Detailed plan and bibliography
Purpose:
1. To determine the feasibility and acceptability of performing ‘FAST’ protocol
non-anaesthetized / sedated MRI scans of the lungs in children with
suspected pneumonia and to evaluate the quality of successful scans.
2. To interpret these scans for a diagnosis of pneumonia, associations that would
point to a causative organism (e.g. fungus or tuberculosis) and detection of
complications.
Background
Pneumonia is the leading infectious cause of morbidity and mortality in children < 5
years globally, accounting for 18% of deaths in this age group (1). Streptococcus
pneumonia (the pneumococcus) and Haemophilus influenzae type b (Hib) are the
most important causes of vaccine-preventable deaths in this age group (2, 3). In 2000,
before the widespread use of bacterial conjugate vaccines, Streptococcus pneumonia
caused an estimated 14.5 million cases of pneumococcal disease (95.6% pneumonia)
and 826,000 deaths (2) while Hib caused 370 000 deaths (3). The UK had 50,844
episodes of lower respiratory tract infection from community acquired pneumonia in
children aged 0-4 in 2010 (4).
The world not only needs better rollout of preventative strategies and treatment, but
also improved diagnostic techniques to make an aetiological diagnosis stronger.
The introduction of the pneumococcal conjugate vaccine (PCV) demonstrated vaccine
efficacy for radiograph confirmed pneumonia (5) of 20% in South Africa (HIV
uninfected children) (6), 37% in Gambia (7), 18% in USA (8) and 23% (9) in the
Philippines. New conjugate vaccines (PCV13) will not only change the aetiology
(more staph + RSV) but also the severity of disease and occurrence of complications
(e.g. initially there was an increase in empyaema reported after PCV7 was introduced
and now there is a clear decline in empyaema with PCV13). Imaging may have a
much larger role to play in diagnosis and management of complications of respiratory
infection. TB is also a cause of acute pneumonia (8-15% high TB areas) and there is a
higher reliance on imaging for making a diagnosis of TB than with community
acquired pneumonias.
Even though the British Thoracic Society advises against routine radiographs for
children suspected of community acquired pneumonia (10), the chest X-ray remains
the most readily available and the most common imaging modality for the assessment
of childhood pneumonia (11). However, the inherent 2 dimensional limitations and
inability to characterise lung infection according to aetiology have led to increased
use of CT scanning of the chest. While CT may be the diagnostic solution in adults, it
is undesirable in children because of the massive radiation dose to the developing
organs, which has recently been highlighted as a major cause of iatrogenic increase in
cancer rates in later life (12). In this context, the advantages of chest MRI are obvious
– it does not involve ionizing radiation and provides high soft tissue contrast without
a need for intravenous contrast agents. However, the length of standard MRI
protocols (resulting in limited patient throughput) and the high cost are major
stumbling blocks for expanding its use to diagnosing more common diseases affecting
children. Recent technical advances in MR sequence speed, higher MRI signal,
improved resolution and the increasing availability of scanners, demands reinvestigation of this modality in identification of more common pathologies. One of
these is imaging of the lung for pneumonia as well as its associations and
complications.
Anaesthesia, which is currently used for MRI in young children because of the
intimidating environment and for reducing patient motion encountered during the
long procedure times, presents an unnecessary risk for patients with co-morbidities,
including pulmonary and airway compromise as well as long-term
neurodevelopmental risks, (particular for children younger than 2 or 3 years of age)
(13). Anaesthesia also results in lung atelectasis, appearing as air-space disease in
dependent areas that may require lung recruitment and controlled-ventilation
technique for avoiding confusion with pathology (14).
Despite these limitations, MRI has been used in children for diagnosing a range of
thoracic diseases. Because of the excellent anatomic detail of the trachea and bronchi
provided by MRI of the chest, it is particularly useful for evaluating suspected
vascular rings and demonstrating aberrant vessels (15). Focal lesions such as abscess,
tumour (15), lobar and segmental collapse (15, 16) and fibrosis are visible with MRI.
Tumors such as lymphoma, neuroblastoma and pulmonary metastases demonstrate
abnormal high signal intensity on T2 weighted imaging (15). MRI has also been
evaluated as a potential imaging alternative in patients with cystic fibrosis (CF) (1618). MRI of the bone marrow allows accurate evaluation of the pathological
conditions involving the bony thorax (15). New strategies are needed specifically for
performing lung parenchymal MRI in young children for it to become a useful tool
for diagnosing more common diseases with high morbidity, such as pneumonia.
The principal investigator in the proposed study has previously reported abnormal
high parenchymal signal abnormality from airspace disease on MRI as well as TBspecific low T2/STIR signal intensity in the parenchyma of children who underwent
(unsedated /non-anaesthetised) MRI. The reason for the shortening of the T2 signal is
not clear, but may be the result of the presence of paramagnetic free radicals in the
enclosed macrophages in TB (19). Modified MRI may prove to be able to distinguish
aetiological agents of pneumonia, something which chest radiographs are currently
unable to do.
In addition, lymphadenopathy (in diseases such as TB, fungal infection and
lymphoma) can easily be detected and characterized to limit a differential diagnosis.
In lymphoma lymphadenopathy demonstrates high signal on T2/STIR imaging, while
TB lymph nodes may demonstrate characteristic low signal (19, 20).
To improve access to MRI, Boiselle and colleagues recommend creating relationships
to use MRI scanners outside of children’s hospitals in order to increase available MRI
capacity (21). They also recommend use of multichannel coils, parallel imaging and
new fast MRI sequences on 3T MRI scanners to improve image quality at decreased
imaging times without sedation (21). We are further adding to these
recommendations by determining the feasibility of limited sequences to develop nonreliance on sedation / anaesthesia which will cut costs and shorten MRI times.
Limited sequences in the form of diffusion-weighted imaging (sensitive for
pathology) and Short Tau Inversion Recovery (STIR) (characteristics of pathology)
can be performed within 10-15 minute slots without sedation for children with
suspected TB (unpublished research in progress Tanyia Pillay, Savvas Andronikou,
Heather Zar - University of Cape Town).
A successful feasibility study of ‘FAST’ MRI for common lung diseases in British
children can serve to transform MRI into a more routine modality for diagnosis of
common diseases affecting children, such as pneumonia and its complications.
Plan of investigation
A prospective feasibility study is proposed for imaging children with suspected
pneumonia using ‘FAST’ limited sequence MRI specifically aimed at imaging the lung
parenchyma.
Children 13 years of age and younger will be enrolled at Bristol Royal Hospital for
children when they are referred for chest X-ray for suspected pneumonia. Once the
radiograph has been taken and they have initiated therapy the research assistant in the
study will meet / contact the parents to explain the study and request the child’s
participation and consent. Possible participants names will be obtained from the PACS
[digital imaging archive] in the department of radiology during the reporting of
radiographs based, on the clinical request and not on the chest X-ray findings. Patients
will be excluded if the radiograph was not performed for any reason and if the patients /
parents /carers do not consent to participation.
Consecutive patients will be selected until 100 have been recruited. Patients will also be
excluded if they are admitted in ICU or if they are in regular wards and are too ill to be
moved to the MRI suite. Recruitment is therefore expected to reflect communityacquired pneumonia in ambulant patients in the majority.
MRI scans will be performed at CRICBristol (a research MRI facility based within a
Hospital setting) or BRHC which both offer high field strength 3 Tesla Siemens
Magnetom Skyra which has a large bore and short length especially designed to
increase patient comfort and compliance for faster MRI sequences and allows for 20
minute scanning slots at a reduced cost.
The MRI protocol will include axial DWI B500, which will be post-processed in the
coronal plane and inverted for viewing, and coronal STIR imaging. These sequences
provide the sensitivity and specificity for detecting air-space disease, lymphadenopathy
and effusions respectively.
Patient safety:
MRI will not be performed during the acute presentation but only after the patient has
stabilized. It is well known that the radiological resolution of pneumonia lags
significantly behind the clinical improvement and that air-space disease remains
positive for some time, allowing for an adequate window to perform a scheduled MRI
that will not endanger the patient. MRI scans will therefore be scheduled within 3 days
of the initial presentation for CXR. No sedation or anaesthesia will be used. No
intravenous contrast will be administered. MRI carries no risk of ionising radiation.
Care will be taken as is standard procedure in MRI units to avoid the inherent risks of
the high magnetic field e.g. metallic objects shall be removed from pockets etc.
Image interpretation:
Images will be reviewed by 3 pediatric radiologists blinded to the clinical findings,
CXR findings and each other. The majority consensus will be recorded. Parameters
recorded on a standardised recording card will include presence, location, extent and
signal of air-space disease, lymphadenopathy, effusion and any other intra-and extrathoracic abnormality noted. Chest radiographs will also be reviewed at a separate
sitting (2 months after the MRI reading) by the 3 radiologists blinded to each other. The
MRI findings and clinical information and the findings will be recorded on a similar
standardized recording card as for MRI. The consensus findings for the two modalities
will be compared and the MRI findings will be compared against the final laboratory
diagnosis where possible to determine whether MRI was able to predict the aetiological
agent. Feasibility of ‘FAST’ MRI for diagnosis of community acquired pneumonia will
be reported as the ‘number of completed scans’, which will be graded for quality (do
we have a scale and criteria for scan quality evaluation?adequate clinical quality; poor
quality but interpretatble; poor quality and uniterpretable).
Reasons for support requested
The financial support is required for funding the MRI scans for each child enrolled in
the study. The MRI scanners are available either on-site at the Bristol Royal Hospital
for Children or off-site at CRICBristol which is situated within St. Michaels Hospital
nearby.
References:
1.
Black R E, Cousens S, Johnson H L, Lawn J E, Rudan I, Bassani D G, et al.
Global, regional, and national causes of child mortality in 2008: a systematic analysis.
Lancet. 2010;375:1969-1987.
2.
O'Brien K L, Wolfson L J, Watt J P, Henkle E, Deloria-Knoll M, McCall N, et
al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5
years: global estimates. Lancet. 2009;374:893-902.
3.
Watt J P, Wolfson L J, O'Brien K L, Henkle E, Deloria-Knoll M, McCall N, et
al. Burden of disease caused by Haemophilus influenzae type b in children younger
than 5 years: global estimates. Lancet. 2009;374:903-911.
4.
Rudan I, O'Brien K L, Nair H, Liu L, Theodoratou E, Qazi S, et al.
Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence,
severe morbidity, mortality, underlying risk factors and causative pathogens for 192
countries. Journal of global health. 2013;3:010401.
5.
Cherian T, Mulholland E K, Carlin J B, Ostensen H, Amin R, de Campo M, et
al. Standardized interpretation of paediatric chest radiographs for the diagnosis of
pneumonia in epidemiological studies. Bulletin of the World Health Organization.
2005;83:353-359.
6.
Madhi S A, Kuwanda L, Cutland C, Klugman K P. The impact of a 9-valent
pneumococcal conjugate vaccine on the public health burden of pneumonia in HIVinfected and -uninfected children. Clinical infectious diseases : an official publication
of the Infectious Diseases Society of America. 2005;40:1511-1518.
7.
Cutts F T, Zaman S M, Enwere G, Jaffar S, Levine O S, Okoko J B, et al.
Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and
invasive pneumococcal disease in The Gambia: randomised, double-blind, placebocontrolled trial. Lancet. 2005;365:1139-1146.
8.
Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen J R, et al. Efficacy,
safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in
children. Northern California Kaiser Permanente Vaccine Study Center Group. The
Pediatric infectious disease journal. 2000;19:187-195.
9.
Lucero M G, Nohynek H, Williams G, Tallo V, Simoes E A, Lupisan S, et al.
Efficacy of an 11-valent pneumococcal conjugate vaccine against radiologically
confirmed pneumonia among children less than 2 years of age in the Philippines: a
randomized, double-blind, placebo-controlled trial. The Pediatric infectious disease
journal. 2009;28:455-462.
10.
Bowen S J, Thomson A H. British Thoracic Society Paediatric Pneumonia
Audit: a review of 3 years of data. Thorax. 2013;68:682-683.
11.
Pitcher R D, Lombard C, Cotton M F, Beningfield S J, Zar H J. Clinical and
immunological correlates of chest X-ray abnormalities in HIV-infected South African
children with limited access to anti-retroviral therapy. Pediatric pulmonology.
2014;49:581-588.
12.
Mathews J D, Forsythe A V, Brady Z, Butler M W, Goergen S K, Byrnes G B,
et al. Cancer risk in 680,000 people exposed to computed tomography scans in
childhood or adolescence: data linkage study of 11 million Australians. BMJ.
2013;346:f2360.
13.
Cauldwell C. Anesthesia risks associated with pediatric imaging. Pediatric
radiology. 2011;41:949-950.
14.
Newman B, Krane E J, Gawande R, Holmes T H, Robinson T E. Chest CT in
children: anesthesia and atelectasis. Pediatric radiology. 2014;44:164-172.
15.
Kangarloo H. Chest MRI in children. Radiologic clinics of North America.
1988;26:263-275.
16.
Failo R, Wielopolski P A, Tiddens H A, Hop W C, Mucelli R P, Lequin M H.
Lung morphology assessment using MRI: a robust ultra-short TR/TE 2D steady state
free precession sequence used in cystic fibrosis patients. Magnetic resonance in
medicine : official journal of the Society of Magnetic Resonance in Medicine /
Society of Magnetic Resonance in Medicine. 2009;61:299-306.
17.
Puderbach M, Eichinger M, Gahr J, Ley S, Tuengerthal S, Schmahl A, et al.
Proton MRI appearance of cystic fibrosis: comparison to CT. European radiology.
2007;17:716-724.
18.
Puderbach M, Eichinger M, Haeselbarth J, Ley S, Kopp-Schneider A,
Tuengerthal S, et al. Assessment of morphological MRI for pulmonary changes in
cystic fibrosis (CF) patients: comparison to thin-section CT and chest x-ray.
Investigative radiology. 2007;42:715-725.
19.
Peprah K O, Andronikou S, Goussard P. Characteristic magnetic resonance
imaging low T2 signal intensity of necrotic lung parenchyma in children with
pulmonary tuberculosis. Journal of thoracic imaging. 2012;27:171-174.
20.
Andronikou S, Vanhoenacker F M, De Backer A I. Advances in imaging chest
tuberculosis: blurring of differences between children and adults. Clinics in chest
medicine. 2009;30:717-744, viii.
21.
Boiselle P M, Biederer J, Gefter W B, Lee E Y. Expert opinion: why is MRI
still an under-utilized modality for evaluating thoracic disorders? Journal of thoracic
imaging. 2013;28:137.