The Pediatric Infectious Disease Journal • Volume 33, Number 2, February 2014
recalculate the risk using the total number of children exposed to antimicrobials instead of the total number of children with bacterial carriage as a denominator, antimicrobial use appears to be associated with increased colonization with resistant bacteria. The method would be appropriate if the overall rate of colonization was the same between the 2 groups with and without antimicrobial usage. However, because the overall rates of colonization are significantly different, the use of the number of children with bacterial carriage as a denominator is more appropriate. Furthermore, their assertion that “antimicrobials reduce overall colonization by eradicating susceptible bacteria” is not supported by our data, as 28% (96/342) of children who had received antimicrobials were colonized by susceptible bacteria compared with 18% (239/1312) of children who did not receive antimicrobials. Therefore, our results indicate that recent exposure to antimicrobials is significantly associated with increased risk of colonization, but not with resistance rates. It is generally accepted that recent exposure to antimicrobials is one of the independent determinants for nasopharyngeal colonization.3,4 We do agree with Drs. Gounder and Hennessy that recent exposure to antimicrobials does increase the absolute number of resistant isolates. Therefore, introduction of appropriate usage of antimicrobials in areas of overuse could contribute to lower colonization of S treptococcus pneumoniae/Haemophilus influenzae, resulting in a decrease in the absolute number of resistant isolates.
Taketo Otsuka, MD, PhD on behalf of the SADO-study Working group Department of Pediatrics Sado General Hospital Chigusa, Sado Niigata, Japan REFERENCES 1. Otsuka T, Chang B, Shirai T, et al.; SADO-study Working Group. Individual risk factors associated with nasopharyngeal colonization with Streptococcus pneumoniae and Haemophilus influenzae: a Japanese birth cohort study. Pediatr Infect Dis J. 2013;32:709–714. 2. Ghaffar F, Friedland IR, McCracken GH Jr. Dynamics of nasopharyngeal colonization by Streptococcus pneumoniae. Pediatr Infect Dis J. 1999;18:638–646. 3. Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004;4:144–154. 4. van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet. 2009;374:1543–1556.
© 2013 Lippincott Williams & Wilkins
Is Pneumonia Among Children in Developing Countries a Different Disease From the 1 Among Patients in the Same Age Group in Developed Countries? To the Editors: The study by Wingerter et al1 assessed the utility of the World Health Organization (WHO) clinical criteria2 to identify children warranting treatment with antibiotics for possible pneumonia. It found a substantial proportion (65%) of children ≤5 years of age presenting to an urban, United States, emergency room with suspected community-acquired pneumonia who were found to have radiologic findings on chest radiograph (CXR) and were not identified by the WHO clinical screening criteria that rely on age specific elevated respiratory rates. The authors speculate that pneumonia in a developed, high access to care setting may be a “different disease” from that of developing countries, the primary target for the WHO screening criteria. Several important questions warrant further analysis, discussion and interpretation. The central issue raised by the study, and by several others before it, is whether existing WHO clinical pneumonia screening criteria require modification because, in some settings, they now lack sensitivity, failing to identify children warranting empiric antibiotic treatment, especially in limited access to care settings where such early treatment would be life saving. We are in agreement that a systematic reevaluation of the WHO screening criteria is warranted, but are not in agreement that pneumonia in the developed and developing world are different diseases as speculated by the authors. The failure of the WHO screening criteria to identify with high sensitivity children in this study with radiologic pneumonia could be attributed to any or all of at least 4 explanations, but additional analyses are needed. First, the CXR readings, which were the basis for evaluating the clinical criteria, may be overinterpreting the diagnosis of pneumonia. Specifically, the study enrollment criteria were ≤5 years of age and CXR performed for suspected respiratory disease. The authors have no funding or conflicts of interest to disclose. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3302-0229 DOI: 10.1097/INF.0000000000000121
Letters
There were no standardized clinical screening criteria to trigger obtaining the CXR; instead, this was done at the discretion of the treating clinician. Of the 2008 study subjects, 1241 (62%) had neither tachypnea nor any changes on CXR, and only 16% of study subjects had any abnormal findings on CXR. The threshold for obtaining a CXR in this setting was very low and therefore has an impact on understanding the CXR-positive cases. The CXR categorization was based on the report of the practicing radiologist and not a study specific, standardized reading. We expect that clinical radiographic readings were done to reach high sensitivity, appropriate for a clinical setting but may inadvertently have led to overdiagnosis of pneumonia. CXR interpretation is observer dependent with poor intra- and interobserver concordance, especially in the absence of dense alveolar consolidation. To minimize this misclassification effect, CXR readings for study purposes should be interpreted using standardized definitions by specifically trained, independent readers.3,4 This could be important in the interpretation of the study results as diagnostic accuracy measures are modified by the prevalence of the disease, which means that in a sample with infrequent disease, sensitivity will be lowered.5 It would be useful to have the CXRs reread using standardized criteria and specifically trained readers. Furthermore, the authors provided very little data on the actual radiographic findings among those with a positive CXR but no tachypnea and provided no further clinical information on those with tachypnea but no radiographic finding. The second explanation for the lack of sensitivity of the WHO clinical criteria relates to the data on the respiratory rates, the index being assessed by the study. These values were abstracted from the triage notes of the medical record. There is no description of any specific training or standardization to assure the accuracy of the measures and no description of whether the method included counting for a full minute, use of specific timers or the status of the child at the time of counting. Substantial interobserver variability in these measures is recognized, especially where specific processes are not in place. An analysis of the respiratory rate distribution by age strata (including disaggregating the 1- to 5-year old category further), CXR findings and other clinical variables like hypoxemia to more clearly understand the likely validity of the measures would assist in interpretation. A third explanation for poor sensitivity of respiratory rate to identify CXR-positive cases may be that the study was conducted in a setting of routine vaccination against Haemophilus influenzae type b (Hib) and www.pidj.com | 229
Letters
pneumococcus. The WHO respiratory rate criteria were selected based on field, observational studies in target epidemiologic settings because of their high sensitivity, reasonable specificity and ease of implementation where access to formal medical assessments was limited. The evidence base for establishing these criteria is from the era before the introduction of vaccines against Hib and pneumococcus, the 2 major causes of pneumonia mortality and the 2 major targets of early empiric antibiotic therapy. In settings with widespread use of Hib vaccine and pneumococcal conjugate vaccine, bacterial pneumonia is of much lower likelihood than the settings in which the screening criteria were formulated and most relevant for use. In vaccine use settings, the etiologic distribution of the remaining pneumonia cases would be much more skewed toward nonbacterial etiologies whose presentation may not be well-represented by the current respiratory rate cutoffs. Fourth, as the authors speculated, the timing of accessing care may impact the measured sensitivity of the clinical screening criteria. The authors speculated that their studied population may have presented early in the disease process when the CXR findings are already present but disease has not progressed sufficiently to establish tachypnea, explaining the difference of the respiratory rate criteria in their setting. The article does not provide a description of the clinical findings or the CXR findings among the 213 whose CXRs were categorized as having an infiltrate but who did not have an elevated respiratory rate. A detailed understanding of the characteristics of the illness episodes among these children is of interest, including the reason for obtaining a CXR.
230 | www.pidj.com
The Pediatric Infectious Disease Journal • Volume 33, Number 2, February 2014
Although there are differences in community-acquired pneumonia incidence, risk factors and mortality rate,6 between developed and developing area populations, there is no evidence that pneumonia itself differs in its biology or pathogenesis. Absent vaccination against Hib or pneumococcus, the distribution of pathogens causing pneumonia is very similar across settings, as evidenced in part by the Hib vaccine and pneumococcal conjugate vaccine trials and routine use impact data. The 36% reduction in all-cause pneumonia hospitalization following 7-valent pneumococcal conjugate vaccine introduction in United States indicates that pneumococcus was a leading cause of pneumonia in developed countries, as is the case in developing countries as well.7 In conclusion, we are in agreement with the authors that a comprehensive reassessment of the WHO clinical screening criteria is now warranted. However, this is required by the widespread global introduction and use of Hib and pneumococcal vaccine, along with other changes in diagnostics, treatment availability and prevalence of community-based risk factors for pneumonia and not because there is any fundamental difference in pneumonia among children in developed countries compared with developing countries.
Cristiana M. Nascimento-Carvalho, MD, PhD Department of Pediatrics, Federal University of Bahia School of Medicine, Salvador, Brazil
Shabir A. Madhi, MD, PhD
Medical Research Council: Respiratory and Meningeal P athogens Research Unit and Department of Science and Technology/
National Research Foundation: Vaccine Preventable Diseases, Faculty of Health Sciences, University of the Witwatersrand, South Africa
Katherine L. O´Brien, MD, MPH
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD REFERENCES
1. Wingerter SL, Bachur RG, Monuteaux MC, et al. Application of the world health organization criteria to predict radiographic pneumonia in a US-based pediatric emergency department. Pediatr Infect Dis J. 2012;31:561–564. 2. World Health Organization. Programme for the control of acute respiratory infections. Acute respiratory infections in children: case management in small hospitals in developing countries. Geneva: WHO; 1990 [online]. Available at: http://whqlibdoc.who.int/hq/1990/WHO_ ARI_90.5.pdf. Accessed May 26, 2013. 3. Xavier-Souza G, Vilas-Boas AL, Fontoura MS, et al.; PNEUMOPAC-Efficacy Study Group. The Inter-observer variation of chest radiograph reading in acute lower respiratory tract infection among children. Pediatr Pulmonol. 2013;48:464–469. 4. Cherian T, Mulholland EK, Carlin JB, et al. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ. 2005;83:353–359. 5. Zhou XH, NA Obuchowski, DK McClish. Statistical methods in diagnostic medicine. New York: Wiley; 2002. 6. Principi N, Esposito S. Management of severe community-acquired pneumonia of children in developing and developed countries. Thorax. 2011;66:815–822. 7. Griffin MR, Zhu Y, Moore MR, et al. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155–163.
© 2013 Lippincott Williams & Wilkins
recalculate the risk using the total number of children exposed to antimicrobials instead of the total number of children with bacterial carriage as a denominator, antimicrobial use appears to be associated with increased colonization with resistant bacteria. The method would be appropriate if the overall rate of colonization was the same between the 2 groups with and without antimicrobial usage. However, because the overall rates of colonization are significantly different, the use of the number of children with bacterial carriage as a denominator is more appropriate. Furthermore, their assertion that “antimicrobials reduce overall colonization by eradicating susceptible bacteria” is not supported by our data, as 28% (96/342) of children who had received antimicrobials were colonized by susceptible bacteria compared with 18% (239/1312) of children who did not receive antimicrobials. Therefore, our results indicate that recent exposure to antimicrobials is significantly associated with increased risk of colonization, but not with resistance rates. It is generally accepted that recent exposure to antimicrobials is one of the independent determinants for nasopharyngeal colonization.3,4 We do agree with Drs. Gounder and Hennessy that recent exposure to antimicrobials does increase the absolute number of resistant isolates. Therefore, introduction of appropriate usage of antimicrobials in areas of overuse could contribute to lower colonization of S treptococcus pneumoniae/Haemophilus influenzae, resulting in a decrease in the absolute number of resistant isolates.
Taketo Otsuka, MD, PhD on behalf of the SADO-study Working group Department of Pediatrics Sado General Hospital Chigusa, Sado Niigata, Japan REFERENCES 1. Otsuka T, Chang B, Shirai T, et al.; SADO-study Working Group. Individual risk factors associated with nasopharyngeal colonization with Streptococcus pneumoniae and Haemophilus influenzae: a Japanese birth cohort study. Pediatr Infect Dis J. 2013;32:709–714. 2. Ghaffar F, Friedland IR, McCracken GH Jr. Dynamics of nasopharyngeal colonization by Streptococcus pneumoniae. Pediatr Infect Dis J. 1999;18:638–646. 3. Bogaert D, De Groot R, Hermans PW. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis. 2004;4:144–154. 4. van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet. 2009;374:1543–1556.
© 2013 Lippincott Williams & Wilkins
Is Pneumonia Among Children in Developing Countries a Different Disease From the 1 Among Patients in the Same Age Group in Developed Countries? To the Editors: The study by Wingerter et al1 assessed the utility of the World Health Organization (WHO) clinical criteria2 to identify children warranting treatment with antibiotics for possible pneumonia. It found a substantial proportion (65%) of children ≤5 years of age presenting to an urban, United States, emergency room with suspected community-acquired pneumonia who were found to have radiologic findings on chest radiograph (CXR) and were not identified by the WHO clinical screening criteria that rely on age specific elevated respiratory rates. The authors speculate that pneumonia in a developed, high access to care setting may be a “different disease” from that of developing countries, the primary target for the WHO screening criteria. Several important questions warrant further analysis, discussion and interpretation. The central issue raised by the study, and by several others before it, is whether existing WHO clinical pneumonia screening criteria require modification because, in some settings, they now lack sensitivity, failing to identify children warranting empiric antibiotic treatment, especially in limited access to care settings where such early treatment would be life saving. We are in agreement that a systematic reevaluation of the WHO screening criteria is warranted, but are not in agreement that pneumonia in the developed and developing world are different diseases as speculated by the authors. The failure of the WHO screening criteria to identify with high sensitivity children in this study with radiologic pneumonia could be attributed to any or all of at least 4 explanations, but additional analyses are needed. First, the CXR readings, which were the basis for evaluating the clinical criteria, may be overinterpreting the diagnosis of pneumonia. Specifically, the study enrollment criteria were ≤5 years of age and CXR performed for suspected respiratory disease. The authors have no funding or conflicts of interest to disclose. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3302-0229 DOI: 10.1097/INF.0000000000000121
Letters
There were no standardized clinical screening criteria to trigger obtaining the CXR; instead, this was done at the discretion of the treating clinician. Of the 2008 study subjects, 1241 (62%) had neither tachypnea nor any changes on CXR, and only 16% of study subjects had any abnormal findings on CXR. The threshold for obtaining a CXR in this setting was very low and therefore has an impact on understanding the CXR-positive cases. The CXR categorization was based on the report of the practicing radiologist and not a study specific, standardized reading. We expect that clinical radiographic readings were done to reach high sensitivity, appropriate for a clinical setting but may inadvertently have led to overdiagnosis of pneumonia. CXR interpretation is observer dependent with poor intra- and interobserver concordance, especially in the absence of dense alveolar consolidation. To minimize this misclassification effect, CXR readings for study purposes should be interpreted using standardized definitions by specifically trained, independent readers.3,4 This could be important in the interpretation of the study results as diagnostic accuracy measures are modified by the prevalence of the disease, which means that in a sample with infrequent disease, sensitivity will be lowered.5 It would be useful to have the CXRs reread using standardized criteria and specifically trained readers. Furthermore, the authors provided very little data on the actual radiographic findings among those with a positive CXR but no tachypnea and provided no further clinical information on those with tachypnea but no radiographic finding. The second explanation for the lack of sensitivity of the WHO clinical criteria relates to the data on the respiratory rates, the index being assessed by the study. These values were abstracted from the triage notes of the medical record. There is no description of any specific training or standardization to assure the accuracy of the measures and no description of whether the method included counting for a full minute, use of specific timers or the status of the child at the time of counting. Substantial interobserver variability in these measures is recognized, especially where specific processes are not in place. An analysis of the respiratory rate distribution by age strata (including disaggregating the 1- to 5-year old category further), CXR findings and other clinical variables like hypoxemia to more clearly understand the likely validity of the measures would assist in interpretation. A third explanation for poor sensitivity of respiratory rate to identify CXR-positive cases may be that the study was conducted in a setting of routine vaccination against Haemophilus influenzae type b (Hib) and www.pidj.com | 229
Letters
pneumococcus. The WHO respiratory rate criteria were selected based on field, observational studies in target epidemiologic settings because of their high sensitivity, reasonable specificity and ease of implementation where access to formal medical assessments was limited. The evidence base for establishing these criteria is from the era before the introduction of vaccines against Hib and pneumococcus, the 2 major causes of pneumonia mortality and the 2 major targets of early empiric antibiotic therapy. In settings with widespread use of Hib vaccine and pneumococcal conjugate vaccine, bacterial pneumonia is of much lower likelihood than the settings in which the screening criteria were formulated and most relevant for use. In vaccine use settings, the etiologic distribution of the remaining pneumonia cases would be much more skewed toward nonbacterial etiologies whose presentation may not be well-represented by the current respiratory rate cutoffs. Fourth, as the authors speculated, the timing of accessing care may impact the measured sensitivity of the clinical screening criteria. The authors speculated that their studied population may have presented early in the disease process when the CXR findings are already present but disease has not progressed sufficiently to establish tachypnea, explaining the difference of the respiratory rate criteria in their setting. The article does not provide a description of the clinical findings or the CXR findings among the 213 whose CXRs were categorized as having an infiltrate but who did not have an elevated respiratory rate. A detailed understanding of the characteristics of the illness episodes among these children is of interest, including the reason for obtaining a CXR.
230 | www.pidj.com
The Pediatric Infectious Disease Journal • Volume 33, Number 2, February 2014
Although there are differences in community-acquired pneumonia incidence, risk factors and mortality rate,6 between developed and developing area populations, there is no evidence that pneumonia itself differs in its biology or pathogenesis. Absent vaccination against Hib or pneumococcus, the distribution of pathogens causing pneumonia is very similar across settings, as evidenced in part by the Hib vaccine and pneumococcal conjugate vaccine trials and routine use impact data. The 36% reduction in all-cause pneumonia hospitalization following 7-valent pneumococcal conjugate vaccine introduction in United States indicates that pneumococcus was a leading cause of pneumonia in developed countries, as is the case in developing countries as well.7 In conclusion, we are in agreement with the authors that a comprehensive reassessment of the WHO clinical screening criteria is now warranted. However, this is required by the widespread global introduction and use of Hib and pneumococcal vaccine, along with other changes in diagnostics, treatment availability and prevalence of community-based risk factors for pneumonia and not because there is any fundamental difference in pneumonia among children in developed countries compared with developing countries.
Cristiana M. Nascimento-Carvalho, MD, PhD Department of Pediatrics, Federal University of Bahia School of Medicine, Salvador, Brazil
Shabir A. Madhi, MD, PhD
Medical Research Council: Respiratory and Meningeal P athogens Research Unit and Department of Science and Technology/
National Research Foundation: Vaccine Preventable Diseases, Faculty of Health Sciences, University of the Witwatersrand, South Africa
Katherine L. O´Brien, MD, MPH
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD REFERENCES
1. Wingerter SL, Bachur RG, Monuteaux MC, et al. Application of the world health organization criteria to predict radiographic pneumonia in a US-based pediatric emergency department. Pediatr Infect Dis J. 2012;31:561–564. 2. World Health Organization. Programme for the control of acute respiratory infections. Acute respiratory infections in children: case management in small hospitals in developing countries. Geneva: WHO; 1990 [online]. Available at: http://whqlibdoc.who.int/hq/1990/WHO_ ARI_90.5.pdf. Accessed May 26, 2013. 3. Xavier-Souza G, Vilas-Boas AL, Fontoura MS, et al.; PNEUMOPAC-Efficacy Study Group. The Inter-observer variation of chest radiograph reading in acute lower respiratory tract infection among children. Pediatr Pulmonol. 2013;48:464–469. 4. Cherian T, Mulholland EK, Carlin JB, et al. Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies. Bull World Health Organ. 2005;83:353–359. 5. Zhou XH, NA Obuchowski, DK McClish. Statistical methods in diagnostic medicine. New York: Wiley; 2002. 6. Principi N, Esposito S. Management of severe community-acquired pneumonia of children in developing and developed countries. Thorax. 2011;66:815–822. 7. Griffin MR, Zhu Y, Moore MR, et al. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med. 2013;369:155–163.
© 2013 Lippincott Williams & Wilkins
