Ten Pathogens Behind Most Severe Pneumonia in Children

Recent data show that, in seven African and Asian countries, 10 pathogens were responsible for 79% to 90% of cases of severe pneumonia requiring hospitalization in young children.

The study, published online in The Lancet, analyzed clinical and microbiological findings from 1,769 children ages 1 to 59 months who had a positive chest X-ray and no HIV infection as well as 5,119 community controls, including 206 with HIV.

The researchers found that respiratory syncytial virus (RSV) was the dominant pathogen, accounting for 31.1% of the etiology distribution of pneumonia causes. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, Streptococcus pneumonia, Mycobacterium tuberculosis, and Hemophilus influenza each accounted for 5% or more of the distribution.

Most cases of pneumonia were attributed to viruses (61.4%), followed by bacteria (27.3%) and Mycobacterium tuberculosis (5.9%). At least one pathogen was detected in the nasopharyngeal and oropharyngeal specimen in 98.9% of cases and in 98.0% of controls.

"Our study clearly shows that the inferential value of nasopharyngeal specimens varies by pathogen, with only a low number of pathogens providing evidence of causality," the study authors wrote.

Although the causes of disease differed by age, severity, and geography, the top 10 bacterial pathogens were responsible for "a substantial proportion of disease," the researchers said.

"From a policy perspective, the low number of pathogens that are common causes of pneumonia requiring hospital admission in children younger than five years across all sites could allow for targeted development of pneumonia interventions," they wrote. "Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes."

In the study, carried out at nine sites in Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia, viruses were less common in very severe pneumonia than they were in severe cases (54.5% vs 68.0%, respectively) and bacteria was more common in very severe pneumonia versus severe cases (33.7% vs 22.8%).

And, notably, the authors found that 14% of pneumonia cases were vaccine-preventable. With the exception of Thailand, all sites routinely used Hemophilus influenza type b (Hib) vaccine. In addition, 70% to 90% of the study populations in The Gambia, Kenya, Mali, South Africa, and Zambia received one or more doses of pneumococcal conjugate vaccine (PCV).

When the study was initiated in 2011, 88% of countries eligible for programs of Gavi, the Vaccine Alliance, were using the Hib vaccine, and 21% were routinely using PCV, the authors noted.

Globally, pneumonia is one of the leading causes of death among children ages five and younger, accounting for an estimated 12.8% of annual deaths beyond the neonatal period, the investigators noted. But the study results "should not be extrapolated as the global etiological distribution of severe childhood pneumonia," they cautioned.

Nevertheless, they advised that dedicated prevention and treatment efforts should primarily target RSV, especially in children younger than 6 months. The remaining bacterial pathogens, which are treatable but commonly fatal, should "remain a target for early access to treatment."

In an accompanying commentary, Trevor Duke, MD, of the Centre for International Child Health, University of Melbourne, and Murdoch Children's Research Institute, Royal Children's Hospital, in Melbourne, said that the current study "enlarges our understanding of the causes of acute lower respiratory infections."

Duke, who is also at the University of Papua New Guinea, in Port Moresby, Papua New Guinea, said the results highlight the need to improve coverage with existing vaccines. Since the study showed that 14% of all cases of acute lower respiratory infections requiring hospital admission could have been prevented by vaccine, improved coverage of existing vaccines could avoid more than 15 million of these cases each year.

"This job will require concerted global efforts to produce an effective vaccine against RSV (the cause of more than 30% of acute lower respiratory infections in all countries), a greater focus on public health strategies to prevent and mitigate the severity of acute lower respiratory infections, and improved case-management strategies," Duke wrote.

The risk of bacterial pneumonia accompanying a viral upper respiratory tract infection varies greatly, particularly in severely unwell children in low-resource settings, the editorialist noted. Most often, bacterial pneumonia develops following mucosal invasion or drip aspiration of nasopharyngeal bacteria.

"In some settings, bacteria colonize the nasopharynx of more than 95% of infants in the first two months of life, whereas in other populations, this number is about 30% by age 1 to 5 years," he explained.

The recent findings also point to the need to restrict antibiotic prescriptions for acute lower respiratory infections, Duke said, noting that most cases had a viral etiology. In addition, children with acute bronchiolitis, a clinical syndrome in which antibiotics can be withheld, need to be identified.

In the past two decades, many useful prevention and case management strategies have been overshadowed by the public health emphasis on conjugate vaccines, Duke wrote. The advantage of strategies such as exclusive breastfeeding, better nutrition in the first two years of life, protection from indoor air pollution and smoke exposure, and improving the quality of primary care and referral case management, "is that they are not cause specific."

Challenges detecting pneumonia

The performance of four respiratory rate timers to detect pneumonia in young children was not consistent between devices or with the reference standard, researchers found.

Results from a large, single-blinded comparative trial in 454 children with history of cough and/or difficulty breathing showed low consistency among four devices used by community health workers in Cambodia, Ethiopia, South Sudan, and Uganda to achieve respiratory rate count. The mean difference of respiratory rate measurements between the devices and the reference standard ranged from 0.5 to 5.5, with moderate agreement for fast and normal breathing.

The devices included the Mark Two ARI timer (MK2 ARI), counting beads with ARI timer, the Rrate Android phone, and the Respirometer feature phone applications.

Performance was consistently lower for young infants ages 2 months and younger than it was for children ages 2 to 59 months, the authors found.

"Our data shows that it was especially difficult for CHWs [community health workers] to obtain an accurate count (±2 breaths) in young infants, in which only 8% to 20% of the assessments were in agreement with the reference standard, regardless of the RR [respiratory rate] device used," they reported online in EClinicalMedicine/The Lancet.

Counting respiratory rate manually is difficult to do accurately, they acknowledged, adding that "more is required of a device than simply supporting the health workers to keep count of the number of breaths a patient takes over 60 seconds."

The agreement between the tested devices and the reference standard was significantly higher for older children, ranging from 30% to 40% in children ages 2 to 59 months. This supports evidence from an earlier study in Zambia in which decreased respiratory rate variability was seen in older children, the researchers said.

"New, automated respiratory rate counters and other diagnostic tools are required if community health workers are to effectively detect the signs and symptoms of pneumonia in children under five," the study authors wrote.

In an accompanying commentary, Israel Amirav, MD, and Moran Lavie, MD, of the Dana-Dwek Children's Hospital, Tel-Aviv Sourasky Medical Center, in Israel, noted that this study and others call for "a radically different approach to better diagnose pneumonia in children."

"We believe that there is an urgent need to re-think our existing dogmas about using RR as a stand-alone or sole diagnostic criterion for diagnosing pneumonia," Amirava and Lavie wrote. "We need to think out of the box as we approach the third decade of the 21st century."

Pointing to evidence that a single clinical sign is unlikely to increase diagnostic precision of childhood pneumonia, they noted that detecting the work of breathing may be superior to breath counting, particularly in the diagnosis of severe pneumonia. Combining respiratory rate with other quantifiable vital signs such as heart rate, O2 saturation, and temperature has also shown promise in the diagnosis of childhood pneumonia.

Similarly, results from a double-blind, randomized clinical trial from Malawi have provided more evidence that challenges the role of respiratory rate in the management of non-severe fast-breathing pneumonia. The study showed that, in 1,343 children ages 2 to 59 months with pneumonia, fast breathing provided a low diagnostic yield for true bacterial pneumonia. This data imply that "fast breathing might be neither an appropriately sensitive nor a specific sign of bacterial pneumonia," the editorialists said.