This post is part of the PEMBlog series on Community Acquired Pneumonia and is focused on laboratory studies. It was contributed by Preston Dean, a senior pediatric resident at Cincinnati Children’s.

Community acquired pneumonia (CAP) is the most common infectious cause of death in children worldwide.1 Though mortality rates are drastically lower in developed nations, it remains a significant cause of morbidity as it is the second most common cause for hospitalization in children 1-17 years old in the United States.2 When a provider is presented with a case of pediatric pneumonia in the emergency department, there are often two important questions to answer:

  1. What is the most likely etiology?
  2. Is this patient safe to be discharged home?

This post will consider the evidence behind lab work in pediatric CAP, specifically in relation to etiology and severity of disease.

Blood Culture

The 2011 Pediatric Infectious Disease Society/Infectious Disease Society of America (IDSA) CAP guidelines state that children who can be managed as an outpatient do not need a blood culture.1 Much of the research that contributes to this recommendation was done after the introduction of the Haemophilus influenzae type B conjugate vaccine but before the introduction of routine pneumococcal vaccination. In these studies, rates of bacteremia in patients managed as an outpatient were < 2 %.1 Studies have suggested the number of true positive blood cultures for children with CAP managed as an outpatient in the pneumococcal vaccination era is < 1 %.3

The 2011 IDSA guidelines recommend that children admitted with CAP should have a blood culture drawn.1 The evidence sited in this recommendation also included many studies before routine pneumococcal vaccination and studies that did not obtain blood cultures on all patients admitted with CAP, thus introducing selection bias with patients with more severe disease more likely to have received a blood culture.1 The majority of these studies cited a true positive blood culture rate of 1.5 – 3.5 %.4-7 In cases of complicated CAP (empyema, lung abscesses, necrotizing pneumonias), recent studies describe a positive blood culture rate of 13-14%.6, 8 The utility of blood cultures for CAP in the ED remains controversial, with many studies questioning the utility of universal blood cultures for patients admitted with CAP, suggesting that a more targeted approach based on those at high risk for bacteremia is more appropriate.9, 10

In 2012, a case-control study was performed to determine the prevalence of bacteremia in children presenting with CAP to the emergency department, identify those at increased risk for bacteremia, and evaluate the impact of positive blood cultures on the management of CAP. In the study, 877 patients were diagnosed with CAP and 291 had a blood culture drawn (227 admitted, 64 discharged home). Of the 64 cases discharged home, 0 had a positive blood culture. Of the 227 cases admitted, 6 (2.6%) had a positive blood culture. Of the 6 cases with bacteremia, 4 of the 6 resulted in narrowing from broad spectrum to narrow spectrum antibiotics and only 1 of the 6 resulted in broadening of coverage. The rate of bacteremia in patients with complicated pneumonia (effusion/empyema, lung abscess, or necrotizing pneumonia) was 13%, which is similar to the rate described in other studies.6

Complete Blood Count/Absolute Neutrophil Count

The utilization of a complete blood count (CBC) in the diagnostic workup of pediatric CAP varies widely between U.S. pediatric Emergency Departments, with rates ranging from 11-54%.11 The 2011 IDSA guidelines do not support the routine use of complete blood counts in the evaluation of pediatric CAP, recommending (under low-quality evidence) that a CBC only be drawn in severe cases.1 Studies have routinely shown that leukocyte count alone is both a poor predictor for etiology (bacterial vs viral) and for severity of pediatric CAP.1, 12-15 More recent studies have suggested that leukocyte count or absolute neutrophil count (ANC) can be used in combination with other biomarkers, such as inflammatory markers, to increase specificity in terms of diagnosing bacterial pneumonia,14, 16 however its role in determining severity of pneumonia appears minimal.

C-Reactive Protein

C-reactive protein (CRP) has limitations in both its ability to determine pneumonia etiology and in its ability to predict pneumonia severity.17 An example of its limitations towards predicting severity, a 2015 cross sectional study of 114 inpatient children < 14 years old diagnosed with CAP showed that CRP was associated with lobar consolidation and pleural effusion but not with factors that could indicate severity (Heart Rate, SpO2, Respiratory Distress). It should be noted that most cases in this study were viral and the overall numbers of pleural effusion and lobar consolidation were low.18

In regards to determining pneumonia etiology, CRP by itself has limitations. A 2008 meta-analysis of >1200 pediatric patients showed that CRP values of 4-6 mg/dL were weak predictors of bacterial etiology (OR 2.58, PPV 64%).19 In a 2014 prospective cohort of >400 pediatric patients admitted with CAP, CRP > 8 mg/dL had an OR of 3.6 for bacterial vs viral pneumonia, however CRP < 2 mg/dL was not able to effectively rule out bacterial infections. CRP may show value in combination with other biomarkers. In the same study, a combined model of CRP > 8 mg/dL and ANC > 10,000 was highly specific and modestly sensitive for bacterial infection (sensitivity 75%, specificity 89%, AUC 0.89).16

The routine use of CRP (or other inflammatory markers) in the evaluation of CAP is not recommended in the 2011 IDSA guidelines. However, it has shown utility in severe cases to track response to therapy and resolution of disease.1, 17

Procalcitonin

Procalcitonin (PCT) is a biomarker that has been steadily gaining popularity in its use to detect various inflammatory and infectious conditions. In regards to determining etiology of pediatric CAP, it has shown promise but results have been conflicting.17 Many studies have concluded that PCT is superior to CRP in detecting bacterial vs viral CAP,15, 20, 21 however several other studies conclude that PCT alone has no utility in the determination of pneumonia etiology.22-24 Other studies suggest that the combination of PCT with other tests such as a CBC or urinary antigen tests significantly increase its effectiveness in diagnosing bacterial pneumonia.14, 17

It should be noted that there are significant limitations with accurately determining pneumonia etiology for a multitude of reasons, including the inability of young children to produce sputum, the high frequency of viral infections in younger children, limitations with current diagnostic testing methods, and the not uncommon mixed bacterial/viral pneumonia. These factors have led to significant heterogeneity in regards to etiologic diagnostic methods between studies which has likely contributed to the conflicting data seen in the published literature.

Read more about Procalcitonin in this PEMBlog post.

Viral Studies

Viruses are common causes of pediatric CAP, especially in younger ages. In children aged 3 months – 5 years viruses account for 50-60% of cases of pneumonia.25 The rate of viral testing varies widely between pediatric emergency departments, ranging from 1-40% (25th-75th %ile: 9-22%).11 Previous studies have shown that positive viral testing has been associated with reduced antibiotic administration, early antibiotic discontinuation, and decreased rates of starting antibiotics at outpatient follow up visits.1 The 2011 IDSA CAP guidelines recommend the use of rapid influenza testing during flu season. They also recommend that non-influenza viral testing should be considered only if it will alter clinical management.1 Non-influenza viral testing panels are often of significant cost, which must be taken into consideration before ordering.

Sputum Cultures

The 2011 IDSA CAP guidelines provide a weak recommendation based on low quality evidence that hospitalized children who can produce sputum should have a sputum culture and gram stain performed.1 From a technical standpoint, this is difficult, as most children are not effective at expectorating sputum. Also complicating matters, is that up to two thirds of children under the age of 5 are colonized with Streptococcus pneumoniae, therefore contaminating sputum specimens.17

Gene Expression Profiles

Gene expression profiles are gaining popularity as markers for severity of illness. From a pediatric lower respiratory tract infection standpoint, a multicenter cohort of 3 pediatric institutions that evaluated children admitted with bronchiolitis showed that genomic severity scores correlated with clinical disease severity scores, length of hospitalization, and duration of supplemental oxygen.26 Gene expression profiles utility in pediatric CAP requires further research.

Take Home Points

  • No lab work needs to be performed on children with pneumonia who meet criteria to be discharged home.
  • Current recommendations state that a blood culture should be obtained for children with pneumonia that require admission. The overall true positive blood culture rate for children hospitalized with pneumonia is 1.5 – 3.5%, increased to ~13% in cases of complicated pneumonia.
  • Complete Blood Counts have no utility in the assessment of pneumonia severity.
  • Inflammatory markers alone are unable to accurately predict disease etiology. A combination of inflammatory markers with complete blood counts or urinary antigen tests have increased specificity in terms of diagnosing bacterial pneumonia, however more research is needed in this area.
  • Inflammatory markers are not able to accurately predict disease severity, but have utility in tracking response to therapy in severe cases.
  • Rapid influenza testing should be performed on children presenting with CAP during flu season. Other viral studies should only be performed if it will alter clinical management.
  • Children over 5 years old diagnosed with CAP who can expectorate sputum should have sputum cultures with gram stains performed.

References

  1. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-76.
  2. Pfuntner A, Wier L, Stocks C. Most Frequent Conditions in U.S. Hospitals, 2011. HCUP Statistical Brief #162.: Agency for Healthcare Research and Quality, Rockville, MD.; 2013.
  3. Black SB, Shinefield HR, Ling S, Hansen J, Fireman B, Spring D, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J. 2002;21(9):810-815.
  4. Hickey RW, Bowman MJ, Smith GA. Utility of blood cultures in pediatric patients found to have pneumonia in the emergency department. Ann Emerg Med. 1996;27(6):721-725.
  5. Bonadio WA. Bacteremia in febrile children with lobar pneumonia and leukocytosis. Pediatr Emerg Care. 1988;4(4):241-242.
  6. Shah SS, Dugan MH, Bell LM, Grundmeier RW, Florin TA, Hines EM, et al. Blood cultures in the emergency department evaluation of childhood pneumonia. Pediatr Infect Dis J. 2011;30(6):475-479.
  7. Sandora TJ, Desai R, Miko BA, Harper MB. Assessing quality indicators for pediatric community-acquired pneumonia. Am J Med Qual. 2009;24(5):419-427.
  8. St Peter SD, Tsao K, Spilde TL, Keckler SJ, Harrison C, Jackson MA, et al. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial. J Pediatr Surg. 2009;44(1):106-111; discussion 111.
  9. Andrews AL, Simpson AN, Heine D, Teufel RJ. A Cost-Effectiveness Analysis of Obtaining Blood Cultures in Children Hospitalized for Community-Acquired Pneumonia. J Pediatr. 2015;167(6):1280-1286.
  10. Mendoza-Paredes A, Bastos J, Leber M, Erickson E, Waseem M. Utility of blood culture in uncomplicated pneumonia in children. Clin Med Insights Pediatr. 2013;7:1-5.
  11. Florin TA, French B, Zorc JJ, Alpern ER, Shah SS. Variation in emergency department diagnostic testing and disposition outcomes in pneumonia. Pediatrics. 2013;132(2):237-244.
  12. Williams DJ, Hall M, Auger KA, Tieder JS, Jerardi KE, Queen MA, et al. Association of White Blood Cell Count and C-Reactive Protein with Outcomes in Children Hospitalized for Community-acquired Pneumonia. Pediatr Infect Dis J. 2015;34(7):792-793.
  13. Korppi M, Heiskanen-Kosma T, Leinonen M. White blood cells, C-reactive protein and erythrocyte sedimentation rate in pneumococcal pneumonia in children. Eur Respir J. 1997;10(5):1125-1129.
  14. Don M, Valent F, Korppi M, Canciani M. Differentiation of bacterial and viral community-acquired pneumonia in children. Pediatr Int. 2009;51(1):91-96.
  15. Prat C, Domínguez J, Rodrigo C, Giménez M, Azuara M, Jiménez O, et al. Procalcitonin, C-reactive protein and leukocyte count in children with lower respiratory tract infection. Pediatr Infect Dis J. 2003;22(11):963-968.
  16. Elemraid MA, Rushton SP, Thomas MF, Spencer DA, Gennery AR, Clark JE. Utility of inflammatory markers in predicting the aetiology of pneumonia in children. Diagn Microbiol Infect Dis. 2014;79(4):458-462.
  17. Florin TA, Ambroggio L. Biomarkers for community-acquired pneumonia in the emergency department. Curr Infect Dis Rep. 2014;16(12):451.
  18. Agnello L, Bellia C, Di Gangi M, Lo Sasso B, Calvaruso L, Bivona G, et al. Utility of serum procalcitonin and C-reactive protein in severity assessment of community-acquired pneumonia in children. Clin Biochem. 2016;49(1-2):47-50.
  19. Flood RG, Badik J, Aronoff SC. The utility of serum C-reactive protein in differentiating bacterial from nonbacterial pneumonia in children: a meta-analysis of 1230 children. Pediatr Infect Dis J. 2008;27(2):95-99.
  20. Moulin F, Raymond J, Lorrot M, Marc E, Coste J, Iniguez JL, et al. Procalcitonin in children admitted to hospital with community acquired pneumonia. Arch Dis Child. 2001;84(4):332-336.
  21. Hatzistilianou M, Hitoglou S, Gougoustamou D, Rekliti A, Tzouvelekis G, Nanas C, et al. Serum procalcitonin, adenosine deaminase and its isoenzymes in the aetiological diagnosis of pneumonia in children. Int J Immunopathol Pharmacol. 2002;15(2):119-127.
  22. Toikka P, Irjala K, Juvén T, Virkki R, Mertsola J, Leinonen M, et al. Serum procalcitonin, C-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children. Pediatr Infect Dis J. 2000;19(7):598-602.
  23. Korppi M, Remes S, Heiskanen-Kosma T. Serum procalcitonin concentrations in bacterial pneumonia in children: a negative result in primary healthcare settings. Pediatr Pulmonol. 2003;35(1):56-61.
  24. Korppi M, Remes S. Serum procalcitonin in pneumococcal pneumonia in children. Eur Respir J. 2001;17(4):623-627.
  25. Gereige RS, Laufer PM. Pneumonia. Pediatr Rev. 2013;34(10):438-456; quiz 455-436.
  26. Mejias A, Dimo B, Suarez NM, Garcia C, Suarez-Arrabal MC, Jartti T, et al. Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection. PLoS Med. 2013;10(11):e1001549.