Community Acquired Bacteremic Syndromes in Young Nigerian Children
Condition: Community-Acquired Infections
MeSH terms: Community-Acquired Infections
Study type: Observational

Summary: 
      To define the etiologic agents of community acquired bacteremic syndromes (defined as
      septicemia, bacteremia, pneumonia and/or meningitis) in a malaria endemic setting.
    

Detailed 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.
    

Observational model: Ecologic or Community
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Pediatric subjects 0-14 years of age
      
Biospecimen description: 
      Blood, urine, stool, nasopharyngeal swab/aspirate as well as cerebrospinal fluid (CSF),
      pleural fluid, induced sputum, gastric aspirates or synovial fluid with clinical indication.
    
Keywords: septicemia; bacteremia; pneumonia; meningitis