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 mark.everard@uwa.edu.au
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.
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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?
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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.
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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.
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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
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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?
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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
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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
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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]
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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
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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…… *
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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
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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
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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
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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 alexander.moeller@kispi.uzh.ch
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].
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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
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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.
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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
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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
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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
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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%
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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%
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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
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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
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– 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
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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
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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
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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
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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
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118
119
120
121
Gao YG. PlosOne; 2014; 9: 3: e90047
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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
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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
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Prof. Fabio Midulla Paediatric Departments. “Sapienza” University of Rome.
Viale Regina Elena 324 00161 Rome
ITALY midulla@uniroma1.it
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].
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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].
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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.
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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
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Fabio Midulla MD
Conflict of interest disclosure
I have no, real or perceived, direct or indirect conflicts of interest that relate to this presentation.
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To discuss diagnosis and criteria for
hospitalization
To discuss criteria for discharge
Aims
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132
64,4
C as
Midulla et al. Arch Dis Child 2010;95(1):35-41. Epub Oct 11
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Effects of the immunological reaction and of the inflammatory mediators.
Pathogenesis
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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)
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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
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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
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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.
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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
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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
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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
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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)%
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breathing (keep upper airways clear)
Restore clinical stability (oxygenation and hydration)
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Respiratory support
Pharmacologic interventions
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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 p.aurora@ucl.ac.uk
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
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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.
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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