Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02946775 |
| Other study ID # |
0444-12 EP |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 13, 2012 |
| Est. completion date |
July 1, 2018 |
Study information
| Verified date |
September 2023 |
| Source |
University of Nebraska |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
To define the etiologic agents of community acquired bacteremic syndromes (defined as
septicemia, bacteremia, pneumonia and/or meningitis) in a malaria endemic setting.
Description:
Specific Aim 1. To define and characterize the etiologic agents of community acquired
bacteremic syndromes in young Nigerian children Hypothesis 1a: the role of
vaccine-preventable infections such as those caused by the Pneumococcus, Hib in the etiology
of CABS is currently underestimated due to widespread use of non-prescription antibiotics.
Hypothesis 1b: Salmonella species are the leading cause of persistent febrile illness (fever
> 2 weeks) in young Nigerian children.
Specific Aim 2. To determine the role of respiratory viruses in promoting the severity of
bacteremic and radio-logic pneumonia Hypothesis 2: Influenza viruses promote the severity of
bacteremic pneumonia
Specific Aim 3. To determine acute host inflammatory response profiles in CABS associated
with respiratory distress Hypothesis 3a: Bacteremia induces a pattern of host inflammatory
profile that is distinct from those induced by malaria or respiratory viral infections.
Hypothesis 3b: Clinical presentation and outcome (death, survival or prolonged
hospitalization) is associated with pro-inflammatory and anti-inflammatory cytokine and
chemokine dissonance.
The global burden of childhood deaths is largely borne by developing countries. Of the
estimated 10 million deaths that occur in children aged less than 5 years, over 90% of these
occur in developing countries and more than half of these in sub Saharan Africa. Causes of
these deaths have been largely classified based on syndrome presentation, such as pneumonia,
malaria, diarrhea, meningitis and septicemia and only recently have attempts been made to
define the etiologic pathogens that are responsible for these deaths, an important step to
implementing primary prevention. In sub Saharan Africa, malaria has for a long time been
perceived as the leading cause of childhood deaths but recent studies from Kenya suggest that
more deaths are in fact caused by bacteremia. However, disease burden varies by region and
disease burden perceptions also vary, particularly in malaria endemic regions where clinical
presentation of acute malaria, pneumonia and sepsis are often indistinguishable. The
situation is compounded further in regions where malaria is present all-year round where
children who are bacteremic may also have malaria parasitemia and healthy children may have
asymptomatic parasitemia. These complex and overlapping features present a challenge for
efficient clinical management and implementation of appropriate preventive measures.
In most developing countries, due to lack of local data, clinical management recommendations
are often obtained from the World Health Organization for common conditions based on the
integrated management of childhood illness approach 3. In such settings, diagnosis is based
on a limited number of clinical syndromes. However, because seriously ill children often meet
criteria for several clinical syndromes, each of which could be caused by several viral or
bacterial pathogens, treatment is empiric and management approach is non-specific. A key
component of clinical management in malaria endemic areas with high incidence of invasive
bacterial disease is the initiation of antibiotic treatment and anti-malarials. While this
approach provides an easy scheme, because it is not pathogen-specific there is a significant
risk of promoting long-term antibiotic resistance due to over prescription of antibiotics and
paradoxically, there is also the risk of increased mortality and morbidity due to
inappropriate medication. An etiology-based management approach would be more effective and
also provide data to explore primary preventive measures such as immunization.
Causes of bacteremia vary from reports in several sub-Saharan countries with high under-five
childhood mortality. These include studies from Malawi and the Central African Republic where
Non-typhoidal Salmonella (NTS) predominate and some reports from Nigeria where staphylococcus
aureus has been the leading cause of bacteremia in young children.
There are only a few studies from Nigeria, the most populated country in sub-Saharan Africa,
and these studies have not identified S. pneumoniae nor Hib as an important pathogen in the
etiology of community acquired bacteremic illness or invasive bacterial disease in young
children. The disparity in prevalence of different bacterial pathogens across countries is
likely due to the different study entry criteria, age groups, bacterial culture methods and
the prevalence of antibiotic exposure in the population. A high rate of antibiotic use is
likely to select for resistant bacterial strains in such populations. It is notable that of
all the studies that identified S. pneumoniae as a leading cause of bacteremia were studies
that utilized the automated Bactec culture system. Thus to determine the true burden of
vaccine-preventable bacterial disease in such a setting would warrant the use of
culture-based and molecular microbiology techniques that would overcome the problem of poor
sensitivity secondary to partially treated infections.
Of the childhood illnesses commonly associated with bacteremia, pneumonia is the leading
cause of death, with Streptococcus pneumonia making a significant contribution to these
deaths in reports from the Gambia but limited data from the West African sub region. Thus
this study will focus on providing further understanding of the etiologic agents of
bacteremia and pneumonia. Determination of the cause of pneumonia remains a challenge, since
bacterial blood culture, the current "gold standard" is useful only when when pneumonia is
associated with bacteremia and is positive only in about 10-15% of cases. The vast majority
of pneumonias are not associated with bacteremia and to ascertain cause in these cases
warrants the use of lung aspirates, a very specific but invasive procedure used only in
research settings.
When a clinical diagnosis of pneumonia is made using the WHO guideline, which is very
sensitive but poorly specific, only a fraction of these have any radio-logic abnormality and
a variable smaller fraction still, have a confluent alveolar density that culminates in a
lobar consolidation. When the lung consolidation is readily assessable to the chest wall, the
more sensitive and specific approach for the etiologic diagnosis is the use of a percutaneous
lung aspirate which is considered invasive and only used in research settings. This approach
improved etiologic diagnosis from 18% with the use of blood culture alone to 52%. Since this
procedure is invasive and reserved for only selected cases, the causes of most non-bacteremic
pneumonia remains poorly defined.
At the population level, another approach for determining the burden of disease-attributable
to an etiologic agent in a population is the use of an efficacious vaccine. For example, in
The Gambia, the pneumococcal conjugate vaccine efficacy trial was associated with 37%
reduction in radio-logic pneumonia and 16% reduction in all-cause childhood mortality; an
important testament to the under-estimation of the true disease burden attributable to the
pneumococcus and the poor sensitivity of the current diagnostic methods for the detection of
invasive pneumococcal disease in young children. While the development and application of
these new generation vaccines are a major advancement with a huge potential for saving
several thousands of lives, they also provide a sensitive tool for probing the burden of
vaccine-attributable preventable disease in a population but are very expensive.
The determination of the causes of pneumonia in childhood presents a further challenge as
other agents such as viruses have often been identified from respiratory secretions but their
role in the patho-genesis of severe pneumonia in developing countries is less well defined.
Understanding the host immune responses to infection is critical to providing insight into
treatment modalities, since these responses and not necessarily the pathogen, determine
outcome. This observation is further supported by the observation that prompt diagnosis and
initiation of antibiotic treatment does not always avert death as recently reported from a
study from the Gambia, where delayed mortality was reported within 28 days of hospital
discharge after appropriate in-patient care at a hospital. The reason for these delayed
deaths is unknown but prolonged immunologic dissonance (imbalance between pro-inflammatory
and anti-inflammatory cytokines) is a likely contributing factor. This deserves further
investigation since if these delayed deaths are due to immunologic dissonance, these deaths
may be averted with the use of steroids or other immunomodulators, in addition to
antibiotics. Characterization of host inflammatory responses among children with community
acquired pneumonia may facilitate understanding of host inflammatory response, provide a
prognostic tool for clinicians or identify potential therapeutic targets.
Children presenting with an acute febrile illness, with respiratory distress in a malaria
endemic region may have severe malaria, bacteremia, sepsis and/or pneumonia. A number of
studies have explored acute inflammatory markers such as C-reactive protein and procalcitonin
but have reported significant overlap in serum concentration of these proteins in both
conditions to justify a diagnostic use for in such settings. While the clinical presentation
with respiratory distress in pneumonia and malaria may be similar, understanding the
molecular basis for this clinical sign could provide valuable information for diagnosis and
treatment.
In summary, community acquired bacteremic syndromes in malaria endemic regions of Africa
presents a diagnostic conundrum for physicians and pose an important clinical management
dilemma that warrants further evaluation. This study proposes to take advantage of new
molecular and genomic technology in addressing this challenge with the ultimate goal of
defining the etiologic agents of community acquired bacteremic syndromes in Nigerian children
and generating information on host inflammatory responses that would be useful in developing
primary and secondary preventative measures.
