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By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN
Dr. Fischer reports no financial relationships relevant to this field of study.
SYNOPSIS: Tachypnea has long been considered to identify which children with acute fever and cough might benefit from antibiotic treatment, especially in resource-limited parts of the world. Now, with declining rates of vaccine-preventable infections with Haemophilus influenzae and pneumococcus, new data suggest that approximately 90% of febrile, tachypneic, coughing (but still well enough for outpatient treatment) preschoolers do fine without antibiotics.
SOURCE: Ginsburg AS, Mvalo T, Nkwopara E, et al. Placebo vs amoxicillin for nonsevere fast-breathing pneumonia in Malawian children aged 2 to 59 months: A double-blind, randomized clinical noninferiority trial. JAMA Pediatrics 2019;173:21-28.
With nearly 1 million children around the world dying of pneumonia before reaching school age, it is important to identify which febrile coughing children would benefit from an antimicrobial agent. The World Health Organization’s (WHO’s) Integrated Management of Childhood Illness guidelines suggest using the presence of tachypnea to identify which children with acute respiratory infection might respond to antibiotic treatment. This strategy maximizes sensitivity to ensure that as few children as possible go untreated; of course, this strategy lacks specificity and might lead to overtreatment and worsened antimicrobial resistance.
Thus, Ginsburg and colleagues evaluated whether antibiotic treatment even helped generally healthy (no HIV) preschoolers with tachypnea and a respiratory illness but without retractions or poor oral intake. Investigators compared placebo to three days of oral amoxicillin (the current WHO-recommended treatment for nonsevere pneumonia) in 1,126 Malawian children. Children who developed worsened respiratory distress during or after treatment were considered to have failed treatment.
By day 4, 4% of amoxicillin-treated children had failed treatment; 7% of placebo-treated children failed (95% confidence interval [CI], 1.07-2.97). Of those who had not failed by day 4, 6.4% of amoxicillin-treated and 5.1% of placebo-treated patients failed treatment by day 14 (with the difference between groups not statistically significant). The number-needed-to-treat analysis suggested that 33 children would need to be treated to help the one who would fare better on antibiotics.
While fast-breathing children in Africa still can benefit statistically from antibiotics during respiratory illnesses, approximately 90% of children would do fine without an antibiotic. The authors pointed out that these data suggest that the African situation now more closely approximates the North American situation in which antibiotics generally are not recommended for community-acquired pneumonia if there are no signs of severe disease (i.e., poor feeding, retractions).
For years, pneumonia has been a frequent killer of children, especially in resource-limited areas of the world where not all children have access to physician care. Based on good evidence, the WHO has advocated for the use of tachypnea as a key discriminating factor to determine which children would benefit from antibiotic therapy.1 With widespread implementation of WHO teaching, the death rate from pneumonia has dropped significantly, and fewer children receive unnecessary antibiotics.
In resource-rich areas of the world where viral lower respiratory tract infection is relatively more common than bacterial pneumonia, tachypnea has been less reliable in determining which children might benefit from antibiotic treatment.2,3,4 With widespread immunization against Haemophilus influenzae and pneumococcus, the relative rates of bacterial pneumonia are declining in resource-limited areas, too. Ginsburg and colleagues wisely evaluated whether tachypnea is still a key discriminator to identify which children would benefit from antibiotic treatment.
Indeed, most children who had acute fever and cough with tachypnea without signs of more serious infection (that is, without poor feeding or retractions) were fine whether they received antibiotic treatment or not. This suggests that even in resource-limited areas where viral lower respiratory tract illnesses are relatively more common, tachypnea lacks good specificity for identifying children with bacterial pneumonia. However, there still were more treatment failures with placebo than with amoxicillin, so tachypnea should not be disregarded; rapid breathing still is a sign of risk for bacterial pneumonia even if it is not as specific as in past years.
How should we diagnose bacterial pneumonia? Wheezing and diffuse findings on auscultation can point toward a nonbacterial cause of illness. Leukocytosis might provide a clue but also lacks specificity. Even consolidation on chest radiographs is subject to subjective interpretation. Studies over the past two decades showed that blinded pediatric radiologists disagreed with themselves and with colleagues a significant amount of time about specific radiographic findings in children with lower respiratory tract infection.5,6 Ultrasound offers some help for point-of-care use in identifying some pneumonias,7,8 but there still is no fully adequate gold standard to determine which children with acute fever, cough, and tachypnea will benefit from antibiotics.9
Physicians caring for children with possible pneumonia still need to be judicious with their diagnosis and with treatment. Many children with bronchiolitis receive treatments (antibiotics, bronchodilators) that have been proven to lack effectiveness. Even in resource-rich areas of the world with readily available blood counts, antigen detection methods, and radiographs, doctors sometimes overtreat children with lower respiratory infection, and helpful guidelines for the management of viral respiratory infections are available.10 Thoughtful clinicians must carefully balance the benefits and risks of antibiotic treatment in each child.
At the same time, nearly 1 million children die of pneumonia each year, mostly in resource-limited areas of the world. Children who are more severely ill, as evidenced by poor oral intake and/or retractions, are more likely to benefit from an antibiotic. For these sicker children, early antibiotic therapy still can be life-saving. In addition, children who are immunocompromised might fall outside the new data from Malawi since that study was done in a population with low HIV prevalence. At the same time, children with malaria can have high temperatures and tachypnea, so clinicians must carefully consider management of the whole child with multiple possible causes of his or her symptoms.
What should we anticipate in the future? Medication for influenza already can help reduce morbidity and mortality in sick children with influenza. Perhaps a medication for respiratory syncytial virus infections will emerge on the horizon. It could be that one day, the odds will favor antiviral treatment of children in Africa with fever, cough, and tachypnea. In the meantime, though, competent clinicians still will consider various clinical findings to try to focus antibacterial treatment on those who truly might benefit.
Financial Disclosure: Peer Reviewer Patrick Joseph, MD, is a consultant for Genomic Health Reference Laboratory, Siemens Clinical Laboratory, and CareDx Clinical Laboratory. Infectious Disease Alert’s Editor Stan Deresinski, MD, FACP, FIDSA, Updates Author Carol A. Kemper, MD, FACP, Peer Reviewer Kiran Gajurel, MD, Executive Editor Shelly Morrow Mark, Editor Jonathan Springston, and Editorial Group Manager Terrey L. Hatcher report no financial relationships to this field of study.