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Acute respiratory infections (ARIs) are classified as upper res- CAUSES OF ARIS AND THE BURDEN OF DISEASE
piratory tract infections (URIs) or lower respiratory tract infec-
tions (LRIs). The upper respiratory tract consists of the airways ARIs in children take a heavy toll on life, especially where med-
from the nostrils to the vocal cords in the larynx, including the ical care is not available or is not sought.
paranasal sinuses and the middle ear. The lower respiratory
tract covers the continuation of the airways from the trachea
Upper Respiratory Tract Infections
and bronchi to the bronchioles and the alveoli. ARIs are not
confined to the respiratory tract and have systemic effects URIs are the most common infectious diseases. They include
because of possible extension of infection or microbial toxins, rhinitis (common cold), sinusitis, ear infections, acute pharyn-
inflammation, and reduced lung function. Diphtheria, per- gitis or tonsillopharyngitis, epiglottitis, and laryngitis—of
tussis (whooping cough), and measles are vaccine-preventable which ear infections and pharyngitis cause the more severe
diseases that may have a respiratory tract component but also complications (deafness and acute rheumatic fever, respec-
affect other systems; they are discussed in chapter 20. tively). The vast majority of URIs have a viral etiology.
Except during the neonatal period, ARIs are the most com- Rhinoviruses account for 25 to 30 percent of URIs; respiratory
mon causes of both illness and mortality in children under five, syncytial viruses (RSVs), parainfluenza and influenza viruses,
who average three to six episodes of ARIs annually regardless of human metapneumovirus, and adenoviruses for 25 to 35 per-
where they live or what their economic situation is (Kamath cent; corona viruses for 10 percent; and unidentified viruses for
and others 1969; Monto and Ullman 1974). However, the pro- the remainder (Denny 1995). Because most URIs are self-limit-
portion of mild to severe disease varies between high- and low- ing, their complications are more important than the infections.
income countries, and because of differences in specific etiolo- Acute viral infections predispose children to bacterial infections
gies and risk factors, the severity of LRIs in children under five of the sinuses and middle ear (Berman 1995a), and aspiration
is worse in developing countries, resulting in a higher case- of infected secretions and cells can result in LRIs.
fatality rate. Although medical care can to some extent mitigate
both severity and fatality, many severe LRIs do not respond to Acute Pharyngitis. Acute pharyngitis is caused by viruses in
therapy, largely because of the lack of highly effective antiviral more than 70 percent of cases in young children. Mild pharyn-
drugs. Some 10.8 million children die each year (Black, Morris, geal redness and swelling and tonsil enlargement are typical.
and Bryce 2003). Estimates indicate that in 2000, 1.9 million of Streptococcal infection is rare in children under five and more
them died because of ARIs, 70 percent of them in Africa and common in older children. In countries with crowded living
Southeast Asia (Williams and others 2002). The World Health conditions and populations that may have a genetic predispo-
Organization (WHO) estimates that 2 million children under sition, poststreptococcal sequelae such as acute rheumatic fever
five die of pneumonia each year (Bryce and others 2005). and carditis are common in school-age children but may also
483
occur in those under five. Acute pharyngitis in conjunction pharyngeal cultures do not always reveal the pathogen that is
with the development of a membrane on the throat is nearly the cause of the LRI. Bacterial cultures of lung aspirate speci-
always caused by Corynebacterium diphtheriae in developing mens are often considered the gold standard, but they are not
countries. However, with the almost universal vaccination of practical for field application. Vuori-Holopainen and Peltola’s
infants with the DTP (diphtheria-tetanus-pertussis) vaccine, (2001) review of several studies indicates that S. pneumoniae
diphtheria is rare. and Hib account for 13 to 34 percent and 1.4 to 42.0 percent of
bacterial pneumonia, respectively, whereas studies by Adegbola
Acute Ear Infection. Acute ear infection occurs with up to and others (1994), Shann, Gratten, and others (1984), and Wall
30 percent of URIs. In developing countries with inadequate and others (1986) suggest that Hib accounts for 5 to 11 percent
medical care, it may lead to perforated eardrums and chronic of pneumonia cases.
ear discharge in later childhood and ultimately to hearing Reduced levels of clinical or radiological pneumonia in clin-
impairment or deafness (Berman 1995b). Chronic ear infection ical trials of a nine-valent pneumococcal conjugate vaccine
following repeated episodes of acute ear infection is common in provide an estimate of the vaccine-preventable disease burden
developing countries, affecting 2 to 6 percent of school-age chil- (valency indicates the number of serotypes against which the
dren.The associated hearing loss may be disabling and may affect vaccine provides protection; conjugate refers to conjugation of
learning. Repeated ear infections may lead to mastoiditis, which polysaccharides to a protein backbone). In a study in The
in turn may spread infection to the meninges. Mastoiditis and Gambia, 37 percent of radiological pneumonia was prevented,
other complications of URIs account for nearly 5 percent of all reflecting the amount of disease caused by S. pneumoniae, and
ARI deaths worldwide (Williams and others 2002). mortality was reduced by 16 percent (Cutts and others 2005).
Upper respiratory tract colonization with potentially patho-
genic organisms and aspiration of the contaminated secretions
Lower Respiratory Tract Infections have been implicated in the pathogenesis of bacterial pneumo-
The common LRIs in children are pneumonia and bronchi- nia in young children. Infection of the upper respiratory tract
olitis. The respiratory rate is a valuable clinical sign for diag- with influenza virus or RSVs has been shown to increase the
nosing acute LRI in children who are coughing and breathing binding of both H. influenzae (Jiang and others 1999) and
rapidly. The presence of lower chest wall indrawing identifies S. pneumoniae (Hament and others 2004; McCullers and
more severe disease (Mulholland and others 1992; Shann, Hart, Bartmess 2003) to lining cells in the nasopharynx. This finding
and Thomas 1984). may explain why increased rates of pneumococcal pneumonia
Currently, the most common causes of viral LRIs are RSVs. parallel influenza and RSV epidemics. A study in South Africa
They tend to be highly seasonal, unlike parainfluenza viruses, showed that vaccination with a nine-valent pneumococcal con-
the next most common cause of viral LRIs. The epidemiology jugate vaccine reduced the incidence of virus-associated pneu-
of influenza viruses in children in developing countries monia causing hospitalization by 31 percent, suggesting that
deserves urgent investigation because safe and effective vac- pneumococcus plays an important role in the pathogenesis of
cines are available. Before the effective use of measles vaccine, virus-associated pneumonia (Madhi, Petersen, Madhi, Wasas,
the measles virus was the most important viral cause of respi- and others 2000).
ratory tract–related morbidity and mortality in children in Entry of bacteria from the gut with spread through the
developing countries. bloodstream to the lungs has also been proposed for the patho-
genesis of Gram-negative organisms (Fiddian-Green and Baker
Pneumonia. Both bacteria and viruses can cause pneumonia. 1991), but such bacteria are uncommon etiological agents of
Bacterial pneumonia is often caused by Streptococcus pneumo- pneumonia in immune-competent children. However, in
niae (pneumococcus) or Haemophilus influenzae, mostly type b neonates and young infants, Gram-negative pneumonia is not
(Hib), and occasionally by Staphylococcus aureus or other strep- uncommon (Quiambao forthcoming).
tococci. Just 8 to 12 of the many types of pneumococcus cause Viruses are responsible for 40 to 50 percent of infection in
most cases of bacterial pneumonia, although the specific types infants and children hospitalized for pneumonia in developing
may vary between adults and children and between geographic countries (Hortal and others 1990; John and others 1991;
locations. Other pathogens, such as Mycoplasma pneumoniae Tupasi and others 1990). Measles virus, RSVs, parainfluenza
and Chlamydia pneumoniae, cause atypical pneumonias. Their viruses, influenza type A virus, and adenoviruses are the most
role as a cause of severe disease in children under five in devel- important causes of viral pneumonia. Differentiating between
oping countries is unclear. viral and bacterial pneumonias radiographically is difficult,
The burden of LRIs caused by Hib or S. pneumoniae is partly because the lesions look similar and partly because bac-
difficult to determine because current techniques to establish terial superinfection occurs with influenza, measles, and RSV
bacterial etiology lack sensitivity and specificity. The results of infections (Ghafoor and others 1990).
484 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
In developing countries, the case-fatality rate in children 34 percent, much higher than the 5 to 10 percent for children
with viral pneumonia ranges from 1.0 to 7.3 percent (John and not infected with HIV (Bobat and others 1999; Madhi,
others 1991; Stensballe, Devasundaram, and Simoes 2003), Petersen, Madhi, Khoosal, and others 2000; Nathoo and others
with bacterial pneumonia from 10 to 14 percent and with 1993; Zwi, Pettifior, and Soderlund 1999). Pneumocystis jirove-
mixed viral and bacterial infections from 16 to 18 percent ci and cytomegalovirus are important opportunistic infections
(Ghafoor and others 1990; Shann 1986). in more than 50 percent of HIV-infected infants (Jeena,
Coovadia, and Chrystal 1996; Lucas and others 1996). Gram-
Bronchiolitis. Bronchiolitis occurs predominantly in the first negative bacteria are also important in more than 70 percent of
year of life and with decreasing frequency in the second and HIV-infected malnourished children (Ikeogu, Wolf, and Mathe
third years. The clinical features are rapid breathing and lower 1997). Patient studies have confirmed the frequent association
chest wall indrawing, fever in one-third of cases, and wheezing of these bacteria but added S. pneumoniae and S. aureus as
(Cherian and others 1990). Inflammatory obstruction of the important pathogens (Gilks 1993; Goel and others 1999). The
small airways, which leads to hyperinflation of the lungs, and first South African report on the overall burden of invasive
collapse of segments of the lung occur. Because the signs and pneumococcal disease reported a 41.7-fold increase in HIV-
symptoms are also characteristic of pneumonia, health workers infected children compared with uninfected children (Farley
may find differentiating between bronchiolitis and pneumonia and others 1994).
difficult. Two features that may help are a definition of the sea-
sonality of RSVs in the locality and the skill to detect wheezing.
RSVs are the main cause of bronchiolitis worldwide and can INTERVENTIONS
cause up to 70 or 80 percent of LRIs during high season (Simoes
1999; Stensballe, Devasundaram, and Simoes 2003). The Interventions to control ARIs can be divided into four basic
recently discovered human metapneumovirus also causes bron- categories: immunization against specific pathogens, early
chiolitis (Van den Hoogen and others 2001) that is indistin- diagnosis and treatment of disease, improvements in nutrition,
guishable from RSV disease. Other viruses that cause bronchi- and safer environments (John 1994). The first two fall within
olitis include parainfluenza virus type 3 and influenza viruses. the purview of the health system, whereas the last two fall
under public health and require multisectoral involvement.
Influenza. Even though influenza viruses usually cause URIs
in adults, they are increasingly being recognized as an impor-
tant cause of LRIs in children and perhaps the second most Vaccinations
important cause after RSVs of hospitalization of children with Widespread use of vaccines against measles, diphtheria, per-
an ARI (Neuzil and others 2002). Although influenza is consid- tussis, Hib, pneumococcus, and influenza has the potential to
ered infrequent in developing countries, its epidemiology substantially reduce the incidence of ARIs in children in devel-
remains to be investigated thoroughly. The potential burden of oping countries. The effects of measles, diphtheria, and pertus-
influenza as a cause of death in children is unknown. Influenza sis vaccines are discussed in chapter 20. The limited data on
virus type A may cause seasonal outbreaks, and type B may influenza in developing countries do not permit detailed
cause sporadic infection. Recently, avian influenza virus has analysis of the potential benefits of that vaccine. This chapter,
caused infection, disease, and death in small numbers of indi- therefore, focuses on the potential effects of Hib and pneumo-
viduals, including children, in a few Asian countries. Its poten- coccal vaccines on LRIs.
tial for emergence in human outbreaks or a pandemic is
unknown, but it could have devastating consequences in devel- Hib Vaccine. Currently three Hib conjugate vaccines are avail-
oping countries (Peiris and others 2004) and could pose a able for use in infants and young children. The efficacy of Hib
threat to health worldwide. New strains of type A viruses will vaccine in preventing invasive disease (mainly meningitis, but
almost certainly arise through mutation, as occurred in the case also pneumonia), has been well documented in several studies in
of the Asian and Hong Kong pandemics in the 1950s and industrialized countries (Black and others 1992; Booy and oth-
1960s. ers 1994; Eskola and others 1990; Fritzell and Plotkin 1992;
Heath 1998; Lagos and others 1996; Santosham and others
1991) and in one study in The Gambia (Mulholland and others
HIV Infection and Pediatric LRIs 1997). All studies showed protective efficacy greater than 90 per-
Worldwide, 3.2 million children are living with HIV/AIDS, cent against laboratory-confirmed invasive disease, irrespective
85 percent of them in Sub-Saharan Africa (UNAIDS 2002). In of the choice of vaccine. Consequently, all industrialized coun-
southern Africa, HIV-related LRIs account for 30 to 40 percent tries include Hib vaccine in their national immunization
of pediatric admissions and have a case-fatality rate of 15 to programs, resulting in the virtual elimination of invasive Hib
486 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
was initially child mortality, it was changed to radiological others 1992). On the basis of these and other data (Campbell,
pneumonia. Nevertheless, the trial showed a 16 percent Byass, and others 1989; Kolstad and others 1997; Perkins and
(95 percent confidence level, 3 to 38) reduction in mortality. others 1997; Redd 1994; Simoes and others 1997; Weber and
This trial was conducted in a rural area in eastern Gambia others 1997), WHO recommends a respiratory rate cutoff of
where access to round-the-clock curative care, including case 50 breaths per minute for infants age 2 through 11 months and
management, is difficult to provide. This trial demonstrates 40 breaths per minute for children age 12 months to 5 years.
that immunization delivered through outreach programs will Rapid breathing, as defined by WHO, detects about 85 per-
have substantial health and economic benefits in such popula- cent of children with pneumonia, and more than 80 percent of
tions. One additional study evaluating the effect of an 11-PCV children with potentially fatal pneumonia are probably suc-
on radiological pneumonia is ongoing in the Philippines; cessfully identified and treated using the WHO diagnostic cri-
results are expected in the second half of 2005. teria. Antibiotic treatment of children with rapid breathing has
been shown to reduce mortality (Sazawal and Black 2003). The
problem of the low specificity of the rapid breathing criterion
Case Management is that some 70 to 80 percent of children who may not need
The simplification and systematization of case management for antibiotics will receive them. Nevertheless, for primary care
early diagnosis and treatment of ARIs have enabled significant workers for whom diagnostic simplicity is essential, rapid
reductions in mortality in developing countries, where access to breathing is clearly the most useful clinical sign.
pediatricians is limited. WHO clinical guidelines for ARI case
management (WHO 1991) use two key clinical signs: respiratory Pneumonia Diagnosis Based on Chest Wall Indrawing.
rate, to distinguish children with pneumonia from those with- Children are admitted to hospital with severe pneumonia when
out, and lower chest wall indrawing, to identify severe pneumo- health workers believe that oxygen or parenteral antibiotics
nia requiring referral and hospital admission. Children with (antibiotics administered by other than oral means) are needed
audible stridor when calm and at rest or such danger signs of or when they lack confidence in mothers’ ability to cope. The
severe disease as inability to feed also require referral. Children rationale of parenteral antibiotics is to achieve higher levels of
without these signs are classified as having an ARI but not pneu- antibiotics and to overcome concerns about the absorption of
monia. Children showing only rapid breathing are treated for oral drugs in ill children.
pneumonia with outpatient antibiotic therapy. Children who The Papua New Guinea study (Shann, Hart, and Thomas
have a cough for more than 30 days are referred for further 1984) used chest wall indrawing as the main indicator of sever-
assessment of tuberculosis and other chronic infections. ity, but studies from different parts of the world show large dif-
ferences in the rates of indrawing because of variable defini-
Pneumonia Diagnosis Based on Rapid Breathing. The initial tions. Restriction of the term to lower chest wall indrawing,
guidelines for detecting pneumonia based on rapid breathing defined as inward movement of the bony structures of the chest
were developed in Papua New Guinea during the 1970s. In a wall with inspiration, has provided a better indicator of the
study of 200 consecutive pediatric outpatients and 50 consecu- severity of pneumonia and one that can be taught to health
tive admissions (Shann, Hart, and Thomas 1984), 72 percent of workers. It is more specific than intercostal indrawing, which
children with audible crackles in the lungs had a respiratory frequently occurs in bronchiolitis.
rate of 50 or more breaths per minute, whereas only 19 percent In a study in The Gambia (Campbell, Byass, and others
of children without crackles breathed at such a rapid rate. 1989), a cohort of 500 children from birth to four years old
Therefore, the initial WHO guidelines used a threshold of was visited at home weekly for one year. During this time,
50 breaths per minute, at or above which a child with a cough 222 episodes of LRI (rapid breathing, any chest wall indrawing,
was regarded as having pneumonia. nasal flaring, wheezing, stridor, or danger signs) were referred
The major concern was the relatively low sensitivity of this to the clinic. Chest indrawing was present in 62 percent of these
approach, which could miss 25 to 40 percent of cases of pneu- cases, many with intercostal indrawing. If all children with any
monia. A study in Vellore, India, found that sensitivity could chest indrawing were hospitalized, the numbers would over-
be improved by lowering the threshold to 40 for children age 1 whelm pediatric inpatient facilities.
to 4, while keeping the 50 breaths per minute cutoff for infants Studies in the Philippines and Swaziland (Mulholland and
age 2 months through 11 months (Cherian and others 1988). others 1992) found that lower chest wall indrawing was more
Subsequent studies showed that when these thresholds were specific than intercostal indrawing for a diagnosis of severe
used, sensitivity improved from 62 to 79 percent in the pneumonia requiring hospital admission. In the Vellore study
Philippines and from 65 to 77 percent in Swaziland, but at (Cherian and others 1988), lower chest wall indrawing cor-
the same time, the specificity fell from 92 to 77 percent in the rectly predicted 79 percent of children with an LRI who were
Philippines and 92 to 80 percent in Swaziland (Mulholland and hospitalized by a pediatrician.
488 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
WHO recommends administering oxygen, if there is ample of pneumococcal vaccines, because global and regional esti-
supply, to children with signs and symptoms of severe pneu- mates of the pneumococcal pneumonia burden are currently
monia and, where supply is limited, to children with any of being developed and will not be available until later in 2005. In
the following signs: inability to feed and drink, cyanosis, res- addition, current vaccine prices are relatively stable in devel-
piratory rate greater than or equal to 70 breaths per minute, oped countries, but the prices for low- and middle-income
or severe chest wall retractions (WHO 1993). Oxygen should countries are expected to be substantially lower when vaccines
be administered at a rate of 0.5 liter per minute for children are purchased through a global tender.
younger than 2 months and 1 liter per minute for older chil- We evaluate case-management intervention strategies for
dren. Because oxygen is expensive and supply is scarce, espe- LRIs in children under five. Health workers who implement
cially in remote rural areas in developing countries, WHO rec- case management diagnose LRIs on the basis of fast breathing,
ommends simple clinical signs to detect and treat hypoxemia. lower chest wall indrawing, or selected danger signs in children
Despite those recommendations, a study of 21 first-level facil- with respiratory symptoms. Because this method does not dis-
ities and district hospitals in seven developing countries found tinguish between pneumonia and bronchiolitis, nor between
that more than 50 percent of hospitalized children with LRI bacterial and viral pneumonia, we group these conditions into
were inappropriately treated with antibiotics or oxygen the general category of “clinical pneumonia” (Rudan and oth-
(Nolan and others 2001)—and in several, oxygen was in short ers 2004). This approach assumes that a high proportion of
supply. Clearly, providing oxygen to hypoxemic babies is clinical pneumonia is of bacterial origin and that health work-
lifesaving, though no randomized trials have been done to ers can considerably reduce case fatality through breathing rate
prove it. diagnosis and timely administration of antibiotics (Sazawal
and Black 2003). We calculated treatment costs by World Bank
Prevention and Treatment of Pneumonia in HIV-Positive region using standardized input costs provided by the volume
Children. Current recommendations of a WHO panel for editors and costs published in the International Drug Price
managing pneumonia in HIV-positive children and for pro- Indicator Guide (Management Sciences for Health 2005) and
phylaxis of Pneumocystis jiroveci are as follows (WHO 2003): other literature (table 25.1). The analysis addresses four cate-
gories of case management, which are distinguished by the
• Nonsevere pneumonia up to age 5 years. Oral co-trimoxazole severity of the infection and the point of treatment:
should remain the first-line antibiotic, but oral amoxicillin
should be used if it is affordable or if the child has been on • nonsevere pneumonia treated by a community health
co-trimoxazole prophylaxis. worker
• Severe or very severe pneumonia. Normal WHO case- • nonsevere pneumonia treated at a health facility
management guidelines should be used for children up to • severe pneumonia treated at a hospital
2 months old. For children from 2 to 11 months, injectable • very severe pneumonia treated at a hospital.
antibiotics and therapy for Pneumocystis jiroveci pneu-
monia are recommended, as is starting Pneumocystis jirove- Information about these categories of case management and
ci pneumonia prophylaxis on recovery. For children age 12 their outcomes is drawn from a report on the methodology
to 59 months, the treatment consists of injectable antibi- and assumptions used to estimate the costs of scaling up select-
otics and therapy for Pneumocystis jiroveci pneumonia. ed health interventions aimed at children (WHO and Child
Pneumocystis jiroveci pneumonia prophylaxis should be Adolescent Health forthcoming). We assumed a total of three
given for 15 months to children born to HIV-infected follow-up visits for each patient treated by a community health
mothers; however, this recommendation has seldom been worker rather than the twice-daily follow-ups for 10 days rec-
implemented. ommended by the report. We also assumed that all severe
pneumonia patients receive an x-ray examination, rather than
just 20 percent as suggested by the report. Moreover, we
COST-EFFECTIVENESS OF INTERVENTIONS
assumed a five-hour workday for a community health worker,
Pneumonia is responsible for about a fifth of the estimated the minimum workday required for community health work-
10.6 million deaths per year of children under five. Where pri- ers under the Child Health and Survival initiative of the U.S.
mary health care is weak, reducing mortality through public Agency for International Development (Bhattacharyya and
health measures is a high priority. As noted earlier, the available others 2001).
interventions are primary prevention by vaccination and sec- Table 25.2 presents region-specific estimates of average
ondary prevention by early case detection and management. treatment costs per episode for the four case-management
The cost-effectiveness of Hib vaccines is discussed in chap- strategies. Because we considered the prices of tradable com-
ter 20. We did not attempt an analysis of the cost-effectiveness modities such as drugs and oxygen to be constant across
Condition and intervention Cost per unit (2001 US$) Quantity Percentage of patients
Table 25.2 Average per Episode Treatment Costs of Case-Management Interventions for Acute Lower Respiratory Infection
(2001 US$)
Region Nonsevere, community level Nonsevere, facility level Severe, hospital level Very severe, hospital level
regions, regional variations were due to differences in hospital We calculated region-specific cost-effectiveness ratios
and health worker costs. Latin America and the Caribbean and (CERs) for a model population of 1 million in each region, fol-
the Middle East and North Africa had the highest treatment lowing the standardized guidelines for economic analyses (see
costs. chapter 15 for details). Input variables included the treatment
490 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
costs detailed in tables 25.1 and 25.2, region-specific LRI mor- than at the community level, and of all four case-management
bidity rates adapted from Rudan and others (forthcoming), categories, treatment of very severe clinical pneumonia at the
region-specific mortality rates and age structures provided by hospital level was the least cost-effective. Treatment of non-
the volume editors, and region-specific urban to rural popula- severe clinical pneumonia at the facility level was more cost-
tion ratios (World Bank 2002). The Europe and Central Asia effective than treatment by a community health worker
region was excluded from this analysis because of a lack of because of the lower cost of a single visit to a health facility than
incidence information. In the absence of region-specific infor- of multiple visits by a health worker. The CER of providing all
mation, we assumed uniform intervention effectiveness rates. levels of treatment to all low- and middle-income countries
Disability-adjusted life years are averted through reduced was estimated at US$398 per disability-adjusted life year.
duration of illness and decreased mortality with treatment. We Because we assumed that effectiveness rates were constant,
assumed an average illness duration of 8.5 days for those not regional variations in the CER for each case-management cat-
treated and of 6.0 days for those treated. We used a case-fatality egory were due only to variations in the intervention costs, and
reduction of 36.0 percent on account of treatment (Sazawal the relative cost-effectiveness rankings for the strategies was the
and Black 2003) and a diagnosis specificity of 78.5 percent for same for all the regions. Variation in the CERs for providing all
patients diagnosed based on breath rate alone. The disability categories of care was also due to region-specific urban to rural
weight cotemporaneous with infection was 0.28. We did not population ratios. We assumed that all patients in urban areas
consider disabilities caused by chronic sequelae of LRIs because seek treatment at the facility level or higher, whereas 80 percent
it is unclear whether childhood LRI causes long-term impaired of nonseverely ill patients in rural areas receive treatment at
lung function or whether children who develop impaired lung the community level and the remainder seek treatment at the
function are more prone to infection (von Mutius 2001). facility level.
Because a single year of these interventions yields only
cotemporaneous benefits—because effectively treated individ-
uals do not necessarily live to life expectancy given that they are IMPLEMENTATION OF ARI CONTROL STRATEGIES:
likely to be infected again the following year—we calculated the LESSONS OF EXPERIENCE
cost-effectiveness of a five-year intervention. This time period The lessons of ARI prevention and control strategies that have
enabled us to consider the case in which an entire cohort of been implemented by national programs include the vaccina-
newborns to four-year-olds avoids early childhood clinical tion and case-management strategies discussed below.
pneumonia mortality because of the intervention and receives
the benefit of living to life expectancy. Finally, this analysis con-
sidered only long-run marginal costs, which vary with the Vaccine Strategies
number of individuals treated, and did not include the fixed Hib vaccine was introduced into the routine infant immuniza-
costs of initiating a program where none currently exists. tion schedule in North America and Western Europe in the
Table 25.3 presents the region-specific CERs of the four early 1990s. With the establishment of the Global Alliance for
case-management categories as well as the CER for providing Vaccines and Immunization (GAVI) and the Vaccine Fund,
all four categories to a population of 1 million people. Among progress is being made in introducing it in developing coun-
all low- and middle-income countries, treatment of nonsevere tries, although major hurdles remain. By 2002, only 84 of the
clinical pneumonia was more cost-effective at the facility level 193 WHO member nations had introduced Hib vaccine. Five
492 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
• In Pakistan, the Lady Health Worker Program employs established, delivery systems will have to be established, and
approximately 70,000 women, who work in communities countries will need financial support so that the vaccines can be
providing education and management of childhood pneu- introduced into their immunization programs. These activities
monia to more than 30 million people (WHO 2004b). are being initiated before the launch of vaccine formulations
designed for use in developing countries, so as to inform capac-
ity planning, product availability, and pricing.
RESEARCH AND DEVELOPMENT AGENDA
The research and development agenda outlined below summa-
rizes the priorities that have been established by advisory Case-Management Strategies
groups to the Initiative for Vaccine Research (vaccine interven- In 2003, WHO’s Division of Child and Adolescent Health con-
tion strategies) and the WHO Division of the Child and vened a meeting to review data and evidence from recent ARI
Adolescent Health (case-management strategies). case-management studies and to suggest the following revisions
to case-management guidelines and future research priorities:
Vaccine Intervention Strategies
The GAVI task force on Hib immunization made a number of • Nonsevere pneumonia:
recommendations that vary depending on the country. — Improve the specificity of clinical diagnostic criteria.
Countries that have introduced Hib vaccine should focus on — Reassess WHO’s current recommended criteria for
documenting its effect and should use the data to inform detecting and managing treatment failure, given the
national authorities, development partners, and other agencies high rates of therapy failure.
involved in public health to ensure sustained support to such — Reanalyze data from short-course therapy studies to
vaccination programs. Countries eligible for GAVI support that better identify determinants of treatment failure.
have not yet introduced Hib vaccines are often hindered by a — Carry out placebo-controlled trials among children pre-
lack of local data and a lack of awareness of regional data. They senting with wheezing and pneumonia in selected set-
can address these issues through subregional meetings at which tings that have a high prevalence of wheezing to deter-
country experts can pool data and review information from mine whether such children need antibiotics.
other countries. In addition, most of the countries need to • Severe pneumonia: In a randomized clinical trial in a con-
carry out economic analyses that are based on a standardized trolled environment, Addo-Yobo and others (2004) showed
instrument. Finally, all countries that face a high Hib disease that oral amoxicillin is as effective as parenteral penicillin or
burden need to develop laboratory facilities so that they can ampicillin; however, the following actions need to be under-
establish the incidence of Hib meningitis at selected sites. taken before it can be recommended on a general basis:
Countries in which the disease burden remains unclear may — Analyze data on exclusions from the trial.
have limited capacity to document the occurrence of Hib dis- — Identify predictors that may help distinguish children
ease using protocols that are based on surveillance for menin- who require hospitalization and who subsequently
gitis invasive disease. They will need to explore the possibilities deteriorate.
of using alternative methods for measuring disease burden, — Reassess WHO’s current recommended treatment
including the use of vaccine-probe studies. failure criteria for severe pneumonia, given the overall
On the basis of experience with introducing Hib and hepa- high rates of therapy failure.
titis B vaccines, GAVI took a proactive approach and in 2003 — Conduct descriptive studies in a public health setting in
established an initiative based at the Johns Hopkins School of several centers worldwide, to evaluate the clinical out-
Public Health in Baltimore to implement an accelerated devel- comes of oral amoxicillin in children age 2 to 59 months
opment and introduction program for pneumococcal vaccines who present with lower chest wall indrawing.
(the PneumoADIP; see http://www.preventpneumonia.org). — Document the effectiveness of WHO’s treatment guide-
The program’s intent is to establish and communicate the value lines for managing children with pneumonia and HIV
of pneumococcal vaccines and to support their delivery. infection.
Establishing the value of the vaccine involves developing local • LRI deaths:
evidence about the burden of disease and the vaccines’ poten- — To help develop more effective interventions to reduce
tial effect on public health. This effort can be accomplished LRI mortality, study the epidemiology of LRI deaths in
through enhanced disease surveillance and relevant clinical tri- various regions in detail, using routine and advanced
als in a selected number of lead countries. Once established, the laboratory techniques.
evidence base will be communicated to decision makers and • Oxygen therapy:
key opinion leaders to ensure that data-driven decisions are — Carry out studies to show the effectiveness of oxygen for
made. Once the cost-effectiveness of routine vaccination is managing severe respiratory infections.
494 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
Booy, R., S. Hodgson, L. Carpenter, R. T. Mayon-White, M. P. Slack, J. A. Fritzell, B., and S. Plotkin. 1992. “Efficacy and Safety of a Haemophilus
Macfarlane, and others. 1994. “Efficacy of Haemophilus influenzae influenzae Type B Capsular Polysaccharide-Tetanus Protein Conjugate
Type B Conjugate Vaccine PRP-T.” Lancet 344 (8919): 362–66. Vaccine.” Journal of Pediatrics 121 (3): 355–62.
Bryce, J., C. Boschi-Pinto, K. Shibuya, R. E. Black, and the WHO Child Gessner B. D., A. Sutanto, M. Linehan, I. G. Djelantik, T. Fletcher, I. K.
Health Epidemiology Reference Group. 2005. “WHO Estimates of the Gerudug, and others. 2005. “Incidences of Vaccine-Preventable
Causes of Death in Children.” Lancet 365: 1147–52. Haemophilus Influenzae Type B Pneumonia and Meningitis in
Campbell, H., J. R. M. Armstrong, and P. Byass. 1989.“Indoor Air Pollution Indonesian Children: Hamlet-Randomised Vaccine-Probe Trial.”
in Developing Countries and Acute Respiratory Infection in Children.” Lancet 365 (9453): 43–52.
Lancet 1 (8645): 1012. Ghafoor, A., N. K. Nomani, Z. Ishaq, S. Z. Zaidi, F. Anwar, M. I. Burney, and
others. 1990. “Diagnoses of Acute Lower Respiratory Tract Infections
Campbell, H., P. Byass, A. C. Lamont, I. M. Forgie, K. P. O’Neill, N. Lloyd-
in Children in Rawalpindi and Islamabad, Pakistan.” Reviews of
Eans, and B. M. Greenwood. 1989. “Assessment of Clinical Criteria for
Infectious Diseases 12 (Suppl. 8): S907–14.
Identification of Severe Acute Lower Respiratory Tract Infections in
Children.” Lancet 1 (8633): 297–99. Gilks, C. F. 1993. “Pneumococcal Disease and HIV Infection.” Annals of
Internal Medicine 118: 393–94.
Catchup Study Group. 2002. “Clinical Efficacy of Co-Trimoxazole versus
Amoxicillin Twice Daily for Treatment of Pneumonia: A Randomized Goel, A., L. Bamford, D. Hanslo, and G. Hussey. 1999. “Primary
Controlled Clinical Trial in Pakistan.” Archives of Disease in Childhood Staphylococcal Pneumonia in Young Children: A Review of 100 Cases.”
86: 113–18. Journal of Tropical Pediatrics 45 (4): 233–36.
Hament, J. M., P. C. Aerts, A. Fleer, H. Van Dijk, T. Harmsen, J. L. Kimpen,
Cherian, T., T. J. John, E. A. Simoes, M. C. Steinhoff, and M. John. 1988.
and T. F. Wolfs. 2004. “Enhanced Adherence of Streptococcus pneumo-
“Evaluation of Simple Clinical Signs for the Diagnosis of Acute Lower
niae to Human Epithelial Cells Infected with Respiratory Syncytial
Respiratory Tract Infection.” Lancet 2: 125–28.
Virus.” Pediatric Research 55 (6): 972–78.
Cherian, T., E. A. Simoes, M. C. Steinhoff, K. Chitra, M. John, Heath, P. T. 1998. “Haemophilus influenzae Type B Conjugate Vaccines:
P. Raghupathy, and others. 1990. “Bronchiolitis in Tropical South A Review of Efficacy Data.” Pediatric Infectious Disease Journal 17
India.” American Journal of Diseases of Children 144 (9): 1026–30. (9 Suppl.): S117–22.
Cutts, F. T., S. M. A. Zaman, G. Enwere, S. Jaffar, O. S. Levine, J. B. Okoko, Hortal, M., C. Mogdasy, J. C. Russi, C. Deleon, and A. Suarez. 1990.
and others. 2005. “Efficacy of Nine-Valent Pneumococcal Conjugate “Microbial Agents Associated with Pneumonia in Children from
Vaccine against Pneumonia and Invasive Pneumococcal Disease in The Uruguay.” Reviews of Infectious Diseases 12 (Suppl. 8): S915–22.
Gambia: Randomised, Double-Blind, Placebo-Controlled Trial.”
Ikeogu, M. O., B. Wolf, and S. Mathe. 1997. “Pulmonary Manifestations in
Lancet 365 (9465): 1139–46.
HIV Seropositive and Malnourished Children in Zimbabwe.” Archives
de Andrade, A. L., J. G. de Andrade, C. M. Martelli, S. A. Silva, R. M. de of Disease in Childhood 76: 124–28.
Oliveira, M. S. Costa, and others. 2004. “Effectiveness of Haemophilus Jeena, P. M., H. M. Coovadia, and V. Chrystal. 1996. “Pneumocystis carinii
influenzae B Conjugate Vaccine on Childhood Pneumonia: A Case- and cytomegalo Virus Infections in Severely Ill HIV-Infected African
Control Study in Brazil.” International Journal of Epidemiology 33 (1): Infants.” Annals of Tropical Paediatrics 16: 361–68.
173–81.
Jiang, Z., N. Nagata, E. Molina, L. O. Bakaletz, H. Hawkins, and J. A. Patel.
Denny, F. W. Jr. 1995. “The Clinical Impact of Human Respiratory Virus 1999. “Fimbria-Mediated Enhanced Attachment of Nontypeable
Infections.” American Journal of Respiratory and Critical Care Medicine Haemophilus influenzae to Respiratory Syncytial Virus-Infected
152 (4, part 2): S4–12. Respiratory Epithelial Cells.” Infection and Immunity 67: 187–92.
Dobson,M.1991.“Oxygen Concentrators Offer Cost Savings for Developing John, T. J. 1994. “Who Determines National Health Policies?” In
Countries: A Study Based on New Guinea.” Anaesthesia 146: 217–19. Vaccination and World Health: Fourth Annual Public Health Forum of
Douglas, R. M., and H. B. Miles. 1984. “Vaccination against Streptococcus the London School of Hygiene and Tropical Medicine, ed. F. T. Cutts and
pneumoniae in Childhood: Lack of Demonstrable Benefit in Young P. G. Smith, 205–11. Chichester, U.K.: John Wiley.
Australian Children.” Journal of Infectious Diseases 149 (6): 861–69. John, T. J., T. Cherian, M. C. Steinhoff, E. A. Simoes, and M. John. 1991.
Duke T, J. Mgone, and D. Frank. 2001. “Hypoxaemia in children with “Etiology of Acute Respiratory Infections in Children in Tropical
severe pneumonia in Papua New Guinea.” International Journal of Southern India.” Reviews of Infectious Diseases 13 (Suppl. 6): S463–69.
Tuberculosis and Lung Disease 5: 511–19. Kamath, K. R., R. A. Feldman, P. S. S. Rao, and J. K. Webb. 1969. “Infection
Eskola, J., H. Kayhty, A. K. Takala, H. Peltola, P. R. Ronnberg, E. Kela, and and Disease in a Group of South Indian Families.” American Journal of
others. 1990. “A Randomized, Prospective Field Trial of a Conjugate Epidemiology 89: 375–83.
Vaccine in the Protection of Infants and Young Children against Karma, P., J. Luotonen, M. Timonen, S. Pontynen, J. Pukander, E. Herva,
Invasive Haemophilus influenzae Type B Disease.” New England Journal and others. 1980. “Efficacy of Pneumococcal Vaccination against
of Medicine 323 (20): 1381–87. Recurrent Otitis Media: Preliminary Results of a Field Trial
Eskola, J., T. Kilpi, A. Palmu, J. Jokinen, J. Haapakoski, E. Herva, and oth- in Finland.” Annals of Otology, Rhinology, and Laryngology Suppl. 89
ers. 2001. “Efficacy of a Pneumococcal Conjugate Vaccine against (3, part 2): 357–62.
Acute Otitis Media.” New England Journal of Medicine 344 (6): 403–9. Kartasasmita, C. 2003. “Three versus Five Days Oral Cotrimoxazole for
Nonsevere Pneumonia.” Paper presented at the World Health
Farley, J. J., J. C. King, P. Nair, S. E. Hines, R. L. Tressier, and P. E. Vink.
Organization Consultative Meeting on Reviewing Current Research and
1994. “Invasive Pneumococcal Disease among Infected and Un-
Management of Acute Respiratory Infections, Geneva, September 29–
infected Children of Mothers with Human Immunodeficiency Virus
October 1.
Infection.” Journal of Pediatrics 124: 853–58.
Kilpi, T., H. Ahman, J. Jokinen, K. S. Lankinen, A. Palmu, H. Savolainen,
Fiddian-Green, R. G., and S. Baker. 1991. “Nosocomial Pneumonia in the and others. 2003. “Protective Efficacy of a Second Pneumococcal
Critically Ill: Product of Aspiration or Translocation?” Critical Care Conjugate Vaccine against Pneumococcal Acute Otitis Media in Infants
Medicine 19: 763–69. and Children: Randomized, Controlled Trial of a Seven-Valent
Fireman, B., S. B. Black, H. R. Shinefield, J. Lee, E. Lewis, and P. Ray. Pneumococcal Polysaccharide-Meningococcal Outer Membrane
2003. “Impact of the Pneumococcal Conjugate Vaccine on Otitis Protein Complex Conjugate Vaccine in 1,666 Children.” Clinical
Media.” Pediatric Infectious Disease Journal 22 (1): 10–16. Infectious Diseases 37 (9): 1155–64.
496 | Disease Control Priorities in Developing Countries | Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and others
Neonates, Infants, and Preschool Children—A Meta-analysis of Wall, R. A., P. T. Corrah, D. C. Mabey, and B. M. Greenwood. 1986. “The
Community-Based Trials.” Lancet Infectious Diseases 3: 547–56. Etiology of Lobar Pneumonia in The Gambia.” Bulletin of the World
Schellenberg, J. A., C. G. Victora, A. Mushi, D. de Savigny, D. Schellenberg, Health Organization 64 (4): 553–58.
H. Mshinda, and others. 2003. “Inequities among the Very Poor: Weber, M. W., E. K. Mulholland, S. Jaffar, H. Troedsson, S. Gove, and B. M.
Health Care for Children in Rural Southern Tanzania.” Lancet 361 Greenwood. 1997. “Evaluation of an Algorithm for the Integrated
(9357): 561–66. Management of Childhood Illness in an Area with Seasonal Malaria in
Schneider, G. 2001.“Oxygen Supply in Rural Africa: A Personal Experience.” The Gambia.” Bulletin of the World Health Organization 75 (Suppl. 1):
International Journal of Tuberculosis and Lung Disease 5 (6): 524–26. 25–32.
Schumacher, R., E. Swedberg, M. O. Diallo, D. R. Keita, H. Kalter, and Wenger, J. D., J. DiFabio, J. M. Landaverde, O. S. Levine, and T. Gaafar.
O. Pasha. 2002. Mortality Study in Guinea: Investigating the Causes of 1999. “Introduction of Hib Conjugate Vaccines in the Non-
Death in Children under Five. Arlington, VA: Save the Children and the industrialized World: Experience in Four ‘Newly Adopting’ Countries.”
Basic Support for Institutionalizing Child Survival Project. Vaccine 18 (7–8): 736–42.
Shann, F. 1986. “Etiology of Severe Pneumonia in Children in Developing Wenger, J. D., and M. M. Levine, eds. 1997. Epidemiological Impact of
Countries.” Pediatric Infectious Disease 5 (2): 247–52. Conjugate Vaccine on Invasive Disease Caused by Haemophilus influen-
zae Type B. New York: Marcel Dekker.
Shann, F., M. Gratten, S. Germer, V. Linnemann, D. Hazlett, and R. Payne.
1984. “Aetiology of Pneumonia in Children in Goroka Hospital, Papua Whitney, C. G., M. M. Farley, J. Hadler, L. H. Harrison, N. M. Bennett,
New Guinea.” Lancet 2 (8402): 537–41. R. Lynfield, and others. 2003. “Decline in Invasive Pneumococcal
Disease after the Introduction of Protein-Polysaccharide Conjugate
Shann, F., K. Hart, and D. Thomas. 1984. “Acute Lower Respiratory Tract Vaccine.” New England Journal of Medicine 348 (18): 1737–46.
Infections in Children: Possible Criteria for Selection of Patients for
Antibiotic Therapy and Hospital Admission.” Bulletin of the World WHO (World Health Organization). 1990. “Antibiotics in the Treatment
Health Organization 62: 749–51. of Acute Respiratory Infections in Young Children.” Unpublished doc-
ument WHO/ARI/90.10, available on request from the Division of
Simoes, E. A. 1999. “Respiratory Syncytial Virus Infection.” Lancet 354 Child Health and Development, formerly the Division of Diarrhoeal
(9181): 847–52. and Acute Respiratory Disease Control, WHO, Geneva.
Simoes, E. A., T. Desta, T. Tessema, T. Gerbresellassie, M. Dagnew, and . 1991. “Management of the Young Child with an Acute
S. Gove. 1997. “Performance of Health Workers after Training in Respiratory Infection. Supervisory Skills Training Module.” Un-
Integrated Management of Childhood Illness in Gondar, Ethiopia.” published document, available on request from the WHO Division of
Bulletin of the World Health Organization 75 (Suppl. 1): 43–53. Child Health and Development, formerly the Division of Diarrhoeal
Sloyer, J. L. J., J. H. Ploussard, and V. M. Howie. 1981. “Efficacy of and Acute Respiratory Disease Control, WHO, Geneva.
Pneumococcal Polysaccharide Vaccine in Preventing Acute Otitis . 1993. “Oxygen Therapy for Acute Respiratory Infections in Young
Media in Infants in Huntsville, Alabama.” Reviews of Infectious Diseases Children in Developing Countries.” Geneva, WHO. http://www.
3 (Suppl.): S119–23. who.int/child-adolescent-health/New_Publications/CHILD_
Stensballe, L. G., J. K. Devasundaram, and E. A. Simoes. 2003. “Respiratory HEALTH/WHO_ARI_93.28.htm.
Syncytial Virus Epidemics: The Ups and Downs of a Seasonal Virus.” . 2002. The Multicountry Evaluation of IMCI Effectiveness, Cost and
Pediatric Infectious Disease Journal 22 (2 Suppl.): S21–32. Impact (MCE): Progress Report, May 2001–April 2002.
Strauss, W. L., S. A. Qazi, Z. Kundi, N. K. Nomani, and B. Schwartz WHO/FCH/CAH/02.16. Geneva: Division of Child and Adolescent
(Co-trimoxazole Study Group). 1998. “Antimicrobial Resistance and Health and Development, WHO.
Clinical Effectiveness of Co-trimoxazole versus Amoxycillin for . 2003. Consultative Meeting on Management of Children with
Pneumonia among Children in Pakistan: Randomised Controlled Pneumonia and HIV Infection, 30–31 Jan. 2003, Harare, Zimbabwe.
Trial.” Lancet 352: 270–74. WHO/FCH/CAH/03.4. Geneva: WHO.
Temple, K., B. Greenwood, H. Inskip, A. Hall, M. Koskela, and M. . 2004a. “Review Panel on Haemophilus influenzae Type B (Hib)
Leinonen. 1991. “Antibody Response to Pneumococcal Capsular Disease Burden in Bangladesh, Indonesia, and Other Asian Countries,
Polysaccharide Vaccine in African Children.” Pediatric Infectious Bangkok, 28–29 January 2004.” Weekly Epidemiological Record 79 (18):
Disease Journal 10 (5): 386–90. 173–75.
Tupasi, T. E., M. G. Lucero, D. M. Magdangal, N. V. Mangubat, M. E. . 2004b. “WHO/UNICEF Joint Statement: Management of
Sunico, C. U. Torres, and others. 1990. “Etiology of Acute Lower Pneumonia in Community Settings.” WHO/FCH/CAG/04.06. WHO,
Respiratory Tract Infection in Children from Alabang, Metro Manila.” Geneva.
Reviews of Infectious Diseases 12 (Suppl. 8): S929–39.
WHO (World Health Organization) and Child Adolescent Health.
UNAIDS (Joint United Nations Programme on HIV/AIDS). 2002. AIDS Forthcoming. Report on the Methodology and Assumptions Used to
Epidemic Update. Geneva: UNAIDS. Estimate Costs of Scaling Up Selected Child Health Interventions to 95%
Usen S., M. Weber, K. Mulholland, S. Jaffar, A. Oparaugo, C. Omosigho, in Order to Reduce Under-Five Mortality. Geneva: WHO.
and others. 1999. “Clinical Predictors of Hypoxaemia in Gambian Williams, B. G., E. Gouws, C. Boschi-Pinto, J. Bryce, and C. Dye. 2002.
Children with Acute Lower Respiratory Tract Infection: Prospective “Estimates of Worldwide Distribution of Child Deaths from Acute
Cohort Study.” British Medical Journal 318 (7176): 86–91. Respiratory Infections.” Lancet Infectious Diseases 2: 25–32.
Van den Hoogen, B. G., J. C. de Jong, J. Groen, T. Kuiken, R. de Groot, R. A. World Bank. 2002. World Development Indicators. CD-ROM. Washington,
Fouchier, and A. D. Osterhaus. 2001. “A Newly Discovered DC: World Bank.
Human Pneumovirus Isolated from Young Children with Respiratory
Tract Disease.” Nature Medicine 7: 719–24. Zwi, K. J., J. M. Pettifior, and N. Soderlund. 1999. “Paediatric Hospital
Admissions at a South African Urban Regional Hospital: The Impact
von Mutius, E. 2001. “Pediatric Origins of Adult Lung Disease.” Thorax of HIV, 1992–1997.” Annals of Tropical Paediatrics 19: 135–42.
56: 153–57.
Vuori-Holopainen, E., and H. Peltola. 2001. “Reappraisal of Lung Tap:
Review of an Old Method for Better Etiologic Diagnosis of Childhood
Pneumonia.” Clinical Infectious Diseases 32 (5): 715–26.