Postgraduate Course 9 Lower respiratory tract infection in
children
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AIMS: To show how to diagnose and manage common and uncommon lower
respiratory tract infections in children. TARGET AUDIENCE:
Pulmonologists, respiratory therapists, respiratory physicians,
clinical researchers, research fellows, and intensivists.
CHAIRS: J. Grigg (London, United Kingdom), E. Eber (Graz, Austria)
COURSE PROGRAMME PAGE
09:30 Evaluation of the child with recurrent chest infections 5 M.
Everard (Perth, Australia)
10:15 Management and prevention of non-cystic fibrosis
bronchiectasis 54 A. Möller (Zurich, Switzerland)
11:00 Break
F. Midulla (Rome, Italy)
12:15 Uncommon lower respiratory infections in childhood 170 P.
Aurora (London, United Kingdom)
Additional course resources 251
Edited by Ernst Eber and Fabio Midulla ISBN 978-1-84984-038-5
Th e ERS Handbook of Paediatric Respiratory Medicine comprises more
than 100 sections covering the whole spectrum of paediatric
respiratory medicine, from anatomy and development to disease,
rehabilitation and treatment.
Th e book is structured to tie in with the paediatric HERMES
syllabus, making it an essential resource for anyone interested in
the fi eld and the ideal training aid for those wishing to take the
European Examination in Paediatric Respiratory Medicine.
Accredited by EBAP for 18 hours of European CME credit
To buy printed copies, visit the ERS Bookshop at the ERS
International Congress 2015 (Hall 1, Stand 1.D_12).
THE ERS HANDBOOK OF paediatric respiratory medicine
Electronic: WWW.ERSPUBLICATIONS.COM Print:
WWW.ERSBOOKSHOP.COM
Prof. Mark L Everard University of Western Australia, Princess
Margaret Hospital
Roberts Rd, Subiaco, Perth WA 6008,
Australia
[email protected]
SUMMARY In this presentation the diverse causes of ‘chest
infections’ amongst infants and children will be
discussed with a view to developing a systematic approach that can
be utilised when faced with a child who has experienced recurrent
‘chest infections’. Evaluation of a child who has experienced
recurrent ‘chest infections’ is one of the more common
scenarios facing a respiratory paediatrician in both the outpatient
and inpatient settings. The primary challenge is to determine
whether child is ‘normal’ or there is a significant underlying
problem that
needs to be addressed. Clearly it is important to consider
non-infectious causes of recurrent ‘chest
infections’ the commonest scenario being the repeated use of
antibiotics to treat children with mild to moderate asthma who
experience exacerbations with inter-current viral infections. This
is particularly the case in pre-school children in whom both under
diagnosis, as above, and over diagnosis [failing to recognise that
a child with a viral bronchitis can wheeze without having asthma]
are common. More rarely conditions such as idiopathic pulmonary
haemorrhage are mis-diagnosed as recurrent severe ‘chest
infections’ due to the extensive CXR consolidation and the
associated respiratory viral illness
that frequently triggers the exacerbations. Challenges in infancy
and early childhood The majority of those with a significant
underlying abnormality such as a significant immunodeficiency,
primary ciliary dyskinesia [PCD], cystic fibrosis or significant
structural airways problems will start to manifest problems during
infancy. However the incidence of significant viral lower
respiratory tract infections amongst normal infants and toddlers is
higher than at any other time of life with high levels of
hospitalisation and significant morbidity. The likelihood of a
virus causing significant lower respiratory infections is
influenced by both the infecting dose and the pre-existing immunity
which is poor in very young subjects once maternally derived
antibodies wane. Inevitably many ‘normal’ children will experience
a number of lower respiratory tract infections [LRTIs] (recurrent
infections) particularly if they attend a nursery or day-care or
have a number of older siblings. Though most acute LRTIs in infancy
and early childhood are viral this is also the age at which
bacterial pneumonia and invasive pneumococcal disease are at their
peak and there no entirely reliable means of distinguishing the
viral and bacterial infections. Conversely it is well described
that children with disease such as PCD, CF and X-linked
agammaglobulinaemia are not diagnosed until well into the first
decade of life and hence age of the patient does not preclude the
need to consider the more serious and persistent causes
Viral-bacterial Interactions It is important to recognise that
respiratory viruses can cause a severe life threatening LRTI but
also appear to create opportunities for more invasive bacterial
organisms to cause lobar pneumonias; trigger exacerbations of a
persistent bacterial bronchitis to cause a bronchopneumonia and are
the major trigger for exacerbations of asthma which often
masquerade as a ‘chest infection’. The combination of a runny nose
temperature and coughing without obvious wheeze leads many on
the
mild to moderate end of the asthmatic spectrum to be
inappropriately treated with frequent courses of antibiotics and is
a common cause for under diagnosis. In these cases the virus is a
facilitator of lower airways disease and/or exacerbation rather
directly being responsible for the ‘chest infection. Importance of
biofilms disease Our relatively recent recognition that bacterial
biofilms develop in the lower airway in response to impaired
mucocillary clearance provides a conceptual working model for
persistent respiratory morbidity and ‘recurrent infections’
generally triggered by viruses. Our current concepts relating to
the development of the radiological appearance ‘bronchiectasis’
[bronchiectasis is not a disease but a
radiological or pathological appearance – the dis-ease is due to
the underlying bacterial bronchitis] are based on Prof P. Cole’s
vicious cycle hypothesis in which impaired mucocillary clearance
resulting
bacterial infection leading to inflammation and damage to the
airway resulting in further impairment of mucocillary clearance.
Though bronchiectasis can result from certain severe infections
such as PVL staphylococcal pneumonia or as part of a condition such
as obliterative bronchitis this hypothesis suggests that chronic
infection plays a central role and in most cases this is due to
impaired mucocillary clearance though in some immune deficiencies
permit the colonisation of the airways. Many have had trouble
reconciling their understanding that organisms such as Strep.
Pneumoniae cause of an acute, but time limited, life threatening
pneumonia with the suggestion that the same organism may cause a
chronic bacterial bronchitis. However the same individuals
recognise the existence of chronic pseudomonal infection of the CF
airway and recognise its change of state to a mucoid form
represents a much more indolent and difficult to treat state while
not understanding the importance of the biofilm. It is now
recognised that organisms such as Strep. Pnuemoniae, non-typable
haemophilus influenza [NTHi] and Moraxella catarrhalis amongst
others are very adept at colonising any niche they can find in the
respiratory tract and are associated with chronic otitis media,
chronic sinusitis and persistent bacterial bronchitis. The list of
conditions predisposing to the establishment of a biofilm is
extensive as outlined in table 1. Amongst the causes are conditions
known to have poor outcomes unless managed aggressively [such as CF
PCD and major immunodeficiencies]. The majority however appear to
be due to a self-limiting insult such as an acute viral infection
that resolves but leads to on- going morbidity due to the secondary
biofilm disease. This may resolve spontaneously in some but equally
[depending on extent and management] may progress to severe
bronchiectasis over a period time that may range from a months to
decades.
6
Primary ciliary dyskinesia
Acute or recurrent aspiration
Poorly controlled asthma
Foreign Body
Types of ‘chest infections’ Pneumonia is an infection of the
respiratory compartment of the lungs [beyond generation 16] and is
characterised by ‘consolidation’ on a chest x-ray [though the CXR
cannot be used to reliably distinguish viral and bacterial
disease]. For bacterial infections they are frequently lobar and
are caused by organisms such as Strep. Pnuemoniae and HiB – the
bacteria are planktonic and divide rapidly causing a severe
potentially life threatening disease. In general they respond
rapidly to antibiotics and it is likely that many cases are treated
in primary care without being recognises as pneumonia. Biofilm
infections of the conducting airways [generations 1 -16] produce
more chronic symptoms with cough predominating. Typically children
do not look unwell until they experience and exacerbation –
generally labelled a chest infection. Any CXR changes are the
scruffy, non-specific changes characteristic of peribronchial wall
thickening which might be seen in asthmatic subjects, those with a
viral infection or PBB. A CXR taken during an exacerbation may
capture patchy consolidation of bronchopneumonia [consolidation due
to planktonic organisms released by the biofilms in adjacent
conducting airways]. Without a clear history seeking evidence of
pre-existing or interval cough these exacerbations can be
mislabelled as a discrete pneumonias.
Questions to be considered in the evaluation of a child with
‘recurrent chest infections Are these episodes ‘chest infections’?
Is this asthma triggered by a viral respiratory infection? Is this
episodic aspiration without associated infection? Is this a rare
episodic problem such as pulmonary haemorrhage masquerading as
infection?
7
Are the episodes completely discrete with no interval symptoms at
all? Makes significant underlying problem less likely Due to the
range of viral and bacterial pathogens that are able to cause
significant lower
respiratory tract infections Inevitably some children will be
experience more than one Does not exclude problems such as
intermittent aspiration with subsequent infection, asthma and
some immunological problems Did problems start in early infancy?
Increased likelihood of inherited conditions such as PCD & CF;
structural airways problems and
aspiration associated with neuromuscular disorders CF but may occur
in some ‘normal’ children. May be associated with some
immunological problems though passively derived maternal
antibody provides some protection in antibody deficiencies Many
post viral PBB cases start in infancy due to frequency of viral
LRTIs.
Are there associated markers of significant underlying disease?
failure to thrive with diarrhoea might suggest CF or significant
immunodeficiency neonatal respiratory distress and/or significant
middle ear problems [PCD] Is there evidence of aspiration with
symptoms during and immediately after a feed which may be
due to problems affecting ability to protect airways due to
neuromuscular disease and significant cerebral palsy or a
structural abnormality such as laryngeal cleft or H-fistula
Has the subject had recent therapy for malignancy with its
associated immunosuppression? If imaging has been undertaken are
the changes always in the same area? Much less common than variable
and multi-lobar May suggest local obstruction such as localised
malacia, external compression [vascular, lymph
nodes, malignancy etc.], foreign body etc. Possibly local
parenchymal pathology
As with much in respiratory medicine a clear history is the most
important component of the assessment focusing on factors such as
the age of onset, pattern of symptoms including chronic cough and
clues to the presence of an ongoing, underlying cause. Examination
is mandatory but can be relatively uninformative. While secretions
in the airways may generate harsh inspiratory and expiratory sounds
the auscultation is often unhelpful though asking the child to
cough, if old enough, is often very valuable. Investigations are
driven by the likelihood of finding a significant underlying cause.
In some no –
investigations need be undertaken as they respond well to therapy
and the problem resolves. In the face of more persistent /recurrent
symptoms or aspects of the history or examination a wide range of
investigations maybe undertaken thought there are no studies on
which to base recommendations. Bronchoscopy – involves and
anaesthetic but provides information regarding airways
structure
and samples for microbiology. If undertaken all blood samples
should be collected at same time. It should be noted that recent
courses of antibiotics appear to greatly reduce the chances of
culturing bacteria and an interval of 4- 6 weeks is desirable. The
presence of significant malacia alter practice in that
physiotherapy utilising PEP strategies can be used to help
clearance
CT scan can also provide information relating to structure such as
airways compression and the presence of bronchiectasis. However the
presence of bronchiectasis suggests that there has [in most cases]
been inappropriate delay in management. Mild bronchiectasis is
reversible with aggressive treatment in the absence of significant
underlying pathologies such as CF. It is now possible to obtain CT
scans of sufficient quality using a radiation dose of 1 -2 CXR
though few centres offer this. Clinicians should be ensuring their
radiology Dept. makes this a priority.
Screening for PCD with nasal NO and nasal brushing.
8
Immunological screening with antibodies, subclasses vaccine
responses, lymphocyte subsets and MBL levels often making up the
initial screen. More detailed analysis in conjunction with the
immunologists on those with severe progressive disease despite
therapy and no other reason for ongoing problems.
In many no specific underlying cause is found and n those with
bacterial disease management should be aimed at cure rather than
mitigating the rate of progression.
REFERENCES 1. Brand PL, Hoving MF, de Groot EP. Evaluating the
child with recurrent lower respiratory tract
infections. Paediatr Respir Rev. 2012;13: 135-8 2. Bush A.
Recurrent respiratory infections. Pediatr Clin North Am. 2009; 56:
67-100 3. Chao Y, Marks LR, Pettigrew MM, et al. Streptococcus
pneumoniae biofilm formation and
dispersion during colonization and disease. Front Cell Infect
Microbiol. 2015; 4:194. 4. Chang AB, Byrnes CA, Everard ML
Diagnosing and preventing chronic suppurative lung disease
(CSLD) and bronchiectasis. Pediatr Resp Rev 2011; 12: 97-103 5.
Cole PJ. Inflammation: a two-edged sword--the model of
bronchiectasis. Eur J Respir Dis Suppl.
1986;147:6-15 6. Couriel J. Assessment of the child with recurrent
chest infections. Br Med Bull. 2002; 61: 115-32 7. Craven V,
Everard ML. Protracted bacterial bronchitis: reinventing an old
disease. Arch Dis
Child. 2013; 98: 72-6 8. Bakaletz LO. Bacterial biofilms in the
upper airway - evidence for role in pathology and
implications for treatment of otitis media. Paediatr Respir Rev.
2012; 13: 154-9 9. Everard ML. 'Recurrent lower respiratory tract
infections' - going around in circles, respiratory
medicine style. Paediatr Respir Rev. 2012 ; 13: 139-43 10. Hoving
MF, Brand PL. Causes of recurrent pneumonia in children in a
general hospital. J
Paediatr Child Health. 2013; 49: E208-1 11. Marsh RL, et al.
Detection of biofilm in bronchoalveolar lavage from children with
non-cystic
fibrosis bronchiectasis. Pediatr Pulmonol. 2014 Mar 18. doi:
10.1002/ppul.23031 12. Reddel H, Ware S, Marks G, Salome C, Jenkins
C, Woolcock A. Differences between asthma
exacerbations and poor asthma control. Lancet. 1999; 353: 364-9 13.
Rodrigues F, Foster D, Nicoli E et al. Relationships between
rhinitis symptoms, respiratory viral
infections and nasopharyngeal colonization with Streptococcus
pneumoniae, Haemophilus influenzae and Staphylococcus aureus in
children attending daycare. Pediatr Infect Dis J. 2013; 32:
227-32
EVALUATION 1. Which of the following are true?
a. Many children with recurrent chest infections do not have a
significant identifiable underlying problem
b. It is important to determine whether symptoms entirely resolve
between episodes c. Symptoms attributable to recurrent infections
may be due to asthmatic exacerbations d. Respiratory viral
infections are often responsible for exacerbations of a persistent
bacterial
bronchitis leading to a bronchopneumonia e. All children with
recurrent chest infections should have a bronchoscopy
3. Which of the following predispose to recurrent ‘chest
infections’?
a. Attendance at day care b. Previous chemotherapy for malignancy
c. diabetes d. Impaired cough e. Laryngeal cleft
4. Which of the following are true of respiratory viral
infections?
a. They may precede the development of a persistent bacterial
bronchitis b. The may precede the development of an acute bacterial
lobar pneumonia c. They may trigger an exacerbation of asthma d.
They may be detected in asymptomatic individuals e. The severity of
a ‘viral cold’ is influenced by the load of potentially pathogenic
bacteria in the
upper airway
Evaluation of the child with recurrent ‘chest infections’
‘When I use a word,’’ Humpty Dumpty said in a rather scornful tone,
‘‘it means just what I choose it to mean, neither more nor
less’’
Lewis Carrol Through the Looking-Glass 1872
Conflict of interest disclosure
I have no, real or perceived, direct or indirect conflicts of
interest that relate to this presentation.
This event is accredited for CME credits by EBAP and speakers are
required to disclose their potential conflict of interest going
back 3 years prior to this presentation. The intent of this
disclosure is not to prevent a speaker with a conflict of interest
(any significant financial relationship a speaker has with
manufacturers or providers of any commercial products or services
relevant to the talk) from making a presentation, but rather to
provide listeners with information on which they can make their own
judgment. It remains for audience members to determine whether the
speaker’s interests or relationships may influence the
presentation. Drug or device advertisement is strictly
forbidden.
12
Lobar pneumonia?
13
• 5 years old • Chronic cough from 10 months of age • 1 previous
admission with pneumonia • Thriving
Possible underlying causes? Asthma
Inhaled foreign body Cystic fibrosis
Agammaglobulinaemia Aspiration Bad luck
14
12 years old - referred by practice nurse Frequent abs as
infant
Eczema as infant - mother with eczema as child ‘Asthma’ at 4 yrs of
age
Seretide 250 bd singulair 5mgs Recent ‘pneumonia’
FEV1 99% Did not appear unwell
Difficult asthma Do recurrent chest infections have a role?
15
12 years old - referred by practice nurse Frequent abs as
infant
Eczema as infant - mother with eczema as child ‘Asthma’ at 4 yrs of
age
Seretide 250 bd singulair 5mgs Recent ‘pneumonia’
FEV1 99%
Difficult asthma or recurrent chest infections?
16
17
Koch's postulates :
The microorganism must be found in abundance in all organisms
suffering from the disease, but should not be found in healthy
organisms.
The microorganism must be isolated from a diseased organism and
grown in pure culture.
The cultured microorganism should cause disease when introduced
into a healthy organism.
The microorganism must be reisolated from the inoculated, diseased
experimental host and identified as being identical to the original
specific causative agent.
a long, long time ago……
* 1890 to be precise
Pneumonia respiratory disease characterized by inflammation of the
lung parenchyma (excluding the bronchi) with congestion caused by
viruses or bacteria or irritants
Congestion
WHO
history of cough and/or difficulty breathing (<14 days duration)
with increased respiratory rate (defined for age)
> 2 months > 60/min 2-11 months > 50/min > 11 months
> 40/min
Cherian et al Bull WHO. 2005;83(5):353–359
21
How is it diagnosed?
UK Bacterial pneumonia should be considered in children aged up to
3
years when there is fever of >38.5°C together with chest
recession and a respiratory rate of >50/min.
For older children a history of difficulty in breathing is more
helpful than clinical signs.
Chest radiography should not be performed routinely in children
with mild uncomplicated acute lower respiratory tract
infection
Radiographic findings are poor indicators of aetiology.
BTS UK Community acquired pneumonia guidelines 22
Consolidation and LRTIs
South Africa (HIV-): 19.2% of 1,106 LRTI episodes had CXR-AC
Phillipines: 13.8% of hospital pneumonia and 5.9% of OP
pneumonia.
USA: 12% of pneumonia episodes had CXR-AC
Fiji: 34% of 174 LRTI episodes had CXR-AC.
Enwere G et al. Trop Med Int Health Nov 2007; 12; Madhi SA et al.
Clin Infect Dis; 2005: 40; Lucero et al. Pediatr Infect Dis J
2009;28: 455–462, Magree HC et al. Bull Wld Health Org; 2005; 83.
23
Aetiology of ‘pneumonia’
Haemophilus influenzae 26.1% 0.6%
Group A Streptococcus 3.2%
The dis-ease is the bacterial bronchitis
26
Biofilms bacterial population(s), encased in an auto-produced
matrix
[EPS], which may contain host components, adhering with each other
and/or to a surface
extracellular polymeric substances [EPS] polysaccarides, proteins,
alginates, eDNA, lipids, collagen etc
NTHi otitis media: ds DNA + pili Bakaletz et al
28
Benefits of biofilm formation Bacteria within a biofilm are
protected by multilayered defences both physical and
biological
Can co-ordinate response to host, physical environment and other
micro-organisms
Highly organised communities Optimise to nutrient availability and
other stresses
Reduced growth rate - low metabolic rate
Different transcriptome – switch on and off virulence factors etc
Exchange genetic information more frequently
Share enzymes Physical barrier to host cells, antibodies and
removal
Sig increase in antibiotic resistance [upto 1000X]
29
Bakaletz L et al 2011
planktonic cells
Quorum Sensing
Chatorajj Thorax 2011
Bacteria have been using extracellular polymeric substances (EPS)
to create their own protected microenvironment for >3.5 billion
yrs
Noffke et al 2013
31
Controls Bronchiectasis ID 9 10 11 1 2 3 4 5 6 7 8 Biofilm Lavage 1
- - - - - + - + - - + Biofilm Lavage 2 - - - + - + + + + + +
BALs of children with non-CF bronchiectasis & PBB
Marsh, Thornton, Chang et al, Pediatric Pulmonology, 2014
WGA and Con A
Koch's postulates :
The microorganism must be found in abundance in all organisms
suffering from the disease, but should not be found in healthy
organisms.
The microorganism must be isolated from a diseased organism and
grown in pure culture.
The cultured microorganism should cause disease when introduced
into a healthy organism.
The microorganism must be reisolated from the inoculated, diseased
experimental host and identified as being identical to the original
specific causative agent.
a long, long time ago…… *
33
PCV Reduces The Incidence Of Hospitalization for Viral- Associated
Pneumonia In Children
Virus PCV Placebo Efficacy 95%C.I. P value
Influenza A/B 31 56 45 14 to 64 0.01
PIV 1-3 24 43 44 8 to 66 0.02
hMPV 26 62 58 34 to 73 0.001
RSV 90 115 22 -3 to 41 0.08
Madhi SA & Klugman KP. Nature Med.2004. 10: 811-813; Madhi SA
et al. J Infect Dis 2006; 193:1236-43
At least one-third of placebo-recipients hospitalized for pneumonia
in whom a virus was identified had concurrent infection due to VT
pneumococcus
Viral infections and IPD
Rodrigues 2010 Ped Inf Dis J
SNOT - Virus and Bacteria
Inflammation
Immunodeficiency Esp antibidody
History & Investigations [see abstract]
? Bronchoscopy
?CT
?Immunological investigations
?videofluroscopy/oesophograms etc
Regression to the mean and tuning out
‘He’s a new boy’
He’s sleeping better and not coughing as much
38
Impact on Quality of Life
Petsky HL J Pediatr Child Health 2010
‘It’s just another virus’ ‘Try this inhaler’
‘You are the first Dr to listen to me’
Morbidity Regression to the mean
39
40
Diagnosis of Biofilm Disease?
NTHi 3.5 X 103 CFU/mL Strep P 4 X 103 CFU/mL Moraxella ++
Pt 1
Pt 2
When bacteria are in the biofilm phenotype they are unlikely to be
in a cultureable state and thus PCR maybe needed for
detection
1 > 10 ?4
Diagnosis of Biofilm Disease?
NTHi 3.5 X 103 CFU/mL Strep P 4 X 103 CFU/mL Moraxella ++
Pt 1
Pt 2
Quantitative versus qualitative cultures of respiratory secretions
for clinical outcomes in patients with ventilator associated
pneumonia
There is no evidence that the use of quantitative cultures of
respiratory secretions results in reduced mortality, reduced time
in ICU and on mechanical ventilation, or higher rates of antibiotic
change when compared to qualitative cultures in patients with
VAP.
When bacteria are in the biofilm phenotype they are unlikely to be
in a cultureable state and thus PCR maybe needed for
detection
1 > 10 ?4
44
Treat with antibiotics until cough resolves [Phelan]
Cough takes 10 -14 days to clear with high dose antibiotics
? Long courses to allow airways to repair
? side effects
45
Treat the bacterial bronchitis and the radiological bronchiectasis
can resolve – at least if treated early enough
Bronchiectasis usual represents medical neglect 46
1980’s
under diagnosis of asthma in 7 yr olds
• Doctors are fearful of using the term asthma
• All too often the (viral) bronchitis is treated with antibiotics
while the wheeze is ignored
• Recent research has undermined this belief [wheezy bronchitis is
a separate clinical entity] and there is little clinical value in
distinguishing them since the treatment is the same
• 96% identified by the single question ‘has your child ever had
attacks of wheezing?’
Speight ANP BMJ 1983 47
Diagnosis? 7 yrs old with chestiness in winter
Some response to ventolin
49
biofilm and planktonic disease
BAL Left Lower Lobe – Heavy growth of NTHi PMNs +++ 50
• Amanda age 6 years. One of 5 children - asthma diagnosed at age
of 2.5 yrs and treated initially with agonist alone. Older brother
has asthma but grew out of it before he went to school.
Subsequently started on ICS and last year commenced LABA.
• Currently symptomatic with cough particularly at night, first
thing in the morning and with exercise.
• Several pets, both parents smoke and are unemployed. • Has had
many courses of antibiotics for chest infections
and is frequently prescribed antibiotics at the same time as oral
steroids which usually helps for a while but symptoms soon
return.
What is the likely problem and what would you do? 51
• April is 3 yrs of age - had many courses of antibiotics for ear
and chest infections during the past 2 years.
• No family history of asthma, eczema when a baby. • Lives in 2
bedroom council flat with mother and 3 siblings. • Generally well
though is very tired and crabby particularly with chest
infections and looses appetite. • Main problem is cough, possibly
wheezed during an earlier chest
infection. • Always has loose stools and is still in nappies. • 1
cat, mother does not smoke. • Mother has applied for re-housing
because of the damp bedrooms
and April’s chest problems.
What is the likely problem and what would you do? 52
The importance of a persistent bacterial bronchitis in recurrent
chest infections
Diagnosis can be difficult, mis-diagnosis is common both under and
over
A persistent bacterial bronchitis [biofilm] causes the dis-ease
Relatively common Cause of significant morbidity Bronchiectasis is
a largely preventable radiological appearance
? Place for bronchoscopy
? Place for CT
? Optimal therapy 53
Dr Alexander Moeller Head Division Respiratory Medicine University
Children's Hospital Zurich
Steinwiesstrasse 75 8032 Zurich
SWITZERLAND
[email protected]
SUMMARY Bronchiectasis in children without cystic fibrosis (non-CF
bronchiectasis) is a morphological term describing abnormal,
irreversibly dilated and often thick-walled bronchi [1,2] and is
believed to be the end result of chronic or repeated episodes of
environmental insults. The pathophysiology is not yet completely
understood, however it is very likely that airway damage is caused
by inflammation and bacterial infection superimposed on a
background of genetic vulnerability [1]. Bronchiectasis is
associated with frequent bacterial infections and inflammatory
destruction of the bronchial and peri- bronchial tree. Whilst
originally described in histopathological terms bronchiectasis is
defined radiologically in clinics [2]. Bronchiectasis is thought to
be the end result of suppurative lung disease and a consequence of
persistent airway bacterial colonization. [3] More than 60% of
children with bronchiectasis have an underlying disorder. In a
systematic review including a total of 989 children with
bronchiectasis infectious (17%), primary immunodeficiency (16%),
aspiration (10%), ciliary dyskinesia (9%), congenital malformation
(3%), and secondary immunodeficiency (3%) were the most common
disease categories, whereas severe pneumonia of bacterial or viral
aetiology and B cell defects were the most common disorders
identified. [4] Reduced mucociliary clearance is the consequence of
different basic disorders and results in mucostasis associated with
airway colonisation and finally chronic infection with mucoid
transformation and biofilm production. The neutrophil mediated
inflammation together with the release of proteolytic enzymes
results in airway and tissue injury leading to further reduction of
mucociliary clearance. [1] Chronic wet cough is the most important
symptom leading to the suspicion of suppuratives lung disease and
bronchiectasis in a child. [5] Both protracted bacterial bronchitis
and failed chronic wet cough response to antibiotics are predictors
of bronchiectasis [5, 6].
54
Table 1. Symptoms / Signs Wet cough Daily sputum production
Hemoptysis Pleuritic chest pain Pulmonary osteoarthropathy Delayed
growth When to suspect bronchiectasis Chronic moist/productive
cough Asthma that does not respond to treatment Incomplete
resolution of a severe pneumonia, or recurrent pneumonia
Pertussis-like illness failing to resolve after six months
Persistent and unexplained physical signs, i.e. persistent lung
crackles Respiratory symptoms in children with structural or
functional disorders of the oesophagus and
upper respiratory tract Unexplained haemoptysis If bronchiectasis
is suspected based on the history, clinical signs and or chest
radiography a high- resolution CT scan should be performed when
possible in inspiration to rule out or confirm the presence of
bronchiectasis. [2,7,8] The key features of bronchiectasis on HRCT
scans are (a) one or more ‘dilated’ bronchi defined as the internal
luminal diameters of the airways exceeding the diameter
of the adjacent vessel, (b) non-tapering of the bronchi, (c)
presence of visible bronchi adjacent to the mediastinal pleura or
within the outer 1- 2 cm of the lung fields. If bronchiectasis is
confirmed in a child, the following diagnostic steps should be
performed (Table 2). Table 2: further diagnostics modified from [9]
Sweat test Mandatory to rule out cystic fibrosis Test of immune
function – Serum immuno-globulins
– IgG-subclasses – Specific antibodies to vaccinations
Pertussis, diphtheria, tetanus toxoid, capsular polysaccharides of
Streptococcus pneumoniae and Haemophilus influenzae type B
Repeat 4 weeks after vaccination-boost if low – Lymphocyte B and T
cell subsets – Mantoux and others – HIV
Testing for PCD Step-wise approach [10]
– Nasal nitric oxide – Nasal brushing – High frequency video
microscopy analysis (HVMA) – Transition-electron microscopy –
Immune-fluorescent microscopy – Genetics
Test for pulmonary aspiration Primary and secondary aspirations,
children with neurological disorders Bronchoscopy Not mandatory,
may give information on non-sputum producing children
55
Bronchiectasis is associated with significantly lower child-rated
physical health quality of life (QOL) scores [11, 12] and lower
sleep quality [13]. Wheezing and dyspnoea severity, number of
exacerbations and frequency of antibiotic requirements were all
associated with lower QOL [11, 12]. Regular microbiological
investigations are a cornerstone of the management of non-CF-
bronchiectasis. A broad range of airway pathogens are regularly
found in children with bronchiectasis including Haemophilus
influenza, Streptococcus pneumonia, Moraxella catarrhalis,
Pseudomonas aeruginosa, Staphylococcus aureus, and Aspergillus
species. [15, 16, 17]. The implementation of preventive measures
has the potential to reduce the risk of development and the
progression of bronchiectasis [18]. In addition appropriate
treatment reduces exacerbations of bronchiectasis and prevents
deterioration of lung function [14, 16, 19]. Some children may need
prolonged antibiotic treatment, whenever possible according to
microbiology. Airway damage can be limited by intensive treatment,
even in those predestined to have bronchiectasis. [20, 21] Table 3:
Preventive measures modified from [21]
Primary prevention Secondary prevention Tertiary prevention
Normal lung development Early detection Reduce morbidity, mortality
and secondary complications
Removal of modifiable risk factors
Appropriate treatment Reduce adverse events from medication
ARI‘s, CSLD, Bronchiectasis
Good follow up of all acute respiratory episodes
Assessment for treatable causes
Early diagnosis of bronchiectasis
Early treatment of exacerbations
Asthma Obtain good asthma control
Mainstays of treatment 1. Airway clearance techniques. These are
similar to the techniques used in the management of
cystic fibrosis and include oscillatory positive expiratory
pressure devices (PEP), selective breathing and chest
physiotherapy. [9]
2. Aerosol therapy including hyperosmolar agents such as hypertonic
saline and mannitol. Bronchodilators are frequently prescribed
without clear evidence. [9,22]
3. Antibiotics are used to either treat exacerbations in an empiric
manner or guided by microbiology or intermittently to reduce
bacterial load. Long-term treatment with azithromycin has been
evaluated in different studies including children with
bronchiectasis or chronic suppurative lung disease. Whereas there
was a clear reduction in the number of exacerbations, there was
a
56
significant increase in azithromycin-resistant airway pathogens.
[24, 25]. A recent meta-analysis did not reveal a significant
effect on lung function by long-term macrolide treatment.
[25]
4. Regular exercise is an important treatment option. 5. Surgery is
rarely indicated and performed only in localised disease in the
case of significant
symptoms unable to be controlled by medical therapy or for the
treatment of complications such as empyema, recurrent haemoptysis,
lung abscess.
6. Vaccinations, including annual influenza vaccination and
5-yearly Pneumococal vaccination are considered an important
preventive measure. [26,27]
REFERENCES 1. Cole PJ. Inflammation: a two edged sword – the model
of bronchiectasis. Eur. J. Respir. Dis.
Suppl. 1986; 147: 6–15. 2. Eastham KM, Fall KJ, Mitchell L, Spencer
DA. The need to redefine non-cystic fibrosis
bronchiectasis in childhood. Thorax 2004; 59: 324–7. 3. Chang AB,
Redding GJ, Everard ML. State of the Art - Chronic wet cough:
protracted bronchitis,
chronic suppurative lung disease and bronchiectasis. Pediatr
Pulmonol 2008;43:519–31 4. Brower, K. S., Del Vecchio, M. T., &
Aronoff, S. C. The etiologies of non-CF bronchiectasis in
childhood: a systematic review of 989 subjects. BMC Pediatrics,
2014, 14(1), 299. 5. Chang, A. B., Robertson, C. F., Asperen, P. P.
Van, Glasgow, N. J., Mellis, C. M., Masters, I. B.,
Landau, L. I. A Multicenter Study on Chronic Cough, CHEST 2015;
943–950. 6. Goyal, V., Grimwood, K., Marchant, J., Masters, I. B.,
& Chang, A. B. Does failed chronic wet
cough response to antibiotics predict bronchiectasis? Archives of
Disease in Childhood, 2014; 99(6), 522–5.
7. Li, a. M., Sonnappa, S., Lex, C., Wong, E., Zacharasiewicz, a.,
Bush, a., & Jaffe, a. Non-CF bronchiectasis: Does knowing the
aetiology lead to changes in management? European Respiratory
Journal 2005; 26(1), 8–14.
8. Chang AB, Masel JP, Boyce NC, Wheaton G, Torzillo PJ. Non-CF
bronchiectasis – clinical and HRCT evaluation. Pediatr. Pulmonol.
2003; 35: 477–83.
9. Lucas JS, Burgess A, Mitchison HM, et al. Diagnosis and
management of primary ciliary dyskinesia. Arch Dis Child 2014;
99:850–856.
10. Bahali, K., D, M., Gedik, A. H., D, M., Bilgic, A., D, M.,
(2014). The relationship between psychological symptoms , lung
function and quality of life in children and adolescents with non-
cystic fibrosis bronchiectasis General Hospital Psychiatry 2014;
36: 528–532
11. Gokdemir, Y., Hamzah, A., Erdem, E., Cimsit, C., Ersu, R.,
Karakoc, F., & Karadag, B. Quality of Life in Children with
Non-Cystic-Fibrosis Bronchiectasis. Respiration, 2014; 88(1),
46–51.
12. Erdem, E., Ersu, R., Karadag, B., Karakoc, F., Gokdemir, Y.,
Ay, P. Dagli, E. Effect of night symptoms and disease severity on
subjective sleep quality in children with non-cystic-fibrosis
bronchiectasis. Pediatric Pulmonology, 2011; 46(9), 919–926.
13. Bastardo, C. M., Sonnappa, S., Stanojevic, S., Navarro, a,
Lopez, P. M., Jaffe, Bush A. Non- cystic fibrosis bronchiectasis in
childhood: longitudinal growth and lung function. Thorax 2009,
64(3), 246–251.
14. Grimwood, K. Airway microbiology and host defences in
paediatric non-CF bronchiectasis. Paediatric Respiratory Reviews
2011; 12(2), 111–118.
15. Kapur, N., Grimwood, K., Masters, I. B., Morris, P. S., &
Chang, A. B. Lower airway microbiology and cellularity in children
with newly diagnosed non-CF bronchiectasis. Pediatric Pulmonology,
2012, 47(3), 300–307.
16. Tunney, M. M., Einarsson, G. G., Wei, L., Drain, M., Klem, E.
R., Cardwell, C.; Elborn, J. S. Lung microbiota and bacterial
abundance in patients with bronchiectasis when clinically stable
and during exacerbation. American Journal of Respiratory and
Critical Care Medicine, 2013, 187(10), 1118–1126.
17. Chang, A. B., Byrnes, C. a., & Everard, M. L. (2011).
Diagnosing and preventing chronic suppurative lung disease (CSLD)
and bronchiectasis. Paediatric Respiratory Reviews, 2011; 12(2),
97–103.
57
18. Chang, A. B., Robertson, C. F., van Asperen, P. P., Glasgow, N.
J., Masters, I. B., Teoh, L.,Morris, P. S. A cough algorithm for
chronic cough in children: a multicenter, randomized controlled
study. Pediatrics, 2013; 131(5), e1576–83.
19. Chang, A. B., Brown, N., Toombs, M., Marsh, R. L., &
Redding, G. J. (2014). Lung disease in indigenous children,
Paediatric Respiratory Reviews 15 (2014) 325–332
20. Rubin BK. Overview of cystic fibrosis and non-CF
bronchiectasis. Semin. Respir. Crit. Care Med. 2003; 24:
619–27.
21. Rubin BK. Aerosolized antibiotics for non-cystic fibrosis
bronchiectasis. J. Aerosol Med. 2008; 21: 1–6.
22. Valery, P. C., Morris, P. S., Byrnes, C. a., Grimwood, K.,
Torzillo, P. J., Bauert, P. ;Chang, A. B. Long-term azithromycin
for Indigenous children with non-cystic-fibrosis bronchiectasis or
chronic suppurative lung disease (Bronchiectasis Intervention
Study): A multicentre, double- blind, randomised controlled trial.
The Lancet Respiratory Medicine, 2013, 1(8), 610–620.
23. Gao, Y. H., Guan, W. J., Xu, G., Tang, Y., Gao, Y., Lin, Z.
Y.,Chen, R. C. Macrolide therapy in adults and children with
non-cystic fibrosis bronchiectasis: A systematic review and meta-
analysis. PLoS ONE, 2014; 9(3).
24. Haciibrahimoglu G, Fazlioglu M, Olcmen A et al. Surgical
management of childhood bronchiectasis due to infectious diseases.
J. Thorac. Cardiovasc. Surg. 2004; 127: 1361–5.
25. Sirmali M, Karasu S, Turut H et al. Surgical management of
bronchiectasis in childhood. Eur. J. Cardiothorac. Surg. 2007; 31:
120–3
EVALUATION A 6 years old non-allergic boy is referred because of
chronic cough since more than 2 years. As he was coughing more
during exercise the GP has initiated an inhalation therapy
including salbutamol and fluticasone proprionate, however without
persistent improvement. At birth he was tachypnoeic and needed some
oxygen for “wet-lungs”. In addition he suffers from a runny nose
all year 3 episodes
of otitis media. He had recurrent chest infections in the past and
several courses of short-time (3-5 days) oral antibiotics in the
past with a good clinical response but a relapse of cough after
some weeks. A chest radiograph showed situs inversus, some
pronounced peribroncho-vascular structures and non- specific
bronchial thickening in both lower lobes and atelectasis of the
middle lobe. You have the suspicion of bronchiectasis. 1. Which
diagnostic investigation do you perform first:
a. Bronchoscopy and bronchoalveolar lavage b. HRCT-scan of the lung
c. Sweat test d. Immunological-work up
2. What are the most common underlying diseases or aetiologies
associated with non-cf-
bronchiectasis in children? a. lung infections b. primary
immunodeficiency c. aspiration d. ciliary dyskinesia e. congenital
malformation f. all of above
3. Which is the most likely underlying disease of this boy?
a. Cystic fibrosis b. B-cell immunodeficiency c. Primary ciliary
dyskinesia d. Congenital pulmonary airway malformation
58
4. As there is a chronic atelectasis of the middle lobe surgery
should be taken into
consideration. a. Yes, this is a source of recurrent infection, the
middle lobe should be excised. b. No, surgery is never indicated in
this situation c. The excision should not be limited to the middle
lobe, as also the lower lobe shows
severe bronchiectasis. d. Surgery is indicated for the treatment of
complications such as empyema, recurrent
haemoptysis, lung abscess
5. As most of children with non-cf-bronchiectasis have chronic
airway colonization and infection antibiotic therapy is a mainstay
of the management. Which of the following statements are
correct
a. Long-term therapy with azithromycin results in significant
reductions of exacerbations and improvement in lung function
b. Whenever possible antibiotic therapy should be based on
bacteriology results c. Long-term inhaled antibiotics such as
tobramycin is associated with a significant
clinical improvement d. Exacerbations should always be treated with
intravenous antibiotics
59
PD Dr. med. Alexander Moeller Head Division Respiratory
Medicine
Pediatric pulmonology
Grant support: Zurich lung league
STARR-Foundation
– No real or perceived conflicts of interest that relate to this
presentation
Disclosure
61
Non-CF bronchiectasis
– the end result of chronic or repeated episodes of environmental
insults
– superimposed on a background of genetic vulnerability (?)
– Sixty-three percent of the subjects had an underlying
disorder
– Spectrum related to airway bacteria
– Associated degradation and inflammation products causing airway
damage
Cole P. Eur J Respir Dis Suppl 1986;147:6:15
62
Definition
– Frequent bacterial infections
– End result of suppurative lung disease
– Radiological definition for a histo- pathological problem
Eastham KM. Thorax 2004; 59: 324–7
63
Chang AB. Pediatr Pulmonol 2008;43:519-31
Protracted bacterial bronchitis
Impaired host
No association 308 34%
Congenital malformation 34 4%
Secondary immunodeficiency 29 3%
Others 7 1%
Congenital malformations associated with non-CF
bronchiectasis
Malformation n=27 Total number % of total
Tracheo-oesophageal fistula 14 52%
Bronchogenic cyst 2 7%
Tracheomalacia 1 4%
Bronchial atresia 1 4%
71
Pneumonia* 66 61%
Measles 15 14%
Tuberculosis 12 11%
Pertussis 5 5%
Adenovirus 1 1%
• Severe viral or bacterial pneumonia. • *Pneumonia at age 6 months
or less
Brower KS. BMC Pediatrics 2014, 14:299
72
Total number % of total
IgG deficiency* 63 48%
IgA deficiency 9 7%
T cell disorders 9 7%
Hyper IgE syndrome 3 2%
Hyper IgM syndrome 2 2%
T cell deficiency 3 2%
Chronic mucocutaneous candidiasis 1 1%
common variable immunodeficiency (30), IgG deficiency (13),
agammaglobulinemia (10) and antibody deficiency or
dysfunction
Brower KS. BMC Pediatrics 2014, 14:299
73
Total number % of total
Combined immunodeficiency 13 10%
Ataxia-telangiectasia 2 2%
Barre lymphocyte syndrome/MHC class II deficiency
2 2%
Other disorders 2 2%
74
Protracted bacterial bronchitis: a predictor of
bronchiectasis
346 children (mean age 4.5 years) newly referred with chronic cough
>.4 weeks)
75
Protracted bacterial bronchitis: a predictor of
bronchiectasis
346 children (mean age 4.5 years) newly referred with chronic cough
>.4 weeks)
76
Protracted bacterial bronchitis: a predictor of
bronchiectasis
77
Goyal V. Arch Dis Child 2014;99:522–525
78
– Asthma that does not respond to treatment
– Incomplete resolution of a severe pneumonia, or recurrent
pneumonia
– Pertussis-like illness failing to resolve after six months
– Persistent and unexplained physical signs, i.e. persistent lung
crackles
– Respiratory symptoms in children with structural or functional
disorders of the oesophagus and upper respiratory tract
– Unexplained haemoptysis.
– Cough – Daily sputum production
– Hemoptysis – pleuritic chest pain – pulmonary osteoarthropathy –
delayed growth
80
Diagnosis
1. Radiologic imaging 2. Sweat test 3. Test of immune function 4.
Testing for PCD 5. Test for pulmonary aspiration 6. Bronchoscopy
(?)
81
Diagnosis 1. Radiologic imaging
– Chest radiograph – Insensitive – If normal Bx not excluded – Poor
correlation to HRCT
– High-resolution CT scan – Inspiration – Distribution of Bx not
correlated
to underlying disease
Eastham KM. Thorax 2004; 59: 324–7 Chang AB. Pediatr. Pulmonol.
2003; 35: 477–83
Li AM. Eur. Respir. J. 2005; 26: 8–14 82
– The key features of bronchiectasis on HRCT scans – (a) one or
more ‘dilated’ bronchi
defined as the internal luminal diameters of the airways exceeding
the diameter of the adjacent vessel,
– (b) non-tapering of the bronchi – (c) presence of visible
bronchi
adjacent to the mediastinal pleura or within the outer 1- 2 cm of
the lung fields.
Diagnosis 1. Radiologic imaging
– Mandatory (caveat: newborns screening) – Experienced laboratory –
May be repeated if non- conclusive
86
– Serum immuno-globulins – IgG-subclasses – Specific antibodies to
vaccinations
– Pertussis, diphtheria, tetanus toxoid, capsular polysaccharides
of streptococcus pneumoniae and Hameophilus influenzae type B
– Repeat 4 weeks after vaccination-boost if low – Lymphocyte B and
T cell subsets – Mantoux and others – HIV
87
88
– Nasal nitric oxide
89
– Nasal nitric oxide – Nasal brushing – High frequency video
microscopy analysis (HVMA)
– Nasal nitric oxide – Nasal brushing – High frequency video
microscopy analysis (HVMA) – Transition-electron microscopy
91
– Nasal nitric oxide – Nasal brushing – High frequency video
microscopy analysis (HVMA) – Transition-electron microscopy –
Immune-fluorescent microscopy
Omran et al., Am J Hum Genet 2008
– Nasal nitric oxide – Nasal brushing – High frequency video
microscopy analysis (HVMA) – Transition-electron microscopy –
Immune-fluorescent microscopy – Genetics
93
Aspirations
primary
Secondary
– significantly lower child-rated physical health QOL scores – all
of the parent-rated QOL scores significantly lower
– Variables associated with lower QOL: – Wheezing severity*
– Dyspnoea severity*
– Not with CT scores**
Bahali K. General Hosp Psychiatry 2014;36: 528–532 Gokdemir Y.
Respiration 2014;88:46–51
* Pediatric Quality of Life Inventory Child/Parent Version
(PedsQL-P) ** St. George’s Respiratory Questionnaire (SGRQ)
QOL in Children with Bronchiectasis Respiration 2014;88:46–51 DOI:
10.1159/000360297
49
Discussion
To our knowledge, this is the first study evaluating the HRQOL of
children with non-CF BE in which the ques- tionnaires were
completed by the children. We evaluated HRQOL in non-CF BE children
and also assessed the ef- fects of clinical characteristics and SES
from generic (SF- 36) and disease-specific (SGRQ) QOL
questionnaires. The SGRQ symptoms score was better in patients with
longer, regular follow-up periods, and patients with low PFT values
had worse symptoms scores. Patients with a low SES were diagnosed
later than those with a higher SES.
One important limitation of this study was that the SGRQ and SF-36
questionnaires have not been validated in children. They have been
previously used for children (6–12 years of age), however [17, 18]
.
Although several QOL scales have been developed for chronic
respiratory diseases (asthma, COPD and cystic fibrosis), there is
no specific QOL scale for non- CF BE [12] . Generic and specific
(CF or adult chronic lung disease) scales have been used to
determine the QOL with non-CF BE adult patients. Studies have shown
that HRQOL has been adversely affected in adults with non-CF BE [9,
12–16] . The SGRQ is the only scale that measures disease-specific
QOL in adult pa- tients which has been used in a few studies in
non-CF BE [9, 12–14] . Although the SGRQ and the SF-36 have been
used for children (6–12 years) previously, they were not actually
validated [17, 18] . They are both com- plex and we consider them
to be valid if completed by children without the help of their
parents [23] . In this study, all of the children completed the
questionnaires on their own.
There is only 1 study evaluating the HRQOL of non- CF BE children
in which the DASS (Depression, Anxiety
Table 2. SF-36 and SGRQ subscales had an inverse correlation
SGRQ SF-36 PCS SF-36 MCS
Symptoms score r p
80.00 100.00
80.00 100.00
80.00 100.00
ar
Fig. 1. Correlation of SGRQ symptoms score with FEV 1 , follow-up
period and antibiotic frequency. a SGRQ symptoms score corre- lates
with FEV 1 (r = –0.417, p = 0.003). b SGRQ symptoms score
correlates with regular follow-up (r = 0.3, p = 0.04). c SGRQ symp-
toms score correlates inversely with frequent antibiotic require-
ments (r = 0.303, p = 0.035).
D ow
n lo
a de
d b
– Sleep disordered breathing more frequent (22 vs 9%; p =
0.003)**
– Variables associated with lower sleep quality: – Sputum –
Wheezing – CT-score – Snoring
Erdem E. Pediatr Pulmonol 2011;46:919–926
* Pittsburgh Sleep Quality Index (PSQI) ** Pediatric Sleep
Questionnaire (PSQ) were
99
Bastardo CM. Thorax 2009;64:246–251
Adequate growth over time
100
101
113 children with newly diagnosed non-CF bronchiectasis
102
103
Management Microbiology
104
Tunney MM. Am J Respir Crit Care Med 2013;187:1118-26
– Similar patterns of phyla distribution when clinically stable and
at the start of treatment for an exacerbation
– No significant difference in microbial community diversity
(Shannon-Wiener diversity index)
– Abundance of the predominant bacteria decreases slightly after
treatment
Management Microbiology
Tunney MM. Am J Respir Crit Care Med 2013;187:1118-26
– Similar patterns of phyla distribution when clinically stable and
at the start of treatment for an exacerbation
– No significant difference in microbial community diversity
(Shannon-Wiener diversity index)
– Abundance of the predominant bacteria decreases slightly after
treatment
Management Microbiology
106
– Similar patterns of phyla distribution when clinically stable and
at the start of treatment for an exacerbation
– No significant difference in microbial community diversity
(Shannon-Wiener diversity index)
– Abundance of the predominant bacteria decreases slightly after
treatment
Management Microbiology
Tunney MM. Am J Respir Crit Care Med 2013;187:1118-26 107
– As natural history of bronchiectasis and mortality has altered
with improvements in health and the environment suggests that with
the implementation of other preventative factors, the progression
of bronchiectasis could be ameliorated in the majority of
children.
– Children at risk of bronchiectasis can have normal lungs with
early diagnosis and appropriate management
– Appropriate treatment reduces exacerbations of
bronchiectasis.
Prevention
Chang AB. Pediatr Respir Rev 2011; 12:97-103 108
– Early and intensive treatment improves lung function in children
with reduced FEV1 at diagnosis and prevents deterioration in the
following 2- 5 year period
– Frequency of exacerbation with hospitalization is significant
predictor of FEV1 decline (over 3- yrs)
– With each exacerbation, the FEV1%predicted decreased by 1.95% –
In a Turkish study of 111 children, ‘intensive medical treatment’
(prompt
antibiotic use, physiotherapy, bronchodilators) reduced
exacerbation rates from 6.6 ± 4 to 2.9 ±2.9 per year
Prevention
Karadag B. Respiration 2005;72:233–8. 109
– Chronic wet cough is not normal: have a close look at these
children – Some children may need prolonged antibiotic treatment,
whenever
possible according to microbiology – Airway damage can be limited
by intensive treatment, even in those
predestined to have bronchiectasis – Children with high risk to
develop bronchiectasis should be carefully
followed up – Mucociliary disorders – Immune dysfunction –
Rheumatic inflammatory conditions
– Role of vaccinations: Measles, Pertussis, Pneumococcal
vaccination
Prevention
Prevention
111
Prevention
Normal lung development Early detection Reduce morbidity, mortality
and secondary complications
Removal of modifiable risk factors
Appropriate treatment Reduce adverse events from medication
ARI‘s, CSLD, Bronchiectasis
Good follow up of all acute respiratory episodes
Assessment for treatable causes
Early diagnosis of bronchiectasis
Early treatment of exacerbations
Chang AB. Pediatr Respir Rev 2014; 15:325-332 112
Therapy Mainstays
4. Regular exercise
2. Huffing / autogenic drainage “selective breathing”
2. Chest physiotherapy
114
2. Intermittent therapy
– Guided by microbiology
3. Long-term treatment
– Co-amoxicillin in infants?
– Azithromycin?
Rubin BK. Semin. Respir. Crit. Care Med. 2003;24:619-27 Rubin BK. J
Aerosol Med. 2008; 21: 1-6
116
Therapy Antibiotics
– Indigenous Australian, Maori, and Pacific Island children aged
1–8 years
– Either bronchiectasis or chronic suppurative lung disease
– multicentre, double- blind, randomised, parallel-group,
placebo-controlled trial
– Eligible children had had at least one pulmonary exacerbation in
the previous 12 months
– Azithromycin (30 mg/kg) or placebo once a week for up to 24
months
Valerie PC. Lancet Respir Med 2013; 1: 610–20
117
118
119
120
121
Gao YG. PlosOne; 2014; 9: 3: e90047
122
2. Significant symptoms unable to be controlled by medical
therapy
3. Localised disease
– empyema, recurrent haemoptysis, lung abscess
Haciibrahimoglu G. Intern. Med. J. 2006; 36: 729–37 Sirmali M. Eur.
J. Cardiothorac. Surg. 2007; 31: 120–3
123
Conclusions
1. Bronchiectasis in children is not that rare
2. Often a consequence from chronic infections and suppurative lung
disease
3. A detailed look to primary diseases associated with
bronchiectasis
4. Management and treatment similar to that in cystic
fibrosis
5. Prevention is important and often possible
6. Surgery is rarely indicated
124
Prof. Fabio Midulla Paediatric Departments. “Sapienza” University
of Rome.
Viale Regina Elena 324 00161 Rome
ITALY
[email protected]
Clarify definition and aetiology of bronchiolitis Discuss diagnosis
and criteria for hospitalization Define the treatment Discuss
criteria for discharge
SUMMARY Bronchiolitis is an acute viral respiratory infection
involving the terminal and respiratory bronchiole in infants [1].
It is clinically defines as a seasonal viral illness in infants
<12 months of age characterized by nasal discharge, cough,
tachypnoea, retractions and bilateral crackles [1]. Bronchiolitis
is the most frequent infectious disease in infants (90% of patients
are < 6 months of age) and it is the leading cause of
hospitalization in this group of infants [2]. Bronchiolitis is
caused by viruses. The most frequent are Respiratory Syncytial
Virus, human Bocavirus, rhinovirus, human Metapneumovirus,
Influenza A and B, and Parainfluenza 1-3 [3]. Only 1-2% of the
infants that are infected with one of this virus will develop
bronchiolitis [1]. Risk factors for severe bronchiolitis are age
<3 months, prematurity with bronchopulmonary dysplasia and
coexisting co-morbidities, such as cardiovascular disease,
immunodeficiency and chronic respiratory diseases [4].
Bronchiolitis is commonly diagnosed on clinical grounds alone. The
criteria for the diagnosis of bronchiolitis include exposure to
other children or adults with an acute upper respiratory airways
viral infection, age < 12 months, preceding upper airways
illness and signs of acute lower respiratory illness and
respiratory distress. Chest X ray and blood tests are required only
if suggested by clinical indications. The initial symptoms of
bronchiolitis are rhinorrhoea, and cough accompanied by low - grade
fever. The first clinical symptom could be episodes of apnoea,
especially in preterm infants, but most infants with bronchiolitis
manifest tachypnoea, retractions, nasal flaring, rales at
auscultation and hypoxaemia. Often the infant with severe
bronchiolitis may have associated dehydration with metabolic
acidosis and syndrome of inappropriate secretion of antidiuretic
hormone). Bronchiolitis is a "dynamic disease" and its clinical
characteristics can quickly change [1]. Admission criteria included
respiratory distress, poor feeding, dehydration, oxygen
requirement, underlying chronic disease, and inappropriate social
and family conditions [5-7]. General management of infants with
bronchiolitis includes therapies intended to reduce the work of
breathing (keep upper airways clear by using gentle nasal suction
and to restore clinical stability (oxygenation and hydration). In
infants with mild bronchiolitis breast feeding should be supported
and small volume and frequent feeding should be encouraged [1].
Nasogastric feeding or intravenous hydration should be considered
in infants with severe bronchiolitis or dehydration [8].
125
According to the American academy of Paediatrics oxygen should be
administered only when saturation at room air is <90% [1], while
the Scottish Intercollegiate Guideline Network guidelines recommend
the use of oxygen saturation remains permanently >95% [9].
Oxygen is usually administered via nasal cannula or a head box.
Recent evidence shows that oxygen can be given efficaciously with
heated humidified high flow nasal cannula [10-11]. Its presumed
role is the reduction of the work of breathing, prevention of
dynamic airways collapse and improvement of gas exchange [12].
Current clinical evidence shows that albuterol produce small
short-term improvements in clinical scores. A trial with albuterol
is justified in infants with severe respiratory distress and it
should be continued only if clinical examination documents a
significant clinical response [13]. Nebulized racemic adrenalin
provides better short-term improvement in the clinical score than
placebo, particularly in the first 24 hours. Clinical trials have
showed that adrenalin to be superior to placebo and albuterol [14].
A recent Cochrane Review of seven trials showed that nebulized 3%
hypertonic saline alone or together with a bronchodilator
effectively reduces the length of hospitalization among infants
with non severe acute viral bronchiolitis and improve s clinical
severity scores in out patients and inpatients populations [15]. On
the contrary, two very recent randomized and double blind
multicenter studies have showed no clinical effects of nebulized
hypertonic saline in children with bronchiolitis. Teunisses et al.
have compared the effects of hypertonic saline 3%, and 6% vs 0.9%
in infants with moderate-severe bronchiolitis and they have showed
non significant difference in the duration of oxygen therapy and
tube feeding between the three groups [16]. Everard et al have
showed no difference in the time for discharge between infants with
bronchiolitis treated with hypertonic saline or placebo [17].
Current evidence provides no support for a clinical beneficial
effect of systemic or inhaled glucocorticoids [18]. No evidence
justified using antibiotics in bronchiolitis because it is a viral
disease and affect infants rarely undergo bacterial superinfection.
Antibiotic treatment should be recommended only in infants with
severe bronchiolitis requiring intubation, a group in whom
bacterial superinfection is more common [19]. Nebulized DNAse and
monetelukast are not indicated in the treatment of bronchiolitis
[20]. Preventive measures include adequate healthcare professional
education about epidemiology and control of viral infection, such
as washing the hands before and after caring for patients with
viral respiratory symptoms [21]. Palivizumab is a humanized
monoclonal RSV antibody. It prevents hospital admission for RSV
infections, but do not decrease length of stay or oxygen require
for those that are hospitalized. Palivizumab is a useful
therapeutic option in infants <12 months who have severe
comorbidity such as extreme prematurity, congenital or acquired
lung diseases, congenital heart disease and immune deficiency [22].
Mild respiratory symptoms may last for 3 weeks after bronchiolitis
and about 50% of the infants children with bronchiolitis may have
episodes of wheezing in later years [23].
126
REFERENCES 1. American Academy of Pediatrics. Subcommitte on
Diagnosis and Management of Bronchiolitis.
Diagnosis and management of bronchiolitis. Pediatrics
2014;134:e1474-e1502 2. Hasegawa K, Tsugawa Y, Brown DF et al.
Trends in bronchiolitis hospitalizations in the United
States, 2000-2009. Pediatrics. 2013; 132(1):28-36. 3. Midulla F,
Scagnolari C, Bonci E, et al. Respiratory syncytial virus, human
Bocavirus and
rhinovirus bronchiolitis in infants. Arch Dis Child 2010 Jan;
95(1):35-41. 4. Ricart S, Marcos MA, Sarda M, et al. Clinical risk
factors are more revelant than respiratory
viruses in predicting bronchiolitis severity. Pediatr Pulmonol
2013; 48(5):456-463. 5. Breese Hall C, Weinberg GA, Blumkin AK, et
al. Breeze H et al. Respiratory Syncytial Virus–
Associated Hospitalizations Among Children Less Than 24 Months of
Age. Pediatrics 2013; 132:e341-e348.
6. Corrard F, de La Rocque F, Martin E, et al. Food intake during
the previous 24 h as a percentage of usual intake: a marker of
hypoxia in infants with bronchiolitis: an observational,
prospective, multicenter study. BMC Pediatr 2013; 13:6.
7. Schuh S, Freedman S, Coates A, et al. Effect of oximetry on
hospitalization in bronchiolitis: a randomized clinical trial.
JAMA. 2014; 312(7):712-8.
8. Oakley E, Borland M, Neutze J, et al. Nasogastric hydration
versus intravenous hydration for infants with bronchiolitis: a
randomised trial. Lancet Respir Med 2013; 1(2):113-20.
9. Scottish Intercollegiate Guideline Network (SIGN). Bronchiolitis
in children. A national guidelinen° 91. Edinburg, SIGN, 2006.
10. McKiernan C, Chua LC, Visintainer PF, et al. High flow nasal
cannulae therapy in infants with bronchiolitis. J Pediatr
156:634-638.
11. Mayfield S, Bogossian F, O'Malley L, et al. High-flow nasal
cannula oxygen therapy for infants with bronchiolitis: pilot study.
J Paediatr Child Health 2014; 50(5):373-8.
12. Milési C, Boubal M, Jacquot A, et al. High-flow nasal cannula:
recommendations for daily practice in pediatrics. Ann Intensive
Care 2014; 4:29.
13. Gadomski AM, Brower M. Bronchodilators for bronchiolitis.
Cochrane Database Syst Rev. 2010; (12):CD001266.
14. Hartling L, Bialy LM, Vandermeer B,et al. Epinephrine for
bronchiolitis. Cochrane Database Syst Rev 2011; (6):CD003123.
15. Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulized
hypertonic saline solution for acute bronchiolitis in infants.
Cochrane Database Syst Rev 2008; (4):CD006458.
16. Teunissen J, Hochs AH, Vaessen-Verberne A, et al. The effect of
3% and 6% hypertonic saline in bronchiolitis. Eur Respi J 2014;
44:913-921.
17. Everard M, Hind D, Ugonna K et al. SABRE: a multicentre
randomized control trial of nebulised hypertonic saline in infants
hospitalized with acute bronchiolitis. Thorax 2014;
69:1105-1112.
18. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids
for acute viral bronchiolitis in infants and young children.
Cochrane Database Syst Rev 2013; 6:CD004878.
19. Spurling GK, Doust J, Del Mar CB, et al. Antibiotics for
bronchiolitis in children. Cochrane Database Syst Rev (2011)
6:DC005189.
20. Nenna R, Tromba V, Berardi R, et al. Recombinant human
deoxyribonuclease treatment in hospital management of infants with
moderate-severe bronchiolitis. Eur J Inflamm 2009; 7:169-
174.
21. Sacri AS, De Serres G, Quach C, et al. Trasmission of acute
gastroenteritis and respiratory illness from children to parents.
Pediatr Infect Dis J 2014;33(6):583-588
22. Andabaka T, Nickerson JW, Rojas-Reyes, et al. Monoclonal
antibodiey for reducing the risk of respiratory syncytial virus
infection in children. Cochrane Database Syst Rev (2013);4:
CD006602
23. Midulla F, Nicolai A, Ferrara M, et al. Recurrent wheezing 36
months after bronchiolitis is associated with rhinovirus infections
and blood eosinophilia. Acta Paediatrica 2014; 103:1094-
1099.
127
EVALUATION 1. A 50 days old infant was admitted to the paediatric
Emergency Room for loss of appetite and
increased work of breathing, started 4 hours before. Parents
reported that the child had rhinitis and cough in the last 5 days,
with mild fever that last 2 days (T max 37.7 ° C). On physical
examination, the infant appears alert and responsive with a
moderate degree of dehydration. He had intercostal and jugular
retractions. The heart rate was 120 bpm, respiratory rate was 58
per minute and SpO2 was 95% at room air. Lung auscultation shows
diffuse fine a rapid test in the nasal wash sample was positive for
Respiratory Syncytial Virus.
What could be the diagnosis of this child?
a. Whooping cough b. Pneumonia c. Flu d. Bronchiolitis e. Wheezing
bronchitis
2. A one month old girl was admitted to the paediatric Emergency
Room for cough followed by vomiting. The mother reports that as a
result of coughing the child seems to remain "out of breath" and
has also perioral cyanosis. On physical examination, the child
looks slightly exhausted but responsive. There was no evidence of
respiratory distress. The heart rate was 126 bpm, respiratory rate
62 per minute and SpO2 to 98% at room air, but decreased to 89%
during paroxysmal cough. Lung auscultation was negative, as well as
cardiac and abdominal examination. Blood tests showed the following
picture: WBC 15630/mm3 (N 38.2%, 63.6% L, and E 0.7%), C reactive
protein 0.54 mg/dl, Hb 13.5 g/dl.
What could be the diagnosis?
a. Pneumonia b. Bronchiolitis c. Whooping cough d. Flu e. Wheezing
bronchitis
3. A 40 days old infant is admitted to the paediatric emergency
room for a mild respiratory distress
(RR = 65 per minute and intercostal retractions), preceded few days
before by rhinitis, cough and low grade fever. Lung auscultation
reveals bilateral fine rales. SpO2 at room air was 95%.
What kind of therapy you plan to start?
a. No medical therapy, only clinical observation b. Aerosol therapy
with salbutamol c. Aerosol therapy with adrenaline and 3%
hypertonic solution d. Antibiotic therapy e. HHFNC
128
Fabio Midulla MD
Conflict of interest disclosure
I have no, real or perceived, direct or indirect conflicts of
interest that relate to this presentation.
130
To discuss diagnosis and criteria for
hospitalization
To discuss criteria for discharge
Aims
131
132
64,4
C as
Midulla et al. Arch Dis Child 2010;95(1):35-41. Epub Oct 11
133
134
Effects of the immunological reaction and of the inflammatory
mediators.
Pathogenesis
135
136
Exposure to RSV leads first to an innate immunoregulatory cascade
beginning with airway responses from cells constitutively present
in airways. (Innate immuno response)
These cells release a variety of mediators, with recruit
circulating monocytes, NKcells and granulocytes that participate in
the inflammatory response. (Adaptative immuno response)
137
Exposure to children or adults with a respiratory viral
infection.
The initial symptoms are rhinorrhoea, cough and sometimes low grade
fever. In 18% of cases the first clinical symptom could be episodes
of apnoea.
With the relief of fever they manifest tachypnoea, retractions,
nasal flaring, rales and hypoxemia
Dehydration and metabolic acidosis.
Syndrome of inappropriate secretion of antidiuretic hormone is
common with severe respiratory distress.
It is a dynamic disease and its clinical characteristics can
quickly change
138
Respiratory distress (RR >60/min, nasal flaring,
retractions) and cyanosis
Oxygen saturation <92-94%
Phase of illness should be considered in the decision for timing of
review or admission to
hospital
139
Breeze Hall, Pediatrics 2013;132;e341
5-year, prospective, population-based surveillance for children
<24 month of age hospitalized with laboratory confirmed RSV,
2000-2005
OR
5
25
18
Very preterm infants (<30 weeks’ gestation) accounted for only
3% of cases, but had RSV hospitalization rates 3 times that of term
infants.
140
Apnoea in children hospitalized with bronchiolitis
Apnea in 5% of children 56 (52%) managed in the ICU 30 (28%)
mechanical ventilation
No difference according to type virus
Shroeder, Pediatrics 2013;132:e1194
2207 children <2 years; PCR in NPA for 16 virus Report of apnoea
in daily chart
OR
9.6
2.2
History of prematurity
Underlying cardiopulmonary disease
142
Food intake during the previous 24 h as a marker of hypoxia in
bronchiolitis
Corrard, BMC Pediatrics 2013;13:6
171 infants aged 0-6 months recruited by 18 community pediatricians
Evaluation of clinical signs and pulsossimetry
143
Food intake during the previous 24 h as a marker of hypoxia in
bronchiolitis
Corrard, BMC Pediatrics 2013;13:6
171 infants aged 0-6 months recruited by 18 community pediatricians
Evaluation of clinical signs and pulsossimetry
24h FI <50% had sensitivity 60% and specificity 90% for SpO2
<95% and had the highest OR (13.8) for SpO2 <95% than other
clinical signs
144
41
25
Schuh, JAMA 2014;312:712
213 infants <12 months with bronchiolitis - SaO2 ≥88% and
non-severe distress. Randomly allocated to either true saturation
or altered saturation (SaO2 points displayed were 3 points
higher)%
145
breathing (keep upper airways clear)
Restore clinical stability (oxygenation and hydration)
146
Respiratory support
Pharmacologic interventions
147
Suctioning and length of stay in infants hospitalized with
bronchiolitis
)
Nasogastric hydration vs intravenous idration (PREDICT)
Oakley, Lancet Respir Med 2013;1:113
381 infants aged 2-12 months admitted for acute bronchiolitis
NG=86 h IV =82 h
149
Supposed mechanisms of action
Reduction of anatomical dead space Reduction of work of breathing
Reduction of metabolic work Improvement of regional
ventilation
distribution CPAP effect
Dysart, Respir Med 2009;103:1400 Hough, Ped Crit Care Med
2014;15:e214 Hag, Paediatr Respir Rev 2014;15:124 Pham, Pediatr
Pulmon 2014; online
150
Gadomski, Cochrane 2010 151
19 RCT, 2256 infants
vs placebo better clinical score, RR, SaO2 reduced admission rate
at Day 1
but not at Day 7
vs salbutamol better clinical score, RR, SaO2 no difference for
admission at
Day 1 and 7
vs salbutamol shorter LOS
152
19 RCT, 2256 infants
vs placebo better clinical score, RR, SaO2 reduced admission rate
at Day 1
but not at Day 7
vs salbutamol better clinical score, RR, SaO2 no difference for
admission at
Day 1 and 7
vs salbutamol shorter LOS
Outpatients Inpatients
There is no evidence of effectiveness of repeated doses or
prolonged use
of epinephrine among inpatients
153
Racemic adrenaline and inhalation strategies in acute
bronchiolitis
RA NS p N. inhalations 14 15 ns Oxygen (%) 43 43 ns Nasogastric
tube (%) 28 29 ns Ventilatory support (%) 7 7 ns
Skjerven, N Engl J Med 2013;368:2286
404 infants <12 months admitted to hospital with clinical score
>4/10 Adrenaline or NS 0.9% / On demand or fixed schedule
154
Skjerven, N Engl J Med 2013;368:2286
OD FS p N. inhalations 12 17 Oxygen (%) 38 48 .04 Nasogastric tube
(%) 26 31 ns Ventilatory support (%) 4 10 .01
Difference = 13.7 hours
404 infants <12 months admitted to hospital with clinical score
>4/10 Adrenaline or NS 0.9% / On demand or fixed schedule
155
Hospital revisits: no benefits
17 RCT, 2596 infants
ICS, either nebulized or administered by MDI:
do not affect the clinical course of the acute phase do not reduce
hospital readmissions do not prevent subsequent wheezing
Duration of treatment, length of follow-up or causative agent (RSV
or not) did not influence the effect
Blome, Cochrane 2011 Fernandes, Cochrane 2013
157
11 RCT, 1090 infants
Inhaled 3% HS vs 0.9% NS causes:
lower clinical score over the first 3 days (in both outpatients and
inpatients)
shorter length of hospital stay (-1 day)
no adverse events
In the majority of the studies, hypertonic saline was mixed with a
bronchodilator (epinephrine or
beta2-agonist)
The effect of 3% and 6% hypertonic saline in bronchiolitis
Teunissen, ERJ 2014;44:913
290 infants aged <24 months with moderate-to-severe
bronchiolitis 0,9% vs 3% vs 6% sodium chloride + salbutamol 2.5 mg
by nebulization
mask every 8 h
No difference between groups in: - Duration of oxyen therapy - Tube
feeding
159
160
Clinicians should not administer antibacterial medications unless
there is a concomitant
bacterial infection!
Bronchiolitis: prevention
All people should disinfect hands before and after direct contact
with patients.
All people should use alcohol based rubs for hand decontamination
when caring for children with bronchiolitis.
Clinicians should counsel caregivers about exposing the infant to
environmental tabacco smoke.
Clinicians should encourage exclusive breastfeeding for at least 6
months.
164
Bronchiolitis: pharmacologic prevention
Palivizumab should be administered in the first year of life in
infants with emodynamically significant heart disease or chronic
lung disease of prematurity (<32 weeks gestation who require
>21% oxygen for at least the first 28 days of life)
Maximum of 5 monthly doses /15 mk/kg/dose) of palivizumab during
the RSV season to infants who qualify for palivizumabn in the first
year of life
165
Absence of respiratory distress
Adequately oral intake to prevent (>75% of usual intake) to
prevent dehydration
Adequate parental care and family education
American Accademy of Pediatrics DOI:10.1542/peds.2014-2742
166
Prospective observational study. 68 infants <18 months requiring
oxygen.Time to obtain SpO2 ≥90% or ≥94%, and time to
re-establish
feeding >75% normal
Cunningham, Arch Dis Child 2012;97:361
Median time to SpO2 stable for at least 4 h ≥90%: 17 h ≥94%: 63
h
167
Prospective observational study. 68 infants <18 months requiring
oxygen.Time to obtain SpO2 ≥90% or ≥94%, and time to
re-establish
feeding >75% normal
Cunningham, Arch Dis Child 2012;97:361
Median time to SpO2 stable for at least 4 h ≥90%: 17 h ≥94%: 63
h
Time to achieve stable SpO2 ≥90% and resolve feeding difficulties
was a median of 22 h sooner than the equivalent
for stable SpO2 ≥94%
"The mainstays of treatment of bronchiolitis remain supportive
interventions, such as oxygen therapy and reydratation. There is
little convincing evidence that any other therapy is consistently
or even occasionally useful"
September ,2015
Dr Paul Aurora Great Ormond Street Hospital for Children
UCL Institute of Child Health Great Ormond St
WCIN 3JH London UNITED KINGDOM
[email protected]
SUMMARY
Introduction This session will first address the primary conditions
that lead to unusual respiratory infections (i.e.
immunodeficiency); describe which infections should be most
suspected in which cases; show the radiological abnormalities seen
with such infections; and, via cases, give some guidance as to the
diagnostic approach when faced with a child with a possible unusual
infection. Immunodeficiency/Immunosuppression It is helpful to
consider this in terms of primary immunodeficiency; acquired
immunodeficiency (HIV); and iatrogenic immunodeficiency or
immunosuppression (e.g. during chemotherapy or following organ
transplantation) Primary Immunodeficiency Primary immunodeficiency
can be classified as disorders of humoral immunity (B lymphocytes
and antibodies); and cellular immunity (T lymphocytes). Such
disorders should be suspected if a child is having very frequent
sinopulmonary infections (but remember how frequently these can
occur in healthy children) or if a child is having unusual
infections, particularly in association with failure to thrive. The
most common humoral immunodeficiencies are X-linked
agammaglobulinaemia (XLA), common variable immunodeficiency (CVID),
and the usually milder conditions of IgA deficiency, IgG subclass
deficiency, and transient hypogammaglobulinaemia of infancy. These
disorders predispose the child to recurrent sinopulmonary
infectiosn with relatively common bacteria, so we will not discuss
that further here. Disorders of T cells can also lead to similar
infections, as B cell function is regulated by T cells. However in
addition these children are susceptible to opportunistic infection
with viruses and fungi, which can be extremely difficult to
diagnose and treat effectively. The commonest such disorders are
severe combined immunodeficiency (SCID) and velocardiofacial
syndrome (also known as DiGeorge syndrome or Catch 22). Management
involves prophylaxis against viral and fungal infection, and prompt
action (often with involvement of a pulmonologist) if infection is
suspected. Stem cell transplantation is also an effective treatment
for SCID, and thymic transplantation can be employed for severe
DiGeorge syndrome immunodeficiency. There are other
immunodeficiencies that fall outside the above classification.
Chronic granulomatous disease is a defect of phagocytosis. These
children can get lung granulomas, abscesses and empyema
170
thoracis, and fungal lung infections are common and extremely
resistant to therapy. Hyper IgE syndreom is characterized by
staphylococcal abscesses of multiple sites, including the lungs,
but also has multiple extrapulmonary manifestations. Wiskott
Aldrich syndrome is an X linked defect of T and B cells which leads
to eczema, thrombocytopaenia, and immunodeficiency, and ataxia
telangiectasia is a deficiency of DNA repair that leads to
immunodeficiency and predisposes to recurrent sinopulmonary
infection Human Immunodeficiency Virus This is an RNA lipid
enveloped retrovirus which impairs function of CD4+ T lymphocytes
and related cytokines. Pulmonary infections are most commonly due
to pneumocystis jiroveci pneumonia (PJP), but also bacterial viral
and fungal pneumonia can occur. PJP was previously classified as a
protozoan infection but is now classified as a fungus. Confirmation
of diagnosis is challenging and treatment is with high dose
cotrimoxazole in the first instance. Lymphocytic interstitial
pneumonitis (LIP) is not currently considered an infection though
it may have a viral trigger. It results in interstitial infiltrate
with lymphocytes and development of nodules of mononuclear cells
and can be difficult to distinguish from opportunistic infection.
Iatrogenic immunodeficiency (immunosuppression) Most patients
receiving solid organ transplants will need lifelong
immunosuppression. As acute cellular rejection is T cell mediated
the main immunosuppressive agents used are calcineurin inhibitors
which inhibit clonal T cell expansion. Patients receiving such
agents are at increased risk of all pulmonary infections, but as
elsewhere, it is viral and fungal infections that are the most
difficult to treat. Post- transplant lymphoproliferative disease is
a clonal expansion of B cells, usually triggered and stimulated by
Epstein Barr virus infection. As with LIP in HIV patients, it is an
important differential from opportunistic pneumonia. It is
relatively common in children receiving lung transplantation. The
other important differential in lung transplant patients is acute
cellular rejection, which can present with non-specific symptoms
and signs of dry cough, hypoxia and radiological infiltrates.
Following stem cell transplantation a variety of infectious
complications can occur, similar to those seen in solid organ
transplant recipients. These need to be distinguished from late
onset non-infectious pulmonary complications, most of which are
related to chronic pulmonary graft versus host disease. During
chemotherapy children are most at risk from regimens that result in
neutrophil depletion. Although bacterial infection is the most
common, viral and fungal infections are of most concern as they are
more difficult to treat. Approach to investigation and treatment If
you suspect an immunodeficient/immunosuppressed child of having an
unusual lung infection then
Consider the primary diagnosis, and construct your differential
from that Take microbiological samples via a non-invasive route
(e.g. sputum or induced sputum, blood
testing for viral infection) Ensure that you are treating common
bacterial causes If the child’s condition is deteriorating despite
this approach then you have the option of either
widening antimicrobial cover based on best guess, or
bronchoalveolar lavage. The choice between these options is based
on the circumstances of each case and depends upon relative risks
and benefits. We will discuss this with the short case
presentations
If BAL is unhelpful and the child is in difficulty then consider
lung biopsy.
171
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1. Farmand, S. and M. Sundin. 2015. Hyper-IgE syndromes: recent
advances in pathogenesis, diagnostics and clinical care.
Curr.Opin.Hematol. 22:12-22.
2. Jesenak, M., P. Banovcin, B. Jesenakova, and E. Babusikova.
2014. Pulmonary manifestations of primary immunodeficiency
disorders in children. Front Pediatr. 2:77.
3. Weber, H. C., R. P. Gie, and M. F. Cotton. 2013. The challenge
of c