Diagnostic Utility of Chest X-rays in Childhood Community Acquired Pneumonia in the Era of ...

243 Pages·2017·3.37 MB·English

Diagnostic Utility of Chest X-rays in Childhood
Community Acquired Pneumonia in the Era of
Bacterial Conjugate Vaccines, Antiretroviral
Therapy, Molecular Diagnostics and Computer
Aided Diagnosis

Nasreen Mahomed
Student Number: 9701757M

A thesis submitted to the Faculty of Health Sciences, University of Witwatersrand,
Johannesburg, in fulfilment of the requirements for the Degree of Doctor of
Philosophy in the branch of Medicine: Diagnostic Radiology

Johannesburg, 2017
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DECLARATION

I, Nasreen Mahomed, declare that this research thesis is my own work. It is being submitted for
the degree of Doctor of Philosophy in the School of Clinical Medicine (Diagnostic Radiology) at
the University of Witwatersrand, Johannesburg. It has not been submitted before for any degree
or examination at this or any other University.

_________________________
Signature of Candidate

6 June 2017
Date

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Publications Arising from this Research
Mahomed N, Madhi SA. Radiologic diagnosis of chest infection in children: WHO end-point
consolidation. Pediatr Radiol. 2014 Jun; 44(6):685-6. Refer Appendix 1.
Conference Presentations Arising from this Research
7th International Pediatric Radiology (IPR) Conjoint Meeting & Exhibition, 15-20 May
2016, Chicago, Illinois
Three oral presentations:
7th International Pediatric Radiology (IPR) Conjoint Meeting & Exhibition, 15-20 May 2016,
Chicago, Illinois. Mahomed N, Moore D, Sewchuran T, Moodley H, Madhi S A. Chest X-ray
Findings in Children Hospitalized with WHO-Defined Severe, Very Severe Pneumonia in a High
HIV Prevalence Setting in the Era of Bacterial Conjugate Vaccines. (PA-137)
7th International Pediatric Radiology (IPR) Conjoint Meeting & Exhibition, 15-20 May 2016,
Chicago, Illinois. Mahomed N, Moore D, Sewchuran T, Moodley H, Madhi S A. Are Chest X-
ray Patterns Associated with Specific Clinical and Acute Phase Reactants in HIV-infected, HIV-
Exposed-Uninfected (HEU) and HIV-Unexposed Children Hospitalized with WHO-Defined
Severe, Very Severe Pneumonia? (PA-082)
7th International Pediatric Radiology (IPR) Conjoint Meeting & Exhibition, 15-20 May 2016,
Chicago, Illinois. Mahomed N, Van Ginneken B, Philipsen R, Melendez J, Moore D,
Sewchuran T, Moodley H, Madhi S A. Computer Aided Diagnosis (CAD4WHOKids) for WHO
Primary Endpoint Pneumonia on Chest X-Ray in Children. (PA-135)
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10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD), 26-30
June 2016 Glascow, Scotland
Two oral electronic poster presentations: Ongoing Challenges of Pneumococcal
Pneumonia:
10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD),26-30 June
2016 Glascow, Scotland. Mahomed N, Moore D, Sewchuran T, Moodley H, Madhi S A. Chest
X-ray Findings in Children Hospitalized with WHO-Defined Severe, Very Severe Pneumonia in
a High HIV Prevalence Setting in the Era of Bacterial Conjugate Vaccines. (Poster 513)
10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD),26-30 June
2016 Glascow, Scotland. Mahomed N, Van Ginneken B, Philipsen R, Melendez J, Moore D,
Sewchuran T, Moodley H, Madhi S A. Computer Aided Diagnosis (CAD4WHOKids) for WHO
Primary Endpoint Pneumonia on Chest X-Ray in Children. (Poster 479)
One poster presentation:
10th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD),26-30 June
2016, Glascow, Scotland. Mahomed N, Moore D, Sewchuran T, Moodley H, Madhi S A. Are
Chest X-ray Patterns Associated with Specific Clinical and Acute Phase Reactants in HIV-
infected, HIV-Exposed-Uninfected and HIV-Unexposed Children Hospitalized with WHO -
Defined Severe, Very Severe Pneumonia? (Poster 512)

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University of the Witwatersrand, Faculty of Health Sciences Research Day & Postgraduate
Expo, 1 September 2016
One oral presentation: Theme 1: Clinical Sciences and Therapeutics for Health
University of the Witwatersrand, Faculty of Health Sciences Research Day & Postgraduate
Expo, 1 September 2016. Mahomed N, Van Ginneken B, Philipsen R, Melendez J, Moore D,
Sewchuran T, Moodley H, Madhi S A. Computer Aided Diagnosis for WHO Chest X-Ray
Primary Endpoint Pneumonia in Children. (CS/TH-O-13)
Awarded Best Oral Presentation in Theme 1; refer Appendix 2 for certificate.

One poster presentation: Theme 4: Infectious Diseases
University of the Witwatersrand, Faculty of Health Sciences Research Day & Postgraduate
Expo, 1 September 2016. Mahomed N, Moore D, Sewchuran T, Moodley H, Madhi S A. Chest
X-ray Findings in Children Hospitalized with WHO-Defined Severe Pneumonia in a High HIV
Prevalence Setting in the Era of Bacterial Conjugate Vaccines. (ID-P-37)

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Acknowledgements

I would like to acknowledge my supervisors, collaborators, organizations and funders:
Supervisor: S A Madhi
Co-supervisor: D P Moore
Chest X-ray Readers: T Sewchuran and H Moodley
Chest X-ray Quality Assurance External Reader: V Manduku
PERCH Core Team, Johns Hopkins Bloomberg School of Public Health, USA: C Prosperi, M
Higdon, Z Wu, Q Shi, M Deloria-Knoll, W Gong, N Fancourt, M Knoll, D Park and K O’Brien
Computer Aided Diagnosis International Collaborators: Diagnostic Image Analysis Group,
Radboud UMC, Nijmegen, The Netherlands, B van Ginneken, J Melendez, R Philipsen
Chest X-ray Quality Assurance International Collaborators: S Andronikou , T Hlabangana,
S Thamthitiwat (Thailand), L Hossain (Bangladesh), L Mwananyanda (Zambia), E Bernard (The
Gambia), M Silaba (Kenya), M Tapia (Mali)
MRC Respiratory and Meningeal Pathogens Research Unit (RMPRU): N Ebrahim, F Seedat
Funders: Carnegie PhD Fellowship (Grant number: B8749.R01) administered by the University
of Witwatersrand, J Pettifor and B Kramer and Discovery Foundation Academic Fellowship
(Reference: 026555)

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Abstract

Introduction: Pneumonia is among the leading infectious causes of morbidity and mortality in
children under 5 years globally. The chest X-ray remains the most readily available and most
common imaging modality for the assessment of childhood pneumonia. Chest X-ray quality
assurance is important to maintain high image quality, allowing for more accurate diagnosis.
Chest X-ray patterns in a high HIV prevalence setting in children hospitalized with pneumonia in
the era of bacterial conjugate vaccines has not been described. Furthermore the association
between chest X-ray findings and microbiological etiology using novel models is important.
Standardization of chest X-ray interpretation is important to allow comparison of research
findings between studies and has been proposed by the World Health Organisation (WHO) as a
measure of bacterial vaccine efficacy (VE). The role of Computer Aided Diagnosis (CAD) for
chest X-ray interpretation is important, especially in countries with limited radiologists.
Objectives: In this thesis we investigated the quality of chest X-rays and the impact of quality
assurance activities in the Pneumonia Etiology Research for Child Health (PERCH) study, from
9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand and
Zambia), by quantifying radiographic errors through use of a customized quality assessment
form. Within the context of the PERCH South African site, we compared chest X-ray patterns in
HIV-unexposed, HIV- exposed-uninfected (HEU) and HIV-infected children hospitalized with
WHO-defined severe or very severe community acquired pneumonia. Further, we evaluated the
association of chest X-ray patterns with clinical parameters and its association with the PERCH
Quantitative Analysis (PQA) model predicted probability of infection by a class or specific
pathogens. Lastly, we evaluated the utility of CAD for identifying chest X-ray primary end-point
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pneumonia (CXR-PEP) versus non CXR-PEP compared to a consensus human interpretation as a
reference standard.
Results: A total of 747 chest X-rays in 9 PERCH sites had chest X-ray quality assessment.
Collimation performed the worse of the 6 parameters, with 5 out of the 9 sites being graded sub-
optimally for this. Three of the 9 sites showed a significant improvement in chest X-ray quality
using a test for trend analysis. At the South African PERCH site, 920 cases were enrolled over
two years, including 858 children with interpretable chest X-rays. The commonest finding was
CXR-PEP, prevalent among 38% HIV-unexposed children, 33% HEU children and 60% of HIV-
infected children, which was consistent between different age categories. CXR-PEP was twice as
common in HIV-infected (OR 2.5; 95% CI 1.6-3.8) compared with these HIV-unexposed
children. Clinical and laboratory features independently associated with CXR-PEP included the
presence of severe malnutrition, fever and CRP > 40mg/dL. CXR-PEP was associated with the
composite outcome of mechanical ventilation or death. However there was no single clinical or
laboratory parameter that had both high sensitivity and specificity to discriminate between CXR-
PEP from non CXR-PEP cases. HIV-unexposed children with a PQA model probability index >
0.5 for bacterial etiology had 2-fold greater odds (95% CI 1.1-4.1) for CXR-PEP compared to
non CXR-PEP, and similarly HIV-unexposed children with microbiologically confirmed
pneumococcal pneumonia (MCPP) had 3-fold greater odds (95% CI 1.3-6.7) of CXR-PEP. HIV-
infected children with a PQA model probability index > 0.5 for respiratory viral etiology and
PQA model probability index > 0.5 for Pneumocystis jiroveci etiology trended to have a greater
odds for CXR-PEP vs non CXR-PEP.
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Using CAD4WHOKids for the 858 interpretable chest X-rays, for CXR-PEP versus non CXR-
PEP, CAD4WHOKids had a sensitivity of 76%, specificity of 80% and area under the ROC
curve of 0.850 (95% CI 0.823-0.876) compared to the radiologist consensus reading.
Conclusion: Chest X-ray quality, in particular collimation was suboptimal in 7 resource limited
countries, in children hospitalized for WHO defined severe or very severe pneumonia. CXR-PEP
remains the most common chest X-ray abnormality in HIV-unexposed, HEU and HIV-infected
children under 5 years of age hospitalized for WHO-defined severe or very severe pneumonia,
even in the era of routine HiB and PCV immunization. Our findings support the literature that
CXR-PEP is of limited use in HIV-infected children as an outcome measure in bacterial VE
studies, due to opportunistic infections like Pneumocystis jiroveci pneumonia and respiratory
viral infections contributing to CXR-PEP. CAD is promising as a diagnostic tool for identifying
WHO defined CXR-PEP in bacterial VE trials and pneumonia epidemiological studies.
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List of Abbreviations

AIDS acquired immunodeficiency syndrome
ALARA as low as reasonably achievable
aOR adjusted odds ratio
AP anterior posterior
ART antiretroviral therapy
ASM active shape model
bpm breaths per minute
CAD computer aided diagnosis
CAP community acquired pneumonia
CHBAH Chris Hani Baragwanath Academic Hospital
CXR-PEP chest X-ray primary end-point pneumonia
CI confidence interval
CRP C-reactive protein
CRES Chest Radiography in Epidemiological Studies
Ct cycle threshold
CT computerized tomography
DICOM Digital Imaging and Communications in Medicine
ELISA enzyme-linked immunosorbent assay
ESR erythrocyte sedimentation rate
ETT endotracheal tube aspirate
EPI expanded programme on immunisation
Hib Haemophilus influenzae type b
HibCV Hib conjugate vaccine
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