COPD 6133 Pathophysiology-Of-bronchiectasis 102909

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Th pathophysiology of b onchi ctasis

Paul T KingD pa tm nt of M dicin , D pa tm ntof r spi ato y and Sl p M dicin ,Monash Uni sity, Monash M dicalC nt , M lbou n , victo ia, Aust alia

Co spond nc : Paul T KingD pa tm nt of M dicin , MonashM dical C nt , 246 Clayton rd, Clayton,M lbou n , victo ia, 3168, Aust aliaT l + 61 3 9594 6666Fax + 61 3 9549 6495email paul.king@m d.monash. du.au

Abstract: Bronchiectasis is de ned by permanent and abnormal widening o the bronchi.This process occurs in the context o chronic airway in ection and infammation. It is usuallydiagnosed using computed tomography scanning to visualize the larger bronchi. Bronchiectasisis also characterized by mild to moderate airfow obstruction. This review will describe the

pathophysiology o noncystic brosis bronchiectasis. Studies have demonstrated that the smallairways in bronchiectasis are obstructed rom an infammatory in ltrate in the wall. As mosto the bronchial tree is composed o small airways, the net e ect is obstruction. The bronchialwall is typically thickened by an infammatory in ltrate o lymphocytes and macrophages whichmay orm lymphoid ollicles. It has recently been demonstrated that patients with bronchiectasishave a progressive decline in lung unction. There are a large number o etiologic risk actorsassociated with bronchiectasis. As there is generally a long-term retrospective history, it may

be di cult to determine the exact role o such actors in the pathogenesis. Extremes o age and smoking/chronic obstructive pulmonary disease may be important considerations. There area variety o di erent pathogens involved in bronchiectasis, but a common nding despite the

presence o purulent sputum is ailure to identi y any pathogenic microorganisms. The bacterialfora appears to change with progression o disease.Keywords: bronchiectasis, infammation, obstructive lung disease, pathophysiology, pathology

IntroductionBronchiectasis is de ned by the presence o permanent and abnormal dilation o the bronchi. 1,2 This usually occurs in the context o chronic airway in ection causinginfammation. The main clinical mani estation is a productive cough. Bronchiectasis iscurrently nearly always diagnosed using high-resolution computed tomography (HRCT)scanning. The main diagnostic eatures are: 1) internal diameter o a bronchus is wider than its adjacent pulmonary artery; 2) ailure o the bronchi to taper; and 3) visualiza-tion o bronchi in the outer 1–2 cm o the lung elds. 3 This review will describe the

pathophysiology o noncystic brosis (CF) bronchiectasis.With the widespread availability o HRCT it has been realized that bronchiectasis

remains a common and important cause o respiratory disease. It has been estimated that there are at least 110,000 adults in the United States with this condition. 4 In addi-tion, there is overlap with chronic obstructive pulmonary disease (COPD) with twostudies reporting an incidence o bronchiectasis in COPD as being 29% 5 and 50%, 6 respectively.

Bronchiectasis is characterized by mild to moderate airfow obstruction 7–11 thattends to worsen over time. 12–14 The most widely known model o the development o

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bronchiectasis is Cole’s “vicious cycle hypothesis”. 15 In thismodel, Cole proposed that an environmental insult o tenon a background o genetic susceptibility impaired muco-ciliary clearance resulting in persistence o microbes in thesinobronchial tree and microbial colonization. The microbialin ection caused chronic infammation resulting in tissuedamage and impaired mucociliary motility. In turn this led to more in ection with a cycle o progressive infammationcausing lung damage. The current view is that the two actorsrequired or the development o this condition are persistentin ection and a de ect in host de ense.

There are no well established animal models o bron-chiectasis nor have there been studies per ormed in theearly stages o the disease. Bronchiectasis is also a veryheterogeneous condition and can be considered the end result o a variety o di erent actors. As a consequence the

pathophysiologic processes are still not well de ned. Thisreview will discuss di erent aspects in which this conditionmay develop.

PathologyMost studies o the pathology o bronchiectasis were reported

between 1930 and 1960 as there was access to signi cant

quantities o operative and postmortem lung specimens at thistime. Reid categorized bronchiectasis as having three main

phenotypes: 1) tubular characterized by smooth dilation o the bronchi; 2) varicose in which the bronchi are dilated withmultiple indentations; and 3) cystic in which dilated bronchiterminate in blind ending sacs. 16 The current major ormseen on HRCT is the tubular orm o bronchiectasis. The CTappearance o these three di erent orms o bronchiectasisis demonstrated in Figure 1.

Arguably the most de nitive study o the pathology o bronchiectasis was per ormed by Whitwell 17 who studied 200 consecutive operative lung specimens. This studydemonstrated marked infammation o the bronchial wall,

principally in the smaller airways. Bronchial dilation wascharacterized by de ciency/loss o elastin and more advancedisease by destruction o muscle and cartilage. The speci cmechanism o how this loss o tissue leads to bronchialdilatation is not known. There was variable bronchial wall

brosis, atelectasis and peribronchial pneumonic change.Whitwell classi ed bronchiectasis into three di erent types:

ollicular, saccular, and atelectatic. Follicular bronchiectasiswas the dominant orm and this corresponded to tubular

bronchiectasis (the main orm commonly seen).

Figure 1 HrCT xampl s of r id’s th fo ms of b onchi ctasis: A ) tubula B), a icos , andC ) cystic.Abbreviation: HrCT, high- solution comput d tomog aphy.











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Follicular bronchiectasis was characterized by the presence o lymphoid ollicles in the bronchial wall. Theinfammatory process commenced in the small airway. Thissmall airway infammation caused the release o mediatorssuch as proteases which damaged the large airways causingloss o elastin and other components such as muscle and cartilage which resulted in bronchial dilation. With progres-sion o the disease lymphoid ollicles enlarged in size and caused airfow obstruction to the small airways. The nalevent was spread o the infammation beyond the airways tocause interstitial pneumonia. This process is demonstrated inFigure 2. Recently Hogg and colleagues 18 described similar lymphoid ollicles in chronic obstructive pulmonary disease(COPD) which had a strong association with bronchial wallthickening and airfow obstruction.

The dominant cell types involved in the infammatory process in bronchiectasis are neutrophils, lymphocytes, and macrophages. 19 Neutrophils are the most prominent cell typein the bronchial lumen 20,21 and release mediators, particularly

proteases/elastase which cause bronchial dilation (ie, bron-chiectasis). 22,23 The in ltrate in the cell wall is predominantlycomposed o macrophages and lymphocytes. 20,24 Studies havereported that the main lymphocyte is the T cell 24,25 and theseare cells that are likely to produce the lymphoid olliclesdescribed by Whitwell.

Emphysema may also occur in bronchiectasis. Loubeyreand colleagues 26 reported that hal o a cohort o subjectshad localized emphysema in association with bronchiectasis.This presumably corresponds to the interstitial pneumoniadescribed by Whitwell that spreads into the parenchyma o the lungs to cause localized damage.

Distribution of bronchiectasisThe distribution o bronchiectasis may be associated withdi erent pathophysiologic processes eg, allergic bronchop-ulmonary aspergillosis is classically associated with central

bronchiectasis. Bronchiectasis has been described as beinglocalized (ie, con ned to one lobe) or generalized. Mostcommonly it is generalized and seems to be most com-mon in the lower lobes. 2,27 The involvement o the lower lobes may refect gravity dependent retention o in ected secretions.

Right middle lobe bronchiectasis has been well described in the context o tuberculosis. 17,28–32 The right middle lobe

bronchus is long, o ten bends sharply at its bi urcation and iso relatively small caliber. A collar o lymph nodes also sur-rounds the proximal bronchus and any condition that causesa prolonged enlargement o these nodes may lead to obstruc-tion and secondary bronchiectasis. This may also occur inmalignancy 33 and in nontuberculous mycobacterial in ection

Small airwayA ) Large airway Small airway

Proteases

Inflammation Inflammation

Obstruction Dilation (bronchiectasis) Dilation (bronchiectasis)

Dilation (bronchiectasis)

Obstruction

Interstitial pneumonia

B )

D )C )

Figure 2 Pathologic chang s in follicula b onchi ctasis as d sc ib d by whit ll.A) The rst process involves infection of the small airways. B) This l ads to th l as of in ammatory mediators such as proteases which damage the large ai rways resulting in bronchial dilation and bronchiectasis. C ) Infection drives progressive in ammation in thesmall airways which become thicker from a combination of cell-mediated in ammatory in ltrate and lymphoid follicles resulting in obstruction. D ) The nal process involvesthe spread of in ammation beyond the airways resulting i n interstitial pneumonia.












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(o ten with the lingula lobe). 34 This event is demonstrated in Figure 3.

It is generally not known i bronchiectasis starts in onesection o the respiratory tract and then spreads or i it beginsas a generalized process. Childhood bronchiectasis has a high

proportion o subjects who have chronic rhinosinusitis aswell. 10,27,35 One report described the apparent spread o sinusin ection to the lungs resulting in bronchiectasis. 36

Lung functionA number o studies have described the lung unction in

bronchiectasis. Patients usually have mild to moderate air-fow obstruction. It has also been demonstrated recently thatthere is a progressive decline in lung unction over time withloss o orced expiratory volume in one second (FEV 1).

12–14 This is a paradoxical nding as the characteristic eature o

bronchiectasis is airway dilation.A CT/lung unction study ound that airfow obstruction in

bronchiectasis was predominantly due to small and mediumairway involvement with eatures o decreased attenuationand mucosal wall thickening. The decreased attenuationwas a marker o small airway constrictive bronchiolitis. Thesmall airway constrictive bronchiolitis is diagnosed by the

presence o a mosaic pattern on expiratory lms. 37

The pathology studies by Whitwell explain the ndingo air low obstruction in bronchiectasis. These studiesshow the large airways become dilated but the small and medium airways are characterized by airfow obstruction

predominantly arising rom thickening o the bronchial wall.As most o the respiratory tree is composed o medium and

small airways the net e ect o the infammatory process in bronchiectasis is airfow obstruction (Figure 2).

Etiologic factorsThere have been a large number o actors that have beendescribed as causative or bronchiectasis. A problem withassigning these actors as being causative is that subjectshave usually had their lung disease or a long time (o tenmore than 10 years) and the attribution may rely on long-termretrospective recall. It may perhaps be more appropriate toconsider them as risk actors rather than the de nitive cause.The etiologic actors that have been described generally allhave some role in impairing host de ence to in ection. Someimportant etiologic actors are discussed below. A list o etiologic actors is given in Table 1.

Postinf ctiousThe most common cause o bronchiectasis is the literatureis postin ectious. This is not a well de ned entity but theusual context appears to be one acute in ectious episodewhich is thought to result in bronchiectasis. To the author’sknowledge, the development o bronchiectasis a ter onein ectious episode have not been de nitively demonstrated in a cohort o patients. At some stage all bronchiectasis

patients become colonized with bacteria but this appears to be a little di erent rom acute process in the postin ectiousentity that is described in the literature. A possible mechanism

or postin ectious bronchiectasis is a signi cant in ectionin early childhood which causes structural damage to thedeveloping lung and permits bacterial in ection which is

A ) B )

Figure 3 Pathologic p oc ss in th ight middl lob ith mycobact ial inf ction.A ) Inf ction caus s nla g m nt of p ib onchial lymph nod s sulting in obst uction.B) Th obst uction sults in b onchi ctasis that p sists h n th nod s tu n to no mal siz .














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not cleared. Over time persistent in ection may then resultin bronchiectasis.

One well characterized orm o bronchiectasis occursin the context o mycobacterial in ection and this orm is

particularly prevalent in the right middle lobe with nontuber-culous mycobacterium. 17,38,39 The mechanism o this orm o

bronchiectasis appears to arise rom lymph node obstruction.The acute in ection causes enlargement o peribronchialnodes which obstruct the bronchus and result in secondary

bronchiectasis. This bronchial dilation persists when themycobacterial in ection resolves and the nodes return tonormal size. This process is demonstrated in Figure 3.

Muco-cilia y cl a ancMuco-ciliary clearance is a key de ence mechanism against

pulmonary in ection. Its compromise is important in thedevelopment o the vicious cycle o bronchiectasis as pro-

posed by Cole. 15 Cystic brosis is associated with de ectivemuco-ciliary clearance but this area is beyond the scope o the current review. There has been renewed interest recentlyin ciliary de ects and this has been recently reviewed. 40–42 Themost prominent cilial disorder is primary ciliary dyskinesia(PCD) which combines upper and lower respiratory tractin ection, male in ertility and in approximately 50%, situsinversus . PCD arises primarily rom a de ect in the dyneinarms which are necessary or normal cilial beating. This areahas been the subject o recent discoveries. 43,44 Bronchiectasisis a prominent mani estation o PCD. The de nitive diagnosiso PCD requires electron microscopy to demonstrate loss o dynein and this requires specialized expertise available onlyin a limited number o centers. Screening can be undertaken

more easily using nasal nitric oxide and in vivo tests o ciliarymotility such as the saccharin test. Young’s syndrome isanother condition in which the primary de ect is thought to

be de ective mucous unction. 45

Malnut ition/socio conomicBronchiectasis has been described as being a major problemin developing nations although the prevalence has not beenwell de ned. Authors rom South America, 46 Hong Kong/China, 47 India, 48 and Turkey 49 all report that bronchiectasis isan important local problem. It is certainly a major problem incertain indigenous populations such as Australian aborigines,

New Zealand Maori, and Alaskan natives. 50–52 A commoneature o these groups is malnutrition and social disadvan-

tage which are likely to be associated with impaired immuneunction (Torzillo and Chang, pers comm.). 53 Malnutrition/

socioeconomic disadvantage is not commonly listed as anetiologic actor or bronchiectasis, but in selected populationsit may be important.

ext m s of agThe immune system is less e ective in young children and eld-erly adults which results in an increased incidence o in ectionin these two groups. 54,55 Bronchiectasis has most commonly

been described as commencing in childhood, particularlyin the rst ve years o li e, with chronic productive coughand unresolved in ection. 2,10,27 Field per ormed a long-term

prospective ollow-up on 225 patients with bronchoscopy.She ound that 74% o the cohort had the onset o chronicrespiratory in ection in the rst ve years o li e and subjectstended to signi cantly improve in late adolescence regardlesso treatment. 27 Our group has studied adult patients with bron-chiectasis who had the onset o symptoms in childhood. 2 Mosto these subjects (about two-thirds) described the improvemento their symptoms in late adolescence and then a worsening o their symptoms rom the age o 50 to 60 years when they repre-sented or medical assessment. These two studies suggest thata common eature o childhood-onset bronchiectasis may bean improvement with adulthood and then clinical deteriorationagain beyond the age o 50 years. This is shown in Figure 4.

We have also described the phenotype o patients who rstdevelop bronchiectasis in adulthood. 35 The onset o chronicchest suppuration cough was uncommon rom the ages o 15–50 years. Eighty-one percent o adult-onset patients had the onset o chronic chest suppuration over the age o 50 years.Weycker and colleauges report a prevalence o bronchiectasisas being 4.2 per 100,000 persons aged 18 to 34 years and 272

per 100,000 in those aged over 75 years. 4 There ore extremes

Table 1 etiologic/ isk facto s associat d ith b onchi ctasisPostinf cti (postpn umonia, hooping cough, m asl s, mycobact ialinf ction)

Mucocilia y diso d (immotil cilia, Ka tag n ’s synd om , Young’ssynd om )

Obst ucti (fo ign body, mycobact ial inf ction, obst ucting canc )

Immun diso d (hypogammaglobulin mia, HIv inf ction, canc , all gicb onchopulmona y asp gillosis, t ansplant j ction)

Rheumatic/in ammatory disease (rheumatoid arthritis, in ammatorybo l dis as )

ext m s of ag

Malnut ition/socio conomic disad antag

Ch onic obst ucti pulmona y dis as

Aspi ation

Alpha1-antitrypsin de ciency

Misc llan ous (y llo nail synd om )












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o age may be important in the development and clinicalmani estations o bronchiectasis. Increasing age has beenrecently described as being an important actor in COPD. 56

Ch onic obst ucti pulmona y dis asA cardinal eature o COPD is the presence o chronic

bronchitis. Recently two studies have reported a high inci-dence o bronchiectasis in COPD patients. O’Brien and colleagues 5 studied 110 patients with COPD who presented with an acute exacerbation in a primary care setting and ound HRCT evidence o bronchiectasis in 29% o the cohort. Pateland colleagues 6 studied 54 patients with severe COPD or the presence o bronchiectasis. They ound that 50% o the

patients had co-existent bronchiectasis and this was associ-ated with bacterial airway colonization and infammatorymarkers and longer duration o exacerbations. 6 Patients withCOPD and bronchiectasis tend to have more dyspnea, worselung unction, and a lack o upper airway involvement whencompared to other bronchiectasis subjects. 35

There is also some overlap in the pathology o COPDand bronchiectasis. Both conditions have neutrophils and T lymphocytes as the predominant infammatory cell, 19,57

protease release causes pulmonary damage and lymphoid ollicles have a role in airfow obstruction. 17,18

Immun dysfunctionThe term immune dys unction covers a wide variety o causes

but some conditions associated with bronchiectasis are pri-marily categorized as immune dys unction disorders. Thesecan be considered in terms o primary immune de cienciessuch as hypogammaglobulinemia, human immunode ciency

virus (HIV), inter eron gamma receptor de ciency, and type Imajor histocompatibility complex de ciency. 2 Detection o hypogammaglobulinemia is important as replacement therapymay have therapeutic implications. The clinical signi canceo immunoglobulin subclass de ciency is controversial.

Bronchiectasis may occur in the late stages o lungtransplant rejection. Allergic bronchopulmonary aspergil-losis (ABPA) is a classic cause o bronchiectasis and this isimportant to diagnose as there are speci c rami cations or treatment. Bronchiectasis may also occur in subjects withvery high levels o immunoglobulin E but without ABPA. 36

Mycobacterial in ections have been recognized to beassociated with bronchiectasis, particularly in older womenwhere the combination o mycobacterium avium complex(MAC) in ections causing obstruction rom lymphad-enopathy with right middle lobe bronchiectasis is a welldescribed syndrome. 58,59 It should also be remembered thatMAC in ections are opportunistic and may cause in ectionin other chronic lung diseases such as COPD and there orein ection with MAC may be secondary to bronchiectasis. Itis not clear rom the literature what the e ect o secondaryMAC colonization is on the progression o bronchiectasis. In

our children who had disseminated mycobacterial in ection,researchers recently ound a mutation de ect in the gene or inter eron gamma receptor, the primary protective cytokineagainst intracellular mycobacterial in ection. 60

Rheumatological/in ammatory conditionsThere is a well described association between bronchiectasisand rheumatoid arthritis. In rheumatoid arthritis the incidenceo bronchiectasis has been described to be 1%–3%. Recentstudies o patients with rheumatoid arthritis have described the prevalence o bronchiectasis on HRCT in such patientsas being up to 30%. 61,62 Bronchiectasis is described as pre-ceding and occurring a ter the development o rheumatoid arthritis. Bronchiectasis may also occur in association withSjogren’s syndrome 63 and Churg–Strauss syndrome. 64 It is

possible that immune suppression may predispose to chronicairway in ection. 64 Bronchiectasis also occurs in subjectswith infammatory bowel disease. 65

Alpha1-antitrypsin de ciencyAlpha1-antitrypsin de ciency (AAT) is associated withincreased risk o COPD and bronchiectasis. Parr and col-leagues studied the prevalence o airways disease in AAT-de cient subjects and ound that 70 o 74 subjects had radiological evidence o bronchiectasis and 20 subjects wereclassi ed as having clinically signi cant bronchiectasis. 66

Symptoms and age

C h a n g e

i n s e v e r i t y o

f s y m p

t o m s

Age

0 20 40 60 80 100

Figure 4 Chang in s ity of symptoms o tim in thos ith childhood-ons tbronchiectasis. A common nding in subjects whose symptoms began in childhoodis imp o m nt in lat adol sc nc and th n d t io ation again f om about th agof 50 y a s.














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MicrobiologyA large number o di erent pathogens have been isolated instudies o microbiologic fora in bronchiectasis. There is o tensigni cant variation between di erent locations. The main

ndings rom recent studies have been that Haemophilus infu-enzae is the most common pathogen (range 29%–70%) ol-lowed by Pseudomonas aeruginosa (range 12%–31%). 7,10,67–71 The other major nding o these studies is that 30%–40% o sputum samples despite being good quality and purulent will

ail to grow any pathogenic bacteria; and this applies evenwhen bronchoscopy and protected brush/bronchoalveolar lavage is used. The bronchi also have a dynamic turnover o

pathogens. A two-year prospective study ound that a propor-tion o patients were continually colonized by Branhamellacatarrhalis (the name Branhamell a has recently been changed to Moxarella ) but there was a continous turnover o strainsevery 2–3 months. 72 In COPD, there is evidence or consider-able turnover o bacteria with the acquisition o new strainsdemonstrated to be associated with exacerbations. 73

An important nding o bronchiectasis is that thereappears to be a change in microbial fora with severity o disease. 71 Typically subjects with the best preserved lung

unction are most likely to have no pathogenic bacteriaisolated. As lung unction declines H. infuenzae becomes

predominant and nally in patients with the most severedisease the usual pathogen isolated is P. aeruginosa .

Speci c pathogens H. infuenzae is the most common isolate and is nearly alwaysthe nontypeable orm (NTHi). P. aeruginosa is associated withmore sputum, more extensive bronchiectasis, more hospitali-zations and worse quality o li e. Nontuberculous mycobacte-rial in ection may be important in bronchiectasis but studieshave reported variable prevalence o 2% 71,74 to 10%. 75

The role o viral in ection in bronchiectasis is not wellde ned. Becro t 76 identi ed adenovirus as a risk actor

or the development o bronchiectasis in young children.Infuenzae A in ection in vitro inhibits neutrophil unctionin bronchiectasis subjects. 77 Viral in ections have a role inexacerbations o COPD but this has not been de ned or

bronchiectasis. 78

eff cts of bact ial pathog nson th spi ato y t actBacterial pathogens may exert a number o direct e ectson the respiratory tract that impairs host de ence. The mostwell described e ects in bronchiectasis are inhibition o themucociliary clearance. Mediators released by H. infuenzae ,

P. aeruginosa , and Streptococcus pneumoniae may directlyinter ere with ciliary unction, damage ciliated epithelium,and inhibit mucous transport. 79 Bacteria release products suchas glycoproteins which attract neutrophils. H. infuenzae hasthe capacity to cause direct damage to airway epithelium and is also able to invade into the bronchial wall and intersti-tium o the lung. 80,81 P . aeruginosa has the capacity to orm

bio lms. 82 Bio lms occur particularly in advanced diseaseand orm an impenetrable matrix around the Pseudomonas ,shielding it rom the e ects o the immune system and anti-

biotics and allowing the bacterial in ection to cause severedamage to the underlying lung.

ConclusionsBronchiectasis is characterized by airway infammation. Theinfammation appears to arise as a combination o immunede ciency and persistent in ection. As proposed by Cole thisinfammatory process is progressive and results in a cycle o worsening pulmonary damage. Patients develop progressiveobstructive lung disease. The airfow obstruction appears toarise predominantly rom involvement o the small airwaysin which the bronchial wall is in ltrated by infammatorycells particularly lymphocytes which may orm lymphoid

ollicles.Bronchiectasis is a heterogeneous condition and there

are a large number o etiologic actors have been described.Because o the long-term nature o the disease it is o tenhard to be clear about the exact role o such actors in the

pathogenesis. It may be more appropriate to consider them as being risk actors rather than the single cause o longstandingairway in ection.

The microbiology o bronchiectasis is complex and variessigni cantly between di erent studies. An important nding isthat despite purulent sputum and optimal collection techniques(eg, bronchoscopy) there is o ten ailure to isolate a pathogenicmicroorganism. The role o viruses is not well understood.A better understanding o the microbiology o bronchiectasiswould have direct implications or patient treatment.

Bronchiectasis is a complex condition and the pathophysi-ology is still not well understood. De ning the infammatory

process particularly be ore there is signi cant lung diseasemay be help ul in developing better strategies o treatment.

AcknowledgmentsThe author would like to thank Associate Pro essor Peter Holmes and Pro essor Stephen Holdsworth or their helpwith this work. The author reports no conficts o interestin this work.












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