Pediatric Community-Acquired Pneumonia

157 Pages·2009·1.08 MB·English

MASSIMILIANO DON
Pediatric Community-Acquired Pneumonia
A serologic study on etiology, with special focus
on newly identified agents
ACADEMIC DISSERTATION
To be presented, with the permission of
the Faculty of Medicine of the University of Tampere,
for public discussion in the Auditorium of Finn-Medi 1,
Biokatu 6, Tampere, on August 21st, 2009, at 12 o’clock.
UNIVERSITY OF TAMPERE
ACADEMIC DISSERTATION
University of Tampere, Medical School
Tampere University Hospital, Department of Paediatrics
Finland
University of Udine, School of Medicine
University Hospital Udine, Pediatric Clinic
Italy
Supervised by Reviewed by
Professor Matti Korppi Docent Marjo Renko
University of Tampere University of Oulu
Finland Finland
Doctor Mario Canciani Docent Eeva Salo
University of Udine University of Helsinki
Italy Finland
Distribution Tel. [phone]
Bookshop TAJU Fax [phone]
P.O. Box 617 [email protected]
33014 University of Tampere www.uta.fi/taju
Finland http://granum.uta.fi
Cover design by
Juha Siro
Acta Universitatis Tamperensis 1423 Acta Electronica Universitatis Tamperensis 851
ISBN 978-951-44-7743-0 (print) ISBN 978-951-44-7744-7 (pdf)
ISSN-L 1455-1616 ISSN 1456-954X
ISSN 1455-1616 http://acta.uta.fi
Tampereen Yliopistopaino Oy – Juvenes Print
Tampere 2009
To my wife Barbara
To my son Michele
To my parents Margherita and Paolo

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CONTENTS

LIST OF ORIGINAL PUBLICATIONS ………………………………………..…………….. 7

ABBREVIATIONS……………………………………………………………………………… 8

ABSTRACT……………………………………………………………………………………... 9

TIIVISTELMÄ…………………………………………………………………………………… 11
RIASSUNTO……………………………………………………………………………………. 13

INTRODUCTION……………………………………………………………………………….. 15

COMMUNITY-ACQUIRED PNEUMONIA IN THE PEDIATRIC AGE:
LITERATURE REVIEW ….……………………………..…………………………………….. 18
DEFINITION ……………………………………………………………………………. 18
EPIDEMIOLOGY ………………………………………………………………………. 18
RISK FACTORS ……………………………………………………………………….. 20
PATHOGENESIS ……………………………………………………………………… 22
ETIOLOGY OF PEDIATRIC CAP ……………………………………………………. 23
GENERAL CONSIDERATIONS ……………………………………………… 23
ETIOLOGICAL CLASSIFICATION OF PEDIATRIC CAP …………………. 25
VIRAL ETIOLOGY …………………………………………………………….. 27
HUMAN METAPNEUMOVIRUS …………………………………….. 27
HUMAN BOCAVIRUS ………………………………………………… 31
BACTERIAL ETIOLOGY ……………………………………………………… 35
SIMKANIA NEGEVENSIS ……………………………………………. 35
ETIOLOGY BY AGE …………………………………………………………… 38
CLINICAL PICTURE ………………………………………………………………….. 40
DIAGNOSIS ……………………………………………………………………………. 42
CHEST RADIOGRAPHY ……………………………………………………… 42
GENERAL INVESTIGATIONS ……………………………………………….. 43
OXYGEN SATURATION (SaO ) ……………………………………... 43
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PROCALCITONIN AND OTHER NON SPECIFIC SERUM
INFLAMMATORY MARKERS…………………………………………. 44
SPECIFIC MICROBIOLOGICAL INVESTIGATIONS ……………………… 46
TYPICAL BACTERIAL PNEUMONIA ……………………………….. 46
ATYPICAL BACTERIAL PNEUMONIA ……………………………… 48
VIRAL PNEUMONIA …………………………………………………... 49

AIMS OF THIS STUDY ……………………………………………………………………... 51

PATIENTS AND METHODS ………………………………………………………………… 52
STUDY DESIGN ………………………………………………………………………. 52
PATIENTS ……………………………………………………………………………… 52
CLINICAL DEFINITIONS ……………………………………………………………... 53
BACTERIOLOGY ……………………………………………………………………… 54
SIMKANIA NEGEVENSIS SEROLOGY …………………………………….. 55
VIROLOGY ……………………………………………………………………………... 55
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HUMAN METAPNEUMOVIRUS SEROLOGY ……………………………… 56
HUMAN BOCAVIRUS SEROLOGY …………………………………………. 56
NON SPECIFIC LABORATORY MARKERS ……………………………………….. 57
STATISTICAL ANALYSIS …………………………………………………………….. 58
ETHICS …………………………………………………………………………………. 59

RESULTS ………………………………………………………………………………………. 60
DEMOGRAPHIC, LABORATORY AND RADIOLOGICAL DATA ………………… 60
OVERALL ETIOLOGY ………………………………………………………………… 60
BACTERIAL INFECTIONS …………………………………………………………… 61
SIMKANIA NEGEVENSIS INFECTIONS …………………………………… 63
VIRAL INFECTIONS …………………………………………………………………... 65
HUMAN METAPNEUMOVIRUS INFECTIONS …………………………….. 65
HUMAN BOCAVIRUS INFECTIONS ………………………………………… 68
MIXED INFECTIONS ………………………………………………………………….. 72
ETIOLOGY BY HOSPITALIZATION ………………………………………………… 73
PROCALCITONIN ……………………………………………………………………... 74

DISCUSSION …………………………………………………………………………………... 81
GENERAL CONSIDERATIONS ……………………………………………………… 82
SIMKANIA NEGEVENSIS ……………………………………………………………..84
HUMAN METAPNEUMOVIRUS ……………………………………………………... 85
HUMAN BOCAVIRUS …………………………………………………………………. 87
PROCALCITONIN ……………………………………………………………………... 89
STRENGTHS AND SHORTCOMINGS OF THE STUDY …………………………. 91
FUTURE PERSPECTIVES …………………………………………………………… 93
CONCLUSIONS ……………………………………………………………………….. 93

ACKNOWLEDGMENTS ……………………………………………………………………… 95

REFERENCES ………………………………………………………………………………… 99

ORIGINAL PUBLICATIONS……………………….…………………………………………123

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LIST OF ORIGINAL PUBLICATIONS

The present thesis is based on the following papers, which are referred to in the text by
their Roman number.

I. Don M, Fasoli L, Paldanius M, Vainionpää R, Kleemola M, Räty R, Leinonen M, Korppi
M, Tenore A and Canciani M.
Aetiology of Community-Acquired Pneumonia: Serologic Results of a Paediatric Survey.
Scandinavian Journal of Infectious Diseases 2005;37(11):806-812.

II. Don M, Valent F, Korppi M, Falleti E, De Candia A, Fasoli L, Tenore A and Canciani M.
Efficacy of serum procalcitonin in evaluating severity of community-acquired
pneumonia in childhood.
Scandinavian Journal of Infectious Diseases 2007;39(29):129-137.

III. Fasoli L, Paldanius M, Don M, Valent F, Vetrugno L, Korppi M and Canciani M.
Simkania negevensis in community-acquired pneumonia in Italian children.
Scandinavian Journal of Infectious Diseases 2008;40(3):269-272.

IV. Don M, Korppi M, Valent F, Vainionpää R and Canciani M.
Human metapneumovirus pneumonia in children: results of an Italian study and mini-
review.
Scandinavian Journal of Infectious Diseases 2008;40(10):821-826.

V. Don M, Söderlund-Venermo M, Valent F, Lahtinen A, Hedman L, Canciani M, Hedman
K and Korppi M.
Serologically verified human bocavirus pneumonia in children.
Submitted.

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ABBREVIATIONS

CAP community-acquired pneumonia
CF complement fixation
CRP C-reactive protein
DNA deoxyribonucleic acid
EIA enzyme immunoassay
ELISA enzyme-linked immunosorbent assay
ESR erythrocyte sedimentation rate
HBoV human bocavirus
Hib type B Haemophilus influenza
hMPV human metapneumovirus
IFA immunofluorescence assay
LRTI lower respiratory tract infection
MIF microimmunofluorescence method
PCR polymerase-chain-reaction
PCT procalcitonin
ROC receiver operator characteristic (curve)
RRIs recurrent respiratory infections
WBC white blood cells
WHO World Health Organization

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ABSTRACT

BACKGROUND: Microbe-specific diagnosis of community-acquired pneumonia
(CAP) in childhood is difficult in clinical practice. Chest X-rays and non-specific
inflammatory markers have been used to separate presumably bacterial from viral
infection but the results have been inconsistent. Serological methods are routinary in the
diagnosis of certain viral and atypical bacterial respiratory infections. Simkania negevensis
is an atypical bacterium recently found to be associated with respiratory infections in
children and pneumonia in adults. In the last 25 years, serological methods have been
applied also to typical bacteria, like Streptococcus pneumoniae. Current knowledge on two
newly identified viruses, human metapneumovirus (hMPV) and human bocavirus (HBoV),
which are also involved in pediatric lower respiratory tract infections, is mainly based on
studies performed in respiratory samples by polymerase chain reaction.
AIMS: The aim of this prospective study is to determine, by using antibody assays,
the etiology of pediatric CAP in both ambulatory and hospitalized children younger than 16
years, with a special focus on the role of S. negevensis, hMPV and HBoV. The sero-
positivity rates to these three pathogens were also evaluated in Northern-Italian children.
In addition, the usefulness of procalcitonin (PCT) in assessing the severity of CAP, as well
as its ability to discriminate the etiology of CAP, was studied.
METHODS: During a 15-month study period, 124 children were admitted for
presumptive pneumonia, and in 101 of them pneumonia was radiologically confirmed.
Twenty-seven children were treated as inpatients and 74 as outpatients. The pulmonary
infiltrate was considered to be alveolar in 63 and interstitial in 38 cases, according to the
radiologic diagnosis. The bacterial and viral etiology of CAP was studied by an extensive
serologic test panel to 16 microbes, including microimmunofluorescence to S. negevensis,
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an enzyme immunoassay (EIA) to hMPV and a newly developed EIA to HBoV. Serum
PCT was measured by an immunoluminometric assay in 100 CAP children.
RESULTS: A potential causing agent was detected in 75 patients (74%) . Evidence
of viral, bacterial and mixed viral-bacterial infection was demonstrated in 49%, 46% and
22% of the CAP cases, respectively. Mycoplasma pneumoniae (27%), S. pneumoniae
(18%) and respiratory syncytial virus (RSV) (17%) were the most commonly found agents.
The age distribution of pneumococcal infections was rather even. Serological evidence of
acute infection due to S. negevensis, hMPV and HBoV was achieved in 5 (5%), 5 (5%)
and 12 (12%) cases, respectively. HBoV was the second most common virus, and 5 (42%)
were mixed infections. In all, 20-30% of the children had measurable antibodies to S.
negevensis, with no association with age. The sero-positivity rate to hMPV and HBoV
increased with age, reaching nearly 100% at school age. No differences were found in
PCT concentrations between the four etiological (pneumococcal, atypical bacterial, viral,
unknown) and the three (<2, 2–4 and ≥5 years) age groups. PCT was higher in inpatients
than in outpatients (medians 17.81 vs. 0.72 ng/mL respectively, p<0.01) and higher in
alveolar than in interstitial pneumonia (medians 9.43 vs. 0.53 ng/mL respectively, p<0.01).
CONCLUSIONS: Our results confirm the importance of S. pneumoniae in pediatric
CAP at all ages. The high proportions of mycoplasmal and mixed viral-bacterial infections
highlight the need to consider antibiotics in all children suffering from CAP and to monitor
clinical responses. S. negevensis and hMPV seem to be real but rare causes of CAP in
children, while HBoV may be considered a fairly common cause. Sero-conversion to
hMPV and HBoV in most children takes place in early childhood. Serum PCT values are
related to the severity of CAP in children even though they do not seem to be capable, at
any serum concentration, to differentiate between bacterial and viral etiology.

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