- Heather J Zar, professor and chair, Department of Paediatrics and Child Health1,
- Savvas Andronikou, professor1 2,
- Mark P Nicol, professor and head, Division of Medical Microbiology3 4
- Correspondence to:
H J Zar
Pneumonia remains a major cause of childhood mortality and morbidity globally. Accurate diagnosis and attribution of the causes of pneumonia are important for measuring the burden of disease, implementing appropriate preventive or treatment strategies, and developing more effective interventions. This review summarizes recent diagnostic advances in radiological techniques, specimen collection, and laboratory methods. Although chest ultrasound and chest magnetic resonance imaging are promising modalities for radiological diagnosis, their role in clinical management and their impact on outcomes need further study. Rapid, highly sensitive, multiplex laboratory tests performed on upper respiratory tract samples or induced sputum can detect nucleic acid from potential pathogens in most children with pneumonia. However, it may be difficult to attribute causality because it is often impossible to distinguish between organisms colonizing or infecting the upper respiratory tract and those causing pneumonia. Currently available host biomarkers lack accuracy for distinguishing bacterial or mixed bacterial-viral infections from viral infections. New biomarkers derived from host transcriptional profile analysis may be more accurate but require validation. Prospective studies with appropriate control populations, including studies of clinical impact, are needed to improve our understanding of the role of tests. Although progress has been made in radiological techniques and laboratory testing, current methods for diagnosing and attributing the causes of pneumonia are suboptimal.
The incidence and severity of pneumonia in childhood, and its related mortality, have declined substantially in the past decade owing to improved socioeconomic conditions; better access to care; wider implementation of effective management and preventive strategies; and the development and availability of improved vaccines, particularly the pneumococcal (PCV) and Haemophilus influenzae type b (Hib) conjugate vaccines.1 However, pneumonia remains the leading cause of childhood mortality globally outside the neonatal period and a major cause of morbidity and hospital admission.23 Furthermore, pneumonia or lower respiratory tract infection (LRTI) in early childhood has increasingly been associated with reduced lung function in infancy and the development of chronic non-communicable respiratory diseases, such as asthma or chronic obstructive pulmonary disease, in children and adults.4567
Pneumonia was formerly thought to occur after invasion of a sterile lower respiratory tract by a single pathogenic organism. However, recent evidence indicates that the healthy lung is not sterile and that the normal lung microbiome exists in a dynamic state.8 A key step in the pathogenesis of pneumonia may be dysbiosis, or imbalance, in the normal microbial ecology of the respiratory tract as a result of factors related to the host, environment, or organism.910 Dysbiosis may result in the overgrowth of a single pathogen, or multiple pathogens, as supported by recent data from studies using sensitive highly multiplexed diagnostics, which identify multiple potentially pathogenic organisms from the respiratory tract of most children with pneumonia.1112
Accurate diagnosis of pneumonia and the attribution of its cause are important for measuring the burden of disease, for implementing appropriate treatment or preventive strategies, and for developing new more effective interventions. The availability and increased uptake of global and national childhood immunization programs of conjugate vaccines against bacterial pathogens have had an impact on the causes of childhood pneumonia. The relative contribution of different pathogens needs to be re-evaluated to inform the development of modified treatment guidelines, such as the widely used World Health Organization Integrated Management of Childhood Illness guideline, and to prioritize vaccine development and implementation.
Diagnostic advances include the use of new radiological methods, better specimen collection, and improved microbiological tests. Advances in radiological techniques include the use of point-of-care (POC) chest ultrasound and chest magnetic resonance imaging (MRI). In addition, telemedicine enables the remote interpretation of radiological investigations by expert radiologists. Improved methods for specimen collection include a better understanding of the role of non-invasive specimens (such as urine or nasopharyngeal samples) and the use of induced sputum. Laboratory based advances encompass rapid tests for pathogen nucleic acid or antigen, simultaneous detection of multiple pathogens, and host transcriptional profile analysis for the identification of novel biomarkers.
This review summarizes recent advances in the diagnosis of community acquired pneumonia in childhood and focuses on radiological techniques, specimen collection, and laboratory methods. The impact of these advances on the current understanding of the pathogenesis of pneumonia and the implications for future strategies and research are discussed.
Incidence of pneumonia in childhood
The incidence of pneumonia in childhood has fallen substantially in recent decades, but pneumonia remains the main cause of death in children outside the neonatal period and of loss of disability adjusted life years in children and adolescents.23 The Global Burden of Diseases study, which used many data sources and mathematical modeling, estimated that pneumonia accounted for almost 900 000 of the 6.3 million deaths in children in 2013, with the greatest burden occurring in low and middle income countries.2 The incidence of pneumonia in children under 5 years of age in high income countries has been estimated at 0.015 episodes per child year, compared with 0.22 episodes per child year in low and middle income countries.13
Several case-control or descriptive studies, mainly in high income countries, have reported that vaccination, especially with the 13-valent PCV (PCV13), has reduced the incidence and severity of pneumonia in children and of complications such as empyema.1415161718 Nevertheless, the incidence of pneumonia in childhood, even in highly vaccinated populations, imposes a substantial burden on healthcare systems. The incidence of pneumonia in children participating in a South African birth cohort study in a peri-urban, poor socioeconomic area was 0.27 episodes per child year during infancy, with the peak incidence occurring at 3 months of age19; this occurred despite high coverage of vaccination, including PCV13.
Specific childhood populations may be especially vulnerable to developing pneumonia or severe disease. A meta-analysis reported that the incidence of and mortality from pneumonia in children infected with HIV is about six times higher than in those not infected with HIV.20 Infants who have been exposed to HIV but are not infected (those born to HIV infected mothers who are HIV negative owing to effective interventions for preventing mother-to-child transmission) are also increasingly recognized as being more vulnerable to pneumonia. These infants have a higher risk of severe disease or hospital admission than children who have not been exposed to HIV (infants born to HIV negative mothers).21 A meta-analysis confirmed several other risk factors for pneumonia associated mortality including malnutrition, lack of breast feeding, crowded living conditions, exposure to indoor air pollution, and low birth weight.22
Sources and selection criteria
This review examines advances in the diagnosis of pneumonia in children, focusing on radiological techniques, specimen collection, and laboratory methods. We identified references through searches of publications listed in PubMed from January 2000 to September 2016 using combinations of medical subject headings (MeSH) that included child AND (pneumonia OR lower respiratory tract infection OR pertussis) AND (diagnosis OR chest radiology OR lung ultrasound OR MRI lung OR induced sputum OR specimen). We reviewed relevant titles and abstracts, and we prioritized randomized studies, systematic reviews or meta-analyses, and case-control or cohort studies. Where higher quality evidence was not available, case series and other observational studies were considered. Individual case reports were not included. Preference was given to publications from the past five years. Because this was not a formal systematic review, we did not grade the included studies but summarized key outcomes or results. We only included articles or abstracts published in English.
Current guidelines for radiological diagnosis
Chest radiography is often performed for suspected pneumonia,2324 which is the most common indication for imaging of the chest.25 This is despite several guidelines advising against the routine use of chest radiography25 and the lack of evidence for its impact on clinical outcomes.2627 Several international or national guidelines including those from the British Thoracic Society (BTS)28 and the National Institute for Health and Care Excellence (NICE) in the United Kingdom,29 the Paediatric Infectious Diseases Society and the Infectious Diseases Society of America (IDSA),30 the South African Thoracic Society (SATS),31 and the International Union against Tuberculosis and Lung Diseases32 do not recommend chest radiography in children who are well enough to be treated as outpatients. Rather, chest radiography is recommended only in children who are admitted to hospital with severe symptoms, hypoxia, or suspected complications such as empyema.
Limitations of chest radiography
Changes seen on chest radiographs may be more specific for pneumonia than clinical signs, with radiological signs associated with more severe disease and treatment failure.3334 However, the use of chest radiography for diagnosis has several limitations. The two dimensional nature of chest radiography may lead to consolidation, adenopathy, or complications being masked by other anatomical structures such as the heart, mediastinum, and diaphragm3536; it may also lead to the problem of summation shadows.37 Furthermore, inter-reader agreement in the interpretation of chest radiographs is poor.232538 In a recent review, 10 of 12 pediatric studies showed only fair to moderate interobserver agreement.38 Agreement is worse for reporting of an “infiltrate” in children under 5 years,23 and it remains moderate even when using WHO standardized radiological criteria for pneumonia.2339 In addition, the lack of abnormality on chest radiography does not exclude pneumonia,4041 and abnormal chest radiographs may be interpreted as normal.23 Other limitations include lack of access to basic radiology services at primary healthcare facilities in many low and middle income countries; expense; exposure to radiation (although low at 0.01-0.02 mSv for a standard chest radiograph)42; and need for specialized equipment, power source, and trained technologists. Imaging with computed tomography is more reliable but discouraged for routine diagnosis because of the resources needed and the radiation risk,25 despite new dose reduction techniques.43
New imaging techniques are therefore needed to increase diagnostic accuracy and improve access. Two alternative forms of diagnostic imaging have emerged—POC ultrasound and rapid sequence MRI, which may have applications across different settings. The use of these techniques is enhanced by the capacity for remote reading by expert radiologists.
Advances in radiological diagnosis
Clinician led POC ultrasound
It is now feasible for ultrasound to be performed by non-radiologists with the advent of affordable handheld machines. Children are ideal candidates for diagnostic imaging using ultrasound because of their thin chest wall and small lung mass. Ultrasound has several advantages over other imaging modalities: it can be performed at POC, it is feasible and less costly than chest radiography, it is less affected by movement or crying than other imaging modalities, it can be done in sleeping children,35 and it is free of ionizing radiation.243541 Although ultrasound performed by non-radiologists is controversial, it has become a useful tool for physicians, emergency medicine doctors, and intensivists.44
Lung ultrasound involves scanning a child in the anterior, lateral, and posterior areas of each hemithorax.454647Consolidation is diagnosed as a hypoechoic area with ill defined borders surrounded by B-lines and loss of or an irregular shredded border of the pleural line.244547484950 Other signs include punctate hyperechoic or linear and branching echogenic structures, reflecting air bronchograms, and a decrease in lung sliding (fig 1⇓). Lobar involvement presents as a liver-like area in the thorax or hepatization of the lung.47 Homogeneous, anechoic, or hypoechoic fluid in the pleural space indicates a pleural effusion (fig 2⇓).47
Evidence for the use of ultrasound to support the diagnosis of pneumonia in children is accumulating. Most studies have compared POC ultrasound performed by clinicians with chest radiography findings reported by radiologists . A literature search of lung ultrasound for pneumonia in children yielded 24 original studies, 11 commentaries, a meta-analysis, and a summary of evidence.62 Only three studies compared ultrasound with a gold standard of pneumonia defined by computed tomography, and only one study provided the diagnostic accuracy of ultrasound and chest radiography against computed tomography for pneumonia. In this last study the positive predictive values for ultrasound and chest radiography were 0.61 and 0.71, respectively, whereas the negative predictive values were 0.86 and 0.8, respectively.58 Four studies provided interobserver agreement, with three reporting high agreement for consolidation on ultrasound (κ=0.8-0.9).505459 Only one study reported the interobserver agreement for chest radiography and ultrasound simultaneously; agreement for ultrasound was fair (κ=0.55) but better than that for chest radiography (κ=0.33).58
The limitations of ultrasound include its inability to visualize the whole lung at the same time or to identify consolidation deep within the lung parenchyma.25 In addition, the spleen or air in the stomach can be misinterpreted as lung consolidation with air bronchograms.54
Overall, the use of POC ultrasound as an alternative to chest radiography in primary screening for triage in the emergency department or clinic is promising. However, even though ultrasound has potential as a screening test, it is not clear whether it affects patient outcome or management. Further studies are needed to compare the impact of chest radiography versus POC ultrasound on patient relevant outcomes and to inform best practice.