b and pneumococcal conjugate vaccines on childhood pneumonia incidence, severe morbidity and mortality. International Journal of Epidemiology39, 172-185.

Trepca., et al.  (2001)  The effect of a community intervention trial on parental knowledge and awareness of antibiotic resistance and appropriate antibiotic use in children.  Pediatrics  107(1) 6.

UNICEF/WHO (2006) . Pneumonia: The Forgotten Killer of Children.

USAID Health: Child Health, acute respiratory infections. Accessed 18 September 2008.www.usaid.gov

WHO, 2005.

WHO. (2008). HIV drives children's pneumonia in sub-Saharan Africa. Bulletin of the World Health Organization86(5), 321-416.

WHO. (2008). Controversial funding mechanism to flight pneumonia. Bulletin of the World Health Organization86(5), 325-326.

WHO. (2009, September). Acute respiratory infections. Retrieved from www.who.int...

WHO | Acute Respiratory Infections (Update September 2009). Available at: www.who.int... [Accessed September 16, 2010].

WHO Integrated Management of Childhood Illness. www.who.int. Accessed 18
September 2008.

Zar HJ.  (2004)  Pneumonia in HIV-infected and HIV-uninfected children in developing countries: epidemiology, clinical features, and management. Current Opinion in Pulmonary Medicine, 10(3), 176-82.

DRAFT: This module has unpublished changes.