Trials test WHO recommendations on treatment for child pneumonia
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The results of two studies published today in The New England Journal of Medicine that challenged WHO treatment recommendations for children with nonsevere pneumonia were “insufficient to change current clinical practice,” experts said.
The first study, a double-blind, randomized, placebo-controlled noninferiority trial in Pakistan, validated the WHO treatment recommendation of 3 days of oral amoxicillin for children younger than age 5 years who have pneumonia with tachypnea.
A related double-blind, randomized, controlled noninferiority trial in Malawi found that 3 days of amoxicillin was noninferior to the recommended 5 days for chest-indrawing pneumonia among children in the same age group.
In an editorial, Anne B. Chang, FRACP, PhD, from Queensland University of Technology and Queensland Children’s Hospital, and Keith Grimwood, FRACP, MD, of Griffith University and Gold Coast Health in Australia, noted that the trials would not change clinical practice and that the results “could not be extrapolated to other definitions of pneumonia.”
The trials “highlight our limited knowledge regarding appropriate antibiotic prescribing for the various types of childhood pneumonia as categorized according to WHO criteria,” they wrote.
“The results of RETAPP” — the Pakistan trial — “support current WHO guidelines, whereas the findings in the trial by Ginsburg [and colleagues] indicate that 3 days of amoxicillin is sufficient for treatment of chest-indrawing pneumonia,” Chang and Grimwood wrote. “However, the relative noninferiority margin in that trial of a 50% higher incidence of treatment failure in the 3-day group than in the 5-day group is large. Additional data from randomized, controlled trials or from meta-analyses that use individual patient data from several large randomized, controlled trials with smaller relative margins conducted in various settings would be required for the current results to change practice.”
RETAPP trial
In the RETAPP trial, children between ages 2 to 59 months were randomly assigned to a 3-day course of amoxicillin or a placebo. Fyezah Jehan, MB, BS, head of pediatric infectious diseases at the Aga Khan University in Pakistan, and colleagues, compared treatment failure in those administered amoxicillin vs. those administered placebo.
A total of 4,002 children were included — 1,999 in the placebo group, and 2,003 in the amoxicillin group. The incidence of treatment failure was 4.9% (95 of 1,929 children approved for per-protocol analysis) in the placebo group. In the amoxicillin group, it was 2.6% (51 of 1,929 children approved for per-protocol analysis), for a difference between the two of 2.3 percentage points (95% CI, 0.9-3.7).
“This trial is providing evidence to continue antibiotics for mild pneumonia in primary care settings, where sophisticated diagnostic tools are not available and where immunization rates are suboptimal,” Jehan told Healio.
Coauthor Imran Nisar, MB, BS, the research director in the department of pediatrics and child health at the Aga Khan University, said the results surprised him.
“We did not expect such a low number of children failing treatment,” Nisar told Healio. “In fact, we had to increase the sample size to account for the low rates and keep the trial powered enough not to miss noninferiority. Historical trials, which these guidelines were based on, showed a much higher rate of treatment failure in spite of amoxicillin.”
According to the study, the number of children with pneumonia and tachypnea who needed to be treated to prevent one treatment failure was 44 — high enough to suggest that antibiotics may not be needed for a large number of children.
“It makes a compelling case to consider a change of clinical criteria for diagnosing mild pneumonia, using additional clinical screening in order to avoid giving antibiotics to those who do not need them,” Jehan said.
Malawi trial
In the second trial, Amy-Sarah Ginsburg, MD, MPH, a research scientist for the University of Washington, and colleagues compared a 3-day course of amoxicillin in children with chest-indrawing pneumonia with a 5-day course, which is recommended by WHO.
“This, potentially, could treat chest-indrawing pneumonia with shorter duration of antibiotics, thereby increasing treatment adherence, decreasing opportunity for emergence of antimicrobial resistance and simplifying treatment options for health care providers,” Ginsburg told Healio.
In all, 3,000 children participated in the trial — 1,497 randomly assigned to 3 days of treatment and 1,503 in the 5-day arm.
The researchers followed participating children for 14 days. The trial’s primary outcome was treatment failure by the sixth day. In order to demonstrate noninferiority of the 3-day program to the 5-day program, the percentage of children with treatment failure in the 3-day group would have to be no more than 1.5 times that of children in the 5-day group, the researchers said.
Treatment failure occurred in 5.9% of the children in the 3-day group (85 of 1,442 children approved for per-protocol analysis), and 5.2% in the 5-day group (75 of the 1,456 children approved for per-protocol analysis) — a difference of 0.7 percentage points (95% CI, –0.9 to 2.4).
Of children with 14-day data available, 12.5% (176 of 1,411 children) in the 3-day group experienced treatment failure by day 6 or a relapse by day 14, whereas 10.8% (154 of 1,429) of the 5-day group experienced treatment failure — a difference of 1.7 percentage points (95% CI, –0.7 to 4.1).
“These important trials ... have contributed to our current knowledge, yet many gaps remain in our understanding of the appropriate management of pneumonia and deserve greater attention,” Chang and Grimwood wrote.
References:
- Chang AB, Grimwood K. N Engl J Med. 2020;doi:10.1056/NEJM2016328.
- Ginsburg AS. et al. N Engl J Med. 2020; doi:10.1056/NEJMoa1912400.
- Jehan F. et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1911998.
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