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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 2  |  Issue : 2  |  Page : 18-24

'Suppurative lung disease' in children


Division of Paediatrics and Child Health, Perth Children's Hospital, University of Western Australia, Nedlands, Western Australia, Australia

Date of Web Publication6-Jul-2018

Correspondence Address:
Mark Lloyd Everard
Division of Paediatrics and Child Health, Perth Children's Hospital, University of Western Australia, Winthrop Avenue, Nedlands, 6009 Western Australia
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/prcm.prcm_6_18

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  Abstract 

A chronic neutrophil dominated bronchitis also known variously as PBB and CSLD is relatively common in childhood. There are numerous risk factors that may contribute to the development of a chronic bronchitis [inc viral LRTIs, malacia, aspiration, poorly controlled asthma etc.]. In most cases a specific significant on-going risk factor such as CF is not identified. It is under-diagnosed due to lack of awareness (if you do not know something exists you will never diagnose it). It is commonly mis-diagnosed as 'asthma' or 'recurrent chest infections'. Diagnosis is based on pattern recognition and response to treatment analogous to accurate diagnosis of asthma. Response to treatment must be dramatic and unequivocal to make a definite diagnosis. Beware regression to the mean PBB is a biofilm disease leading to challenges in treatment. A PBB is the cause of most cases of 'bronchiectasis'. Bronchiectasis is a radiological or pathological appearance, not a disease. Most cases are curable in the absence of a major underlying risk factor such as cystic fibrosis, PCD or significant immunodeficiency. Hence bronchiectasis is a largely preventable radiological appearance.

Keywords: Biofilms, chronic bacterial bronchitis, chronic cough, neutrophils, persistent bacterial bronchitis


How to cite this article:
Everard ML. 'Suppurative lung disease' in children. Pediatr Respirol Crit Care Med 2018;2:18-24

How to cite this URL:
Everard ML. 'Suppurative lung disease' in children. Pediatr Respirol Crit Care Med [serial online] 2018 [cited 2018 Jul 20];2:18-24. Available from: http://www.prccm.org/text.asp?2018/2/2/18/236140


  Introduction Top


Suppurative lung disease will have accompanied humankind from the earliest times. The physical consequences of chronic suppurative lung disease (CSLD) were first described by Rene Laennec some 200 years ago in his classic, original description of bronchiectasis, correctly identifying the role of the chronic purulent secretions in its aetiology (though bacteria had not been identified as the cause of the purulent secretions).[1] Equally importantly, he used the term bronchiectasis to describe a physical appearance and not a disease. The disease was the consequence of the chronic endobronchial infection resulting in a range of symptoms that included chronic cough, chronic expectoration of sputum and malaise accompanied by intermittent exacerbations. Severity ranged from a troublesome productive cough to cachexia and respiratory failure. Death might result from a severe episode of bronchopneumonia (an exacerbation characterised by areas of pneumonia accompanying chronic bronchitis) or terminal respiratory failure and wasting. In the following 150 years, the condition remained a major cause of ill health in childhood.[2],[3],[4],[5],[6],[7]

By the early C20th, the usual suspects regarding pathogenic bacteria had been identified [8] and an understanding of the role of chronic infection and impaired airways clearance became established over the subsequent 50 years.[9],[10],[11],[12],[13],[14],[15],[16] With the advent of effective antibiotics in the second half of the C20th, the quality of life of those with a chronic endobronchial infection was transformed [17] and many in more affluent countries coming to believe that 'bronchiectasis' had largely disappeared attributing this to improved hygiene and vaccinations as much as to the use of antibiotics.[18],[19] The focus on asthma (in part driven by pharma who were starting to develop products in portable inhalers that they could sell in vast quantities such as b-agonists and then, from the early 1979's, inhaled corticosteroids [ICS])[20] further marginalised interest in chronic bacterial infection outside the chronic bronchitis that was typically associated with smokers. The mantra that 'asthma should not be treated with antibiotics' was, as with so much in medicine, rolled out for the best of reasons. The intention was to try and ensure exacerbations of asthma were not treated with antibiotics for a 'chest infection' but managed appropriately with β-agonists and if necessary corticosteroids.[21] This further helped solidify in the minds of many the concept that bacteria produced acute pneumonic illnesses and occasionally produce an acute infection of the conducting airways such as a staphylococcal tracheitis but did not cause chronic bronchitis in children.

As a result, the concept of a 'chronic bronchitis' in children faded from the collective memory of many resulting in a self-fulfilling outcome. If one is not aware a condition exists, it is impossible to recognise or diagnose it and if it is not being diagnosed and recognised, it effectively ceases to exist.

While the vast majority of paediatric opinion leaders were saying that chronic bronchitis did not exist in children and that it was really all unrecognised asthma, adult physicians were refining the long-held concept that 'bronchiectasis', in most but not all cases, was the result of a vicious cycle of impaired mucociliary clearance and/or impairment of immunity leading a persistent infection associated with chronic inflammation that resulted in damage to the epithelium, and in time, the structure of the airway that further impaired mucociliary clearance promoting infection with the inflammation.[11],[12],[13],[14],[15],[16] Over a variable period ranging from months to decades, this would lead to the dilation of proximal airways evident on CT scans as bronchiectasis and as Laennec almost uniquely observed, obliteration of smaller more distal airways which presumably accounts for the fall in forced vital capacity over time.[1],[22]

This of course gave rise to a largely unrecognised period of cognitive dissonance– individuals believing that children did not get a chronic bronchitis (despite all the historical evidence to the contrary) while at the same time holding the belief that chronic infection of the conducting airways was the cause of bronchiectasis. To resolve this, they convinced themselves that really it was only those with cystic fibrosis (CF), primary ciliary dyskinesia (PCD), significant immunodeficiencies and those damaged by conditions such as whooping cough or measles who developed to 'CSLD'.[23] Many presumed the bronchiectasis following whooping cough or measles was a consequent of damage wrought during the acute illness without understanding that these infections could, in a minority of patients, initiate persistent bacterial bronchitis (PBB).

The recognition that children experienced chronic endobronchial infection in the absence of the major risk factors outlined above did not disappear completely in the 1980s and 1990s,[24] but our understanding was muddled [25],[26] as reflected in the wide range of terms being used to describe the same condition including 'bronchiectasis' (inappropriately being used to denote a disease), pre-bronchiectasis, chronic bronchitis, chronic juvenile bronchitis, persistent endobronchial infection, a protracted or persistent bronchitis and suppurative lung disease.[27] As interest in the condition was reignited in the early C21st, at least in developed countries,[27],[28],[29],[30],[31],[32],[33],[34],[35] some even suggested that a chronic (or 'protracted') bacterial bronchitis was a 'new disease' and tried to differentiate it from 'CSLD'.

For the purposes of this review, the term PBB will be used since it describes the chronic nature of the condition and clearly describes an on-going inflammation of the conducting airways resulting from a persistent bacterial infection. The ability of a patient to expectorate or for there to be sufficient damage to demonstrate bronchiectasis on computed tomography scan are simply features of the condition that may or may not be present. This is analogous to the child with asthma who may have a dry night time cough without wheeze or have such a severe exacerbation that they have a 'silent chest' – both still have asthma.


  The Importance of Bacterial Biofilms in Pulmonary Disease Top


The recognition that has come in the last couple of decades that most bacteria exist not as rapidly dividing planktonic organisms but as highly organised communities within biofilms finally provided a mechanism for persistence of bacteria in the conducting airways. Bacteria have been forming communities held together by an extracellular matrix, thus forming biofilms, for more than 3.5bn years.[35] As part of this process, it is now clear that bacteria communicate with each other using quorum-sensing molecules that influence their behaviour and metabolism. A range of strategies are adopted by bacteria in biofilms to facilitate their persistence and resist environmental threats such as host responses, antibiotics, other micro-organisms and nutrient-poor environments. These include the physical barrier provide by the extracellular matrix, the ability to down regulate metabolism, low rates of replication, the ability to share genes such as antibiotic resistance gene within members of the community and the development of collective strategies for eliminating threats such as antibiotics.[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41]

This survival strategy permits them to persist very effectively in potentially hostile environments. Over the past 10 years, it has been increasingly recognised that a PBB is both relatively common and a major cause of respiratory morbidity. The relevant bacteria persist in biofilms driving a sustained, but ineffective neutrophilic bronchitis with most of the symptoms attributable to this chronic bronchitis. However, the concepts still have not reached much of the respiratory community including many, but not all, of those interested in chronic obstructive pulmonary disease (COPD).

Much of our understanding of the behaviour of biofilms and their role in respiratory illness comes from the ear, nose and throat world and chronic otitis media and to a lesser extent, chronic sinusitis. The interplay of microorganisms within a given ecological niche is complex with competition for dominance and/or collaboration being key to their success.[42],[43],[44],[45],[46],[47],[48]

Conventionally, acute febrile bacterial illnesses have been associated with rapidly dividing organisms such as the Streptococcus pneumoniae in an acute pneumonia or E Coli in an acute urinary infection. Both of these are generally 'commensals' living with the host but not causing illness. During an acute illness caused by planktonic, rapidly dividing organisms, they can be identified if an appropriate sample is obtained using conventional (i.e., >100-year-old) microbiological techniques using culture plates (though this is rapidly being augmented by the use of matrix-assisted laser desorption ionisation time-of-flight). As the organisms in these acute diseases are planktonic and are dividing very rapidly 'rules,' such as it is likely to be a 'real' result if a pure growth of a likely suspect is obtained at levels of >1 × 105/ml, were adopted for diagnostic purposes. Such 'rules' do not apply to more chronic biofilm diseases.

In a biofilm, the organisms turn over very slowly and hence such 'rules' are inappropriate [40] giving rise to debate regarding their value when assessing bronchoalveolar lavage (BAL) fluid, the guidelines being written before the recognition that biofilms were directly relevant to respiratory health. Consequently, some laboratories continue to produce qualitative results while others produce qualitative results such as scanty, few, moderate or heavy growths. Some authorities suggest if the organism should not be there and it is cultured then it is highly relevant while others argue that some degree of quantification is required to eliminate the effect of upper airways contamination of the sample. To complicate the issue further there is evidence to suggest that 'pathogens' can be cultured in BAL samples from healthy children (Craven personal communication) and certainly they are observed in all 16S microbiome studies. This adds a further layer of complexity to the interpretation of BAL results.

Intercurrent viral infections commonly cause exacerbations through the release of increased numbers of planktonic bacteria. This may simply result in increased symptoms as they colonise other areas of the conducting airway, but if the organisms extend into the respiratory portion of the lung, the patient may present as a 'bronchopneumonia'. The exact mechanism that leads to the release of planktonic bacteria and the change in the bacterial behaviour is unclear but the enzymatic degradation of the surface of the biofilm matrix appears to contribute to the process.[49] In the past, bronchopneumonia was considered to be a more potent killer than acute pneumonia in all age groups. In some COPD and otitis media studies, an exacerbation has been associated in many cases with the appearance of an apparently new strain or pathogen.[50] It is unclear whether these have been newly acquired or just happen to be the organism identified on that occasion or even simply represent gene switching in malleable organisms such as non-typeable  Haemophilus influenzae Scientific Name Search THi).


  The 'lung Microbiome' Top


Further challenges to our understanding of microbial events in the lower airway come from our recognition that the lower airways are not sterile but have a normal microbiota.[51],[52],[53],[54] In disease states such as PBB, the diversity of this community is greatly reduced with increased density of certain operational taxonomic units, that is bacteria characterised on sequence similarity.[51] It appears that the pathogens that appear to cause PBB are also present in the 'healthy' microbiome of the conducting airways.[51],[52],[53],[54] 'Pulmonary disease' appears to result from a disruption of a 'healthy' dynamically changing community probably mediated through the formation of biofilms. It is the ability of one or more organisms to dominate the local environment through establishing biofilms that initiate the chronic inflammation characteristic of PBB and other related diseases. 16S RNA techniques have also confirmed that organisms such as certain  Neisseria More Details species, usually dismissed as 'oral commensals,' probably do drive disease and account for a significant proportion of 'negative' BAL samples.[51]

Quite how the 'healthy' microbiome of the conducting airway is maintained is unclear. A 'wash in, wash out' concept in which continual clearance through mucociliary clearance and macrophages is matched by replenishment by microaspiration is favoured by some,[52],[53] but others believe that there is a stable local community that remains in equilibrium unless disturbed by events such as antibiotic therapy or acquisition of a pathogen.

Criteria for diagnosing biofilm-related disease remain challenging [39],[40] and the implications of positive and 'negative' cultures will be discussed below.

Persistent bacterial bronchitis is neutrophil-dominated bronchitis

A neutrophil polymorphonuclear neutrophil (PMN)-dominated response leads to release of mediators such as elastase, myeloperoxidase and metalloproteases which drives mucus production and cough.[55] The inability of the PMNs to clear the bacteria biofilms leads to a chronic and persistent neutrophilic bronchitis which over time damages the conducting airways. Macrophages fail to cope with the intensity and persistence of the neutrophilia resulting in products such as DNA and myeloperoxidase from PMN nets and necrotic PMNs mixing with mucus altering it rheology and colour (the greater the neutrophil influx and death through necrosis the deeper the colour of the sputum ranging from yellow through to dark green).[56] The 'phlegm' resulting from this chronic suppuration maybe expectorated but more commonly is swallowed due to inability to expectorate in younger children and often due to embarrassment in older children (especially girls) who learn to quietly huff and swallow rather than cough loudly and expectorate.

Clinical symptoms – pattern recognition

The symptoms of a persistent bacterial endobronchial infection include a chronic cough, sleep disturbance and in many, a significant malaise due to both lack of high-quality sleep resulting from the coughing and the effects of chronic suppuration are attributable to the chronic inflammation.[27],[31],[32],[33] They are often reported to 'wheeze' but this a typical misuse of the term.[27],[57],[58] Older individuals they may produce sputum but pre-school children general swallow any sputum. Just because they are young, it does not mean they have a different disease.

Recognising the condition is largely pattern recognition, as indeed it is for most conditions. History can suggest the likely diagnosis but is far from infallible.[27],[30] The clinical features have been discussed elsewhere and hence will not be discussed in detail in this article.

Diagnosis

Diagnosis is confirmed in much the same way as a robust asthma diagnosis is established. A diagnosis of possible or probable asthma or endobronchial infection is made on the basis of the history and examination (though examination is often not particularly helpful). The diagnosis is only confirmed and becomes definite when there is a dramatic and unequivocal response to therapy.

For a diagnosis of asthma, the response may be an increase of >12%–15% in forced expiratory volume in one second following a selective b-agonist or complete resolution of wheeze and significant increased work of breathing within 10 min of a dose of a b-agonist. Similarly, a dramatic and unequivocal change in a child's symptoms after 6 weeks of an ICS should be sufficient. That is not 'they are coughing a bit less' 'they seem to be sleeping a bit better' all of which may simply regression to the mean.

The parents report 'he is a new child' 'I have my cheerful little girl back and we are all sleeping'! Unfortunately, as much of diagnosis is based on an inadequate history and failure to truly understand the nature of the response if any to a given treatment, over- and under-diagnosis of asthma are still common place.[59],[60]

For PBB, the typical response to treatment is slow when compared to the dramatic lysis with resolution of fever that occurs within 24 h of starting antibiotics in most patients with pneumococcal pneumonia (excepting those developing an empyema or necrotising pneumonia). Often there is a discernible difference at around a week, but the cough does not usually resolve until around 10–14 days. As such the point of review should be 14 days with the same criteria as for asthma – a dramatic change such that the parents report something along the lines of 'its amazing, he is not 'coughing for the first time in 9 months', 'she is sleeping through the night and is so much happier, it is wonderful'.

Regression to the mean and other potential catches

The reason for seeking a dramatic and unequivocal response is that parents will generally seek help during an escalation of symptoms which with respiratory symptoms are generally associated with an intercurrent illness. If the physician chooses to do nothing other than reassure the mother and then reviews the patient in a couple of weeks, the patient will almost certainly have improved due to them 'regressing to the mean' irrespective of whether they have asthma, PBB, both of these conditions or simply have a virus. For an asthmatic, this will be towards the day-to-day 'bother' commensurate with their normal level of control and severity;[61] for PBB, it will be towards their baseline level of coughing and sleep disturbance and for an otherwise healthy individual it will be to normal respiratory health unless they contract another respiratory virus in the interval.

It is all too easy to take credit for the improvement if one prescribes an intervention and thus be misled if we are not critical and demand a dramatic and unequivocal change to support our presumed diagnosis.

Recurrent chest infections

Physicians frequently fail to take an adequate history when a child is admitted with 'pneumonia' or 'recurrent chest infections'. One of the most important questions in the former is 'when was your child last completely well without any respiratory symptoms, in particular a cough', and in the latter 'was he/she completely well between episodes or did they get better but still have cough every day'.

In the former, the 'pneumonia' may be an acute exacerbation of a chronic bronchitis (hence a 'bronchopneumonia') and later, when the child has developed bronchiectasis, the 'cause' will be attributed to 'post-pneumonic' bronchiectasis when in fact the problem was an on-going bacterial bronchitis that preceded and persisted after treatment of the 'pneumonia'. In those with recurrent 'chest infections,' the damage is much more likely to be attributable to the chronic inflammation manifest by the chronic cough than the acute flare-ups as is the case in patients with CF.

If the cough and symptoms completely resolve between episodes without aggressive antibiotic therapy, this makes PBB much less likely with recurrent viral infections and relatively mild asthma much more likely (mild asthma often presenting with viral-induced exacerbations which do not induce severe shortness of breath but whose symptoms can drag on for many weeks).

Timing and quality of cough

A 'wet' or 'productive' sounding cough suggest secretions within the airways. While those with a chronic bacterial bronchitis will typically have a 'wet' cough that can be compared with that of a chronic smoker ('does your child sound like a 60 a day smoker first thing in the morning?' is often a much more informative question that is their cough dry or wet?), they can on occasions have a dry cough despite the presence of large amounts of secretions at bronchoscopy. Parental reporting of the quality of cough appears to be unreliable (unpublished data) and listening to the child cough where possible is the most important part of the examination. A wet cough is not entirely specific as it just indicates secretions and poorly controlled asthmatic or one recovering from a viral exacerbation may have a wet cough though typically the asthmatic cough is said to be dry and non-productive. Many children with viral infections will develop a wet sounding cough, but equally many appear to have a dry irritating cough with respiratory viruses. A persistent dry cough as assessed by both parents and physicians being likely to resolve over time.

The timing of a cough is also potentially informative with those having a chronic endobronchial infection typically worse when they first go to bed and first thing in the morning – the parents are aware they have woken up because of the coughing that precedes breakfast. However, a poorly controlled asthmatic whose symptoms are worse in the early hours may still be symptomatic as they get up from a disturbed nights' sleep.

As noted above, undue shortness of breath on exercise with some coughing is more common amongst asthmatics while severe coughing leading to difficulty catching one's breath is more likely to be due to airways suppuration, but the history can again be misleading.


  Investigation and Management Top


Confirming the diagnosis

As noted above a clear, complete resolution of symptoms, including cough, at 14 days after commencing an appropriate antibiotic makes the diagnosis highly likely. For some, there is an incomplete response which maybe attributable to more severe disease (uncommon but does occur and occasionally symptoms require 2 weeks of intravenous antibiotics to resolve), poor adherence which appears to be relatively uncommon (parents are often desperate to find a solution and are highly motivated) or there is a comorbidity resulting in on-going symptoms.

For example, asthma and a persistent endobronchial infection can and do exist. Poor control of asthma results in impaired mucociliary clearance and thus predisposes to a PBB. Hence, the persistence of a 'wet' cough should raise the specter that either it is not asthma or if the patient has clearly been correctly diagnosed with asthma such as demonstrating marked reversibility but still has a persistent wet cough PBB should be considered as a possible co-morbidity.

'Difficult asthma' is due to one or more of three possibilities in the vast, vast majority of cases – (1) it is not asthma (2) it is asthma and something else that also causes respiratory symptoms (3) the patient is not taking their inhaled steroids effectively either because they are not taking >80% of doses or are not using their inhaler effectively-that is poor regimen and/or poor device adherence.

Investigations

There is no general consensus as to when and what to investigate. Given that the majority of cases resolve without sequel if treated aggressively, it would appear reasonable to defer investigations in an otherwise apparently healthy individual until the condition has relapsed two or three times after a prolonged course of antibiotics providing there are no other reasons for concern such as failure to thrive, unusually severe non-respiratory infections, history of inhaled foreign body, suspicion of aspiration or concern about airways abnormality with symptoms from birth or soon afterward. Significant conditions such as x-linked agammaglobulinaemia and other antibody deficiencies, variants of CF (particularly in countries without neonatal screening) and PCD can present in older pre-school and school-aged children and hence appropriate investigations should be considered when the setting appears atypical. Timing of investigations is also, in part influenced by parental wishes, some parents wanting investigations at the outset and others preferring to wait to see if the condition will resolve with treatment. Approaches to investigation have been discussed previously.

Treatment

This, as with so much in this neglected field, is largely an evidence-free zone. Treatment is aimed at eliminating the bacteria and permitting recovery of structure and function using antibiotics and physiotherapy which in most cases should result in a cure. The lung disease associated with CF is in large part due to the development of a persistent bacterial bronchitis. Unlike most patients with a PBB the underlying defect currently prevents a cure though with aggressive therapy the airways can often be kept free from significant suppuration for many years.

As noted above perhaps, the best guide to treatment is 'coughing is a clinical marker of inflammation'. If there is on-going inflammation at best the airways will not be repairing themselves and more at worst; there will be slowly progressive damage. If a child has an intercurrent viral the illness, any wet cough should have resolved within 10–14 days. The only published trial to date utilised a 2-week course with a number of those on placebo becoming cough free, and many of those on active treatment did not becoming cough free [62] calling into question the diagnosis. In long-term retrospective reports, relapse is common even if a longer initial course of 6 or 8 weeks is used.[27],[63] These longer treatment courses are largely empirical being chosen as they appear to cover the period taken for cilia to recover following a viral respiratory tract infection.[63] However, in many cases the inflammation has persisted for months or years so recovery times for cilia obtained from previous health infants may not be relevant and longer courses may be optimal. The risk of not curing the bronchitis is long-term morbidity with the risk of treatment being largely the side effects of the antibiotics. Clearly prevention with early intervention is the goal, but this requires large community-based studies to determine whether advice such as 'do not give antibiotics for a cold but if the child still has a wet cough at 14 or 21 days treat with a 5 or 7 days course of antibiotics and ensure the cough resolves' would strike the right balance.

Immunologists have long used 'prophylactic' antibiotics for prolonged periods presumably based on experience that their patients seem healthier on these without really understanding the role of the biofilm disease. Which antibiotic should be used is again unclear. Co-amoxiclav is widely used as the 'usual suspects', namely S. pneumoniae, NTHi and  Moraxella More Details catarrhalis are generally sensitive. In some areas, a macrolide such as azithromycin is widely used for 'convenience' in that once loaded some prescribe it 3x per week such as Monday/Wednesday/Friday to aid adherence, and others are attracted by its 'anti-inflammatory' properties. However, resistance is a major issue in countries using relatively high quantities of macrolides, and this remains a concern for the individual as well as society.[64]

It is well known that adherence with treatment is poor in most therapeutic areas. This is one in which my experience is that parents do not delay contacting the medical team at the recurrence of a cough and this is presumably because the difference between the child with symptoms and the same child when cough free is so dramatic the parents are highly motivated.

The role of physiotherapy is unclear. In theory, it should be very helpful, but it requires greater commitment from parents than the antibiotic regimen. Some parents find it very helpful though usually it is only introduced if the cough reoccurs after one or two courses of treatment.

Natural history

The natural history of PBB and ill health associated with bronchiectasis has been discussed elsewhere.[31],[32],[33]


  Summary Top


On-Going chronic bronchitis due to a persistent bacterial infection is a relatively common cause of chronic respiratory symptoms and morbidity in childhood [65],[66] though its true prevalence in any setting is unclear due to lack of any robust prevalence data based on accurate diagnosis (the same is true of asthma). The lack of a simple diagnostic test means that pattern recognition and unequivocal response to treatment form the basis of a robust diagnosis (again this is no different to asthma). If a clinician is not aware of the condition, they can never make the diagnosis and failure to make an accurate diagnosis can result in chronic, often lifelong and unnecessary morbidity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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