intramuscular route gained

Treatment Guidelines. Current recommendations severe pneumonia, Addo-Yobo and others (2004)
are for co- Intramuscular Antibiotics for find similar wide acceptance following clinical
Treatment of Severe reports that confirmed its
trimoxazole twice a day for five days for pneumonia cure rates. Because patients were treated with
and intra- Pneumonia. Even though oxygen when efficacy. Local complications of
chloramphenicol is active against intramuscular chlorampheni-
muscular penicillin or chloramphenicol for children needed for hypoxemia and were switched to other
with severe both S. pneumoniae and H. influenzae, antibiotics if col succinate are rare, unlike the earlier
its oral absorption is intramuscular prepara-
pneumonia. The problems of increasing resistance to the treatment failed, this regimen is not appropriate
co- erratic in extremely sick children. Thus, the for treating tions. Although concerns about aplastic
WHO guidelines anemia following
trimoxazole and unnecessary referrals of children severe pneumonia in an outpatient setting.
with any chest recommend giving intramuscular 488 | Disease Control Priorities in Developing Countries |
Eric A. F. Simoes, Thomas Cherian, Jeffrey Chow, and
chloramphenicol at half the
others
wall indrawing have led to studies exploring
WHO recommends administering oxygen, if there is
alternatives to the daily dose before urgent referral of
ample supply, to children with signs and symptoms of severe
severe pneumonia cases. An
pneu- monia and, where supply is limited, to children with
antibiotics currently used in ARI case management.
any of the following signs: inability to feed and drink,
One study additional rationale is that extremely sick
cyanosis, res- piratory rate greater than or equal to 70 breaths
children may have
per minute, or severe chest wall retractions (WHO 1993).
indicated that amoxicillin and co-trimoxazole are
Oxygen should be administered at a rate of 0.5 liter per
equally effec- sepsis or meningitis that are difficult
minute for children younger than 2 months and 1 liter per
to rule out and must be
minute for older chil- dren. Because oxygen is expensive and
tive for nonsevere pneumonia (Catchup Study Group
supply is scarce, espe- cially in remote rural areas in
2002), treated immediately. Although intravenous
developing countries, WHO rec- ommends simple clinical
chloramphenicol is
signs to detect and treat hypoxemia. Despite those
though amoxicillin costs twice as much as
recommendations, a study of 21 first-level facil- ities and
co-trimoxazole. With superior to intramuscular
district hospitals in seven developing countries found that
chloramphenicol, the procedure can
more than 50 percent of hospitalized children with LRI were
respect to the duration of antibiotic treatment, studies
inappropriately treated with antibiotics or oxygen (Nolan and
in delay urgently needed treatment and adds to its
others 2001)—and in several, oxygen was in short supply.
cost.
Clearly, providing oxygen to hypoxemic babies is lifesaving,
Bangladesh, India, and Indonesia indicate that three
though no randomized trials have been done to prove it.
days of oral Investigators have questioned the
adequacy and safety of
co-trimoxazole or amoxicillin are as effective as five Prevention and Treatment of Pneumonia in HIV-Positive
days of intramuscular chloramphenicol. Although Children. Current recommendations of a WHO panel for
early studies sug- managing pneumonia in HIV-positive children and for pro-
either drug in children with nonsevere pneumonia phylaxis of Pneumocystis jiroveci are as follows (WHO
(Agarwal gested that adult blood levels after 2003):
intramuscular administra-
and others 2004; Kartasasmita 2003). In a • Nonsevere pneumonia up to age 5 years. Oral
multicenter study of tion were significantly less than co-trimoxazole should remain the first-line antibiotic, but
those achieved after intra- oral amoxicillin should be used if it is affordable or if the
intramuscular penicillin versus oral amoxicillin in child has been on co-trimoxazole prophylaxis.
children with venous administration, the
• Severe or very severe pneumonia. Normal WHO case- assumes that a high proportion of clinical pneumonia is of
management guidelines should be used for children up to 2 bacterial origin and that health work- ers can considerably
months old. For children from 2 to 11 months, injectable reduce case fatality through breathing rate diagnosis and
antibiotics and therapy for Pneumocystis jiroveci pneu- timely administration of antibiotics (Sazawal and Black
monia are recommended, as is starting Pneumocystis jirove- 2003). We calculated treatment costs by World Bank region
ci pneumonia prophylaxis on recovery. For children age 12 to using standardized input costs provided by the volume
59 months, the treatment consists of injectable antibi- otics editors and costs published in the International Drug Price
and therapy for Pneumocystis jiroveci pneumonia. Indicator Guide (Management Sciences for Health 2005) and
Pneumocystis jiroveci pneumonia prophylaxis should be other literature (table 25.1). The analysis addresses four cate-
given for 15 months to children born to HIV-infected gories of case management, which are distinguished by the
mothers; however, this recommendation has seldom been severity of the infection and the point of treatment:
implemented.
• nonsevere pneumonia treated by a community health
worker
COST-EFFECTIVENESS OF
• nonsevere pneumonia treated at a health facility
INTERVENTIONS
• severe pneumonia treated at a hospital
Pneumonia is responsible for about a fifth of the estimated • very severe pneumonia treated at a hospital.
10.6 million deaths per year of children under five. Where
pri- mary health care is weak, reducing mortality through Information about these categories of case management
public health measures is a high priority. As noted earlier, the and their outcomes is drawn from a report on the
available interventions are primary prevention by vaccination methodology and assumptions used to estimate the costs of
and sec- ondary prevention by early case detection and scaling up select- ed health interventions aimed at children
management. (WHO and Child Adolescent Health forthcoming). We
The cost-effectiveness of Hib vaccines is discussed in assumed a total of three follow-up visits for each patient
chap- ter 20. We did not attempt an analysis of the treated by a community health worker rather than the
cost-effectiveness twice-daily follow-ups for 10 days rec- ommended by the
of pneumococcal vaccines, because global and regional es report. We also assumed that all severe pneumonia patients
mates of the pneumococcal pneumonia burden are current receive an x-ray examination, rather than just 20 percent as
being developed and will not be available until later in 200 suggested by the report. Moreover, we assumed a five-hour
In addition, current vaccine prices are relatively stable workday for a community health worker, the minimum
devel- oped countries, but the prices for low- an workday required for community health work- ers under the
middle-income countries are expected to be substantial Child Health and Survival initiative of the U.S. Agency for
lower when vaccines are purchased through a global tender. International Development (Bhattacharyya and others 2001).
We evaluate case-management intervention strategies f Table 25.2 presents region-specific estimates of average
LRIs in children under five. Health workers who impleme treatment costs per episode for the four case-management
case management diagnose LRIs on the basis of fa strategies. Because we considered the prices of tradable com-
breathing, lower chest wall indrawing, or selected dang modities such as drugs and oxygen to be constant across
signs in children with respiratory symptoms. Because th
method does not dis- tinguish between pneumonia an
bronchiolitis, nor between bacterial and viral pneumonia, w
group these conditions into the general category of “clinic
pneumonia” (Rudan and oth- ers 2004). This approa
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
than costs detailed in tables 25.1 and 25.2, region-specific LRI
at the community level, and of all four case-management morbidity rates, adapted from Rudan and others (2004),
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 likely to be infected again the
following year—we calculated the
IMPLEMENTATION OF ARI CONTROL STRATEGIES: LESSONS OF EXPERIENCE
cost-effectiveness of a five-year intervention. This time period enabled us to consider the case in which an entire
cohort of newborns to four-year-olds avoids early childhood clinical pneumonia mortality because of the
intervention and receives
The lessons of ARI prevention and control strategies that have been implemented by national programs include the
vaccina- tion and case-management strategies discussed below.
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

specific countries have since been approved for support from GAVI for
mortality was reduced by 42, 36, and 36 percent, Hib vaccine introduction in 2004–5.
respectively. These data clearly show that relatively simplified, The United States added 7-PCV to the infant
immunization
but standardized, ARI case management can have a significant program in 2000. Several other industrialized
countries have
effect on mortality, not only from pneumonia, but also from plans to introduce the vaccine into their national
immuniza-
other causes in children from birth to age four. Currently, the tion programs in 2005, whereas others recommend the
use of
ARI case-management strategy has been incorporated into the vaccine only in selected high-risk groups. In some of
these
the IMCI strategy, which is now implemented in more than last countries, the definition of high risk is quite broad
and
80 countries (see chapter 63). includes a sizable proportion of all infants. The currently
Despite the huge loss of life to pneumonia each year, the licensed 7-PCV lacks certain serotypes important in
developing
promise inherent in simplified case management has not been
countries,butthe9-PCVand11-PCVwouldcoveralmost80per-
successfullyrealizedglobally.Onemainreasonistheunderuseof cent of serotypes that cause serious disease worldwide.
health facilities in countries or communities in which many chil- Despite the success of Hib vaccine in industrial
countries
dren die from ARIs. In Bangladesh, for example, 92 percent of and the generally appreciated importance of LRIs as
a cause of
sick children are not taken to appropriate health facilities (WHO childhood mortality, as a result of a number of
interlinked fac-
2002). In Bolivia, 62 percent of children who died had not been tors, uptake in developing countries has been slow.
Sustained
taken to a health care provider when ill (Aguilar and others use of the vaccine is threatened in a few of the countries
that
1998). In Guinea, 61 percent of sick children who died had not have introduced the vaccine. First, the magnitude of
disease
been taken to a health care provider (Schumacher and others and death caused by Hib is not recognized in these
countries,
2002). Schellenberg and others’ (2003) study in Tanzania shows partly because of their underuse of bacteriological
diagnosis
that children of poorer families are less likely to receive antibi- (a result of the lack of facilities and resources).
Second, because
otics for pneumonia than children of better-off families and that the coverage achieved with traditional Expanded
Program on
only 41 percent of sick children are taken to a health facility. Immunization vaccines remains low in many countries,
adding
Thus, studies consistently confirm that sick children, especially more vaccines has not been identified as a priority.
Third,
from poor families, do not attend health facilities. developing countries did not initiate efforts to establish the
A number of countries have established large-scale, sustain- utility of the vaccine until after the vaccine had been
licensed
able programs for treatment at the community level: and used routinely for several years in industrialized countries.
Consequently, Hib vaccination has been perceived as an inter-
• The Gambia has a national program for community-level vention for rich countries. As a result of all these factors,
actual
management of pneumonia (WHO 2004b). demand for the vaccine has remained low, even when support
• In the Siaya district of Kenya, a nongovernmental organiza- has been available through GAVI and the Vaccine
Fund.
tion efficiently provides treatment by community health In 2004, the GAVI board commissioned a Hib task force to
workers for pneumonia and other childhood diseases explore how best to support national efforts to make evidence-
(WHO 2004b). based decisions about introducing the Hib vaccine. On the
• In Honduras, ARI management has been incorporated in basis of the task force’s recommendations, the GAVI
board
the National Integrated Community Child Care Program, approved establishment of the Hib Initiative to support
those
whereby community volunteers conduct growth monitor- countries wishing either to sustain established Hib
vaccination
ing, provide health education, and treat pneumonia and or to explore whether introducing Hib vaccine should be a
diarrhea in more than 1,800 communities (WHO 2004b). priority for their health systems. A consortium consisting
of
• In Bangladesh, the Bangladesh Rural Advancement the Johns Hopkins Bloomberg School of Public Health, the
Committee and the government introduced an ARI control London School of Hygiene and Tropical Medicine, the
Centers
program covering 10 subdistricts, using volunteer commu- for Disease Control and Prevention, and the WHO has
been
nity health workers. Each worker is responsible for treating selected to lead this effort.
childhood pneumonia in some 100 to 120 households after a three-day training program.
Case-Management Strategies
• In Nepal during 1986–89, a community-based program for management of ARIs and diarrheal disease was tested
in Sazawal and Black’s (2003) meta-analysis of community-based
 two districts and showed substantial reductions in LRI trials of the ARI case-management strategy includes 10
studies
mortality (Pandey and others 1989, 1991). As a result, the that assessed its effects on mortality, 7 with a concurrent
program was integrated into Nepal’s health services and is control group. The meta-analysis found an all-cause
mortality
being implemented in 17 of the country’s 75 districts by reduction of 27 percent among neonates, 20 percent among
female community health volunteers trained to detect and infants, and 24 percent among children age one to four.
LRI-
treat pneumonia.
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 approximately 70,000 women, who work in communities providing
education and management of childhood pneu- monia to more than 30 million people (WHO 2004b).

RESEARCH AND DEVELOPMENT AGENDA

The research and development agenda outlined below summa- rizes the priorities that have been established by advisory
groups to the Initiative for Vaccine Research (vaccine interven- tion strategies) and the WHO Division of the Child and
Adolescent Health (case-management strategies).

Vaccine Intervention Strategies

The GAVI task force on Hib immunization made a number of recommendations that vary depending on the country.
Countries that have introduced Hib vaccine should focus on documenting its effect and should use the data to inform national
authorities, development partners, and other agencies involved in public health to ensure sustained support to such
vaccination programs. Countries eligible for GAVI support that have not yet introduced Hib vaccines are often hindered by a
lack of local data and a lack of awareness of regional data. They can address these issues through subregional meetings at
which country experts can pool data and review information from other countries. In addition, most of the countries need to
carry out economic analyses that are based on a standardized instrument. Finally, all countries that face a high Hib disease
burden need to develop laboratory facilities so that they can establish the incidence of Hib meningitis at selected sites.
Countries in which the disease burden remains unclear may have limited capacity to document the occurrence of Hib dis-
ease using protocols that are based on surveillance for menin- gitis invasive disease. They will need to explore the
possibilities of using alternative methods for measuring disease burden, including the use of vaccine-probe studies.
On the basis of experience with introducing Hib and hepa- titis B vaccines, GAVI took a proactive approach and in
2003 established an initiative based at the Johns Hopkins School of Public Health in Baltimore to implement an accelerated
devel- opment and introduction program for pneumococcal vaccines (the PneumoADIP; see
http://www.preventpneumonia.org). The program’s intent is to establish and communicate the value of pneumococcal
vaccines and to support their delivery. Establishing the value of the vaccine involves developing local evidence about the
burden of disease and the vaccines’ poten- tial effect on public health. This effort can be accomplished through enhanced
disease surveillance and relevant clinical tri- als in a selected number of lead countries. Once established, the evidence base
will be communicated to decision makers and key opinion leaders to ensure that data-driven decisions are made. Once the
cost-effectiveness of routine vaccination is
established, delivery systems will have to be established, and countries will need financial support so that the vaccines can be
introduced into their immunization programs. These activities 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.

Case-Management Strategies
In 2003, WHO’s Division of Child and Adolescent Health con- vened a meeting to review data and evidence from recent
ARI case-management studies and to suggest the following revisions to case-management guidelines and future research
priorities:

• Nonsevere pneumonia: — Improve the specificity of clinical diagnostic criteria. — Reassess WHO’s current recommended
criteria for detecting and managing treatment failure, given the high rates of therapy failure. — Reanalyze data from
short-course therapy studies to
better identify determinants of treatment failure. — Carry out placebo-controlled trials among children pre- senting with
wheezing and pneumonia in selected set- tings that have a high prevalence of wheezing to deter- mine whether such
children need antibiotics.
• Severe pneumonia: In a randomized clinical trial in a con- trolled environment, Addo-Yobo and others (2004) showed that
oral amoxicillin is as effective as parenteral penicillin or ampicillin; however, the following actions need to be under- taken
before it can be recommended on a general basis: — Analyze data on exclusions from the trial. — Identify predictors that
may help distinguish children who require hospitalization and who subsequently deteriorate. — Reassess WHO’s current
recommended treatment failure criteria for severe pneumonia, given the overall high rates of therapy failure. — Conduct
descriptive studies in a public health setting in several centers worldwide, to evaluate the clinical out- comes of oral
amoxicillin in children age 2 to 59 months who present with lower chest wall indrawing. — Document the effectiveness of
WHO’s treatment guide- lines for managing children with pneumonia and HIV infection.
• LRI deaths: — To help develop more effective interventions to reduce LRI mortality, study the epidemiology of LRI deaths
in various regions in detail, using routine and advanced laboratory techniques.
• Oxygen therapy: — Carry out studies to show the effectiveness of oxygen for
managing severe respiratory infections.

Acute Respiratory Infections in Children | 493

vaccine — Collect baseline information about the availability and
may fall with the entry of more manufacturers into the delivery of oxygen and its use in hospital settings in low-
market in the next few years. Nevertheless, convincing evidence income countries.
of the vaccines’ cost-effectiveness is required to facilitate — Explore the utility of pulse oximetry for optimizing
oxy-
national decisions on introducing the vaccine and using it sus- gen therapy in various clinical settings.
tainedly. In low-income countries, positive cost-benefit and — Undertake studies to improve the specificity of
clinical
cost-effectiveness ratios alone appear to be insufficient to signs in the overlapping signs and symptoms of malaria
enable the introduction of these vaccines into national immu- and pneumonia.
nization programs. — Study rapid diagnostic tests for malaria to assess their effectiveness in differentiating between
malaria and pneumonia.