Unusua| Lung Infecnons,

8ronch|ectas|s, and Cysnc I|bros|s

Llsa Moores, Mu, lCC
AsslsLanL uean for Cllnlcal Sclences
rofessor of Medlclne
1he unlformed Servlces unlverslLy of Lhe PealLh Sclences
Iacu|ty D|sc|osures
nCnL
Learn|ng Cb[ecnves
Aer Lhls sesslon, learners wlll be able Lo:
8ecall Lhe classlc presenLauons and radlographlc ndlngs of
acunomycosls and nocardlosls lnfecuons of Lhe lung
ulscuss Lhe LreaLmenL of acunomycosls and nocardlosls
lnfecuon ln Lhe lung
LlsL Lhe causes of bronchlecLasls
ulscuss Lhe Lherapeuuc opuons for Lhe LreaLmenL of
bronchlecLasls
uescrlbe Lhe geneuc defecLs underlylng Cl
LlsL Lherapeuuc approaches Lo Lhe LreaLmenL of pulmonary
dlsease ln pauenLs wlLh Cl
Cverv|ew
unusual lnfecuons
nocardlosls
Acunomycosls
Cysuc llbrosls
Ceneucs/paLhogenesls
ulmonary manlfesLauons
ManagemenL of lung dlsease
non-Cl 8ronchlecLasls
Classlcauon/dlagnosls
Cllnlcal and radlographlc characLerlsucs
ManagemenL
Nocard|a
Aeroblc, non-moblle, non-spore formlng organlsms
llve as soll saphrophyLes
8ranchlng, lamenLous forms LhaL are gram + and
usually acld fasL
Seven specles assoclaLed wlLh human dlsease
n. ostetolJes mosL common
22 sLudles lnvolvlng 448 cases LhroughouL Lhe
llLeraLure
Sm||ack I. N Lng| I Med 1999,341:88S
uesnon 1
nocardla pulmonary lnfecuon:
1. ls more common ln women
2. Commonly occurs ln lmmunocompromlsed
hosLs
3. Commonly lnvolves chesL wall lnvaslon
4. ls uncommonly assoclaLed wlLh dlssemlnauon
Nocard|a
Commonly recognlzed as an opporLunlsuc dlsease
Cnly 3 of cases reporLed ln prevlously healLhy adulLs
Cell medlaLed lmmune declencles
Solld organ LransplanL (especlally lung)
Plv (Cu4 <100)
Lymphoma
Anu-1nl Lherapy (monoclonal > soluble)
Local lmpalrmenL of lung defenses
CCu, A, granulomaLous dlseases
MosL lmporLanL rlsk facLor ls LreaLmenL wlLh
corucosLerolds
Nocard|a
8adlographlc manlfesLauons
Alrspace consolldauon mosL common
nodules also seen frequenLly
MosL common feaLure ls cavlLauon, boLh ln
consolldauons and nodules
Oh, Y. W. et al. Radiology 2000;217:647-656
Leung, A. N. et al. Radiology 1999;210:699-710
Sm||ack I. N Lng| I Med 1999,341:88S
C||n|ca| resentanon
SubacuLe pneumonla mosL common
Medlasunlus, perlcardlus reporLed from dlrecL
spread
LxLrapulmonary dlssemlnauon common
8raln mosL common, especlally ln alcohollcs
Skln, bone, muscle
ulssemlnauon more common ln pauenLs wlLh Plv and
alcohollsm
Nocard|a
ulagnosls
Can oen culLure, buL bronchoscopy may be
needed for adequaLe speclmen
CulLures lncubaLed aeroblcally for up Lo 4 weeks
+ smear/culLure ln lmmunocompromlsed pauenL
= dlsease
Advances ln unA exLracuon and C8 may speed
dlagnosls
Nocard|a
1reaLmenL
uCC are sulfonamlde agenLs
Mlnocycllne can be used ln sulfa allerglc pauenLs
Llnezolld hlgh ln vlLro acuvlLy, cosL and LoxlclLy
llmlL use Lo refracLory cases
6-12 monLhs of Lherapy
conslder surglcal dralnage of abcesses
uesnon 2
As opposed Lo pulmonary lnfecuon from nocardla
specles, lnfecuon wlLh acunomyces specles more
commonly:
1. Spreads dlsLally
2. lnvolves Lhe chesL wall
3. Can be dlagnosed by spuLum culLure
4. 8equlres surglcal LreaLmenL
Acnnomycos|s
Anaeroblc or mlcroaerophlllc gram posluve bacllll
Colonlze mouLh, colon, vaglna
lnfecuon mosL commonly caused by A. lstoelll
Acunomycouc lnfecuon ln Lhe lung usually
polymlcroblal
Acnnomycos|s
MosL lnfecuons occur ln normal hosLs, pauenLs wlLh
alcohollsm or poor denLal hyglene aL lncreased rlsk
3:1 male predomlnance
8esplraLory lnfecuon Lyplcally follows asplrauon, buL
exLenslon of dz from abdomlnal cavlLy or neck can
occur
Crow ln mlcrocolonles or granules (sulfur granules)
ChesL wall lnvaslon noL uncommon
Acnnomycos|s
8adlographlc manlfesLauons
Alrspace consolldauon mosL common
erlphery, lower lung elds
necrosls (low auenuauon areas) and cavlLauon on C1
AdenopaLhy, bronchlecLasls, pleural dlsease
Lung abscess---empyema---osLeomyellus of rlbs----chesL wall
slnus LracL formauon
k|m, 1. S. et a|. Am. I. koentgeno|. 2006,186:22S-231
k|m, 1. S. et a|. Am. I. koentgeno|. 2006,186:22S-231
C||n|ca| resentanon
Cervlcofaclal lnfecuon followlng denLal work
ulmonary dlsease usually lndolenL, subacuLe
presenLauon, oen noL suspecLed
8ronchocuLaneous sLula hlghly suggesuve
Cen confused wlLh lung CA and Luberculosls

Acnnomycos|s
ulagnosls
ux oen noL made wlLhouL hlsLologlc examlnauon
lsolauon of organlsm ln spuLum or bronchlal
washlngs noL slgnlcanL wlLhouL sulfur granules
Acnnomycos|s
1reaLmenL
unLreaLed, dlsease ls ulumaLely faLal
enlclllln ls drug of cholce
1eLracycllnes, eryLhromycln, cllnda ln allerglc
pauenLs
rolonged Lherapy usually needed, ad[uvanL surglcal
debulklng may allow shorLer course
Nocardiosis Actinomycosis
Gram positive Aerobic Gram positive Anaerobic
Incidence increasing Incidence decreasing
Male 3:1 predominance Male 3:1 predominance
Occurs primarily in
immunocompromised hosts
Occurs primarily in
immunocompetent hosts;
alcoholism and poor dental
hygiene a risk
Pulmonary manifestations
predominate
Pulmonary manifestations in
minority (approximately 15%)
Chest wall involvement
uncommon
Chest wall involvement and bony
erosion common
Metastatic spread (esp. to brain)
common
Metastatic spread uncommon;
spread by direct contiguous
invasion
Granuloma formation and fibrosis
rare
Granuloma and intense fibrosis
common; form the characteristic
sulfur granule
Diagnosis can usually be made
on sputum, BAL or pleural fluid
culture
Diagnosis often requires
cytologic or histologic
examination
Treatment with sulfonamides Treatment with penicillin
Surgical drainage often needed Often treated successfully with
antibiotics alone

uesnon 3
1he mosL common underlylng cause of non-Cl
bronchlecLasls ln adulLs ls:
1. lnfecuon
2. Collagen vascular dlsease
3. unknown (ldlopaLhlc)
4. lmmune declency
8ronch|ectas|s
Syndrome
lrreverslble dllaLauon and desLrucuon of bronchl
lnadequaLe clearance and poollng of mucus ln Lhe alrways
CharacLerlzed by
erslsLenL mlcroblal lnfecuon and lnammaLory response
ulvlded lnLo Cysuc llbrosls (Cl) and non-Cl forms
Cysnc I|bros|s
Lpldemlology/Ceneucs
aLhophyslology
ulmonary compllcauons
ManagemenL of lung dlsease
Cl loundauon auenL 8eglsLry Annual 8eporL 2009
CI
MosL common geneuc dz ln Lhe uS (1 ln 3,000 blrLhs
ln whlLe populauon)
AuLosomal recesslve wlLh varlable peneLrance
Cl gene on Lhe long arm of chromosome 7
Lncodes Lhe Cl Lransmembrane regulaLor proLeln (Cl18)
CI1k
LocaLed aL cell surface
lon channel LhaL regulaLes llquld volume on eplLhellal
surfaces
Chlorlde secreuon and lnhlbluon of sodlum absorpuon
May regulaLe oLher cell proLelns
Cver 1600 muLauons ldenued
l308 mosL common, accounLs for 90 of cases of
Luropean descenL
uue Lo deleuon of slngle phenylalanlne aL posluon 308
Lxpressed ln all eplLhellal cells (lung, pancreas, sweaL
glands, llver, lnLesune, LesLes)
athogenes|s
1he defecuve Cl18 proLeln leads Lo defecuve
LransporL of lons
AlLerauon ln composluon of secreuons ln resplraLory LracL,
pancreas, Cl LracL, sweaL glands
Low waLer volume
Plgh salL concenLrauon
8educed blcarbonaLe secreuon-mucln crossllnklng
uysregulauon of lnammaLory response
rlmary pre-dlsposluon Lo lnfecuon
ln lung, changes properues of Lhe mucus layer llnlng
Lhe alrways
lmpalred mucoclllary clearance
erslsLenL bacLerlal lnfecuon
lncreased lnammauon (accumulauon of cellular debrls,
lncludlng unA and elasLase)
Alrway obsLrucuon
rogresslve lung dysfuncuon
lahy !v, ulckey 8l. nL!M 2010, 363:2233-47
Cl18 Cene MuLauons
Cl18 uysfuncuon
AlLered lon 1ransporL
Loss of Alrway Surface Llquld
1hlck vlscous mucold secreuons
lmpalred mucoclllary LransporL
Chronlc 8acLerlal lnfecuon
Chronlc lnammaLory 8esponse
Mns
LlasLase
Cxldauve 8adlcals
unA acun
8ronchlecLasls
know|es M and Dur|e . N Lng| I Med 2002,347:439-442
D|agnosnc 1ests
SweaL chlorlde remalns gold sLandard
Molecular dlagnosls, genoLyplng lu's 20-30 of Lhe
mosL common muLauons
u across resplraLory eplLhellum
lncreased levels of lmmunoreacuve Lrypsln, newborn
screenlng
Elevated sweat chloride level on two occasions
-OR-
Identification of mutations known to cause CF in both CFTR genes
-OR-
In vivo demonstration of characteristic abnormalities in ion transport
across the nasal epithelium
-PLUS-
One or more phenotypical features of CF
Sino-pulmonary disease
Characteristic GI or nutritional disorders
Obstructive azoospermia
Salt loss syndrome
-OR-
Sibling with CF
-OR-
Positive newborn screening


D|agnosnc Cr|ter|a for CI
D|agnos|s: Atyp|ca| CI
When Lo suspecL:
Chronlc lnfecuon wlLh pseudomonas, S. aureus,
nM18
8ecurrenL/chronlc ldlopaLhlc pancreauus
8llaLeral absence of vas deferens
nasal polyposls/chronlc slnuslus
unexplalned bronchlecLasls
u|monary Man|festanons
Lungs normal aL blrLh
lnfecuon occurs early and ls perslsLenL
P. lofoeozoe, S. ooteos early, pseudomonas laLer
seudomonas lndependenL prognosuc facLor
8otkbolJetlo cepoclo even worse prognosls
erslsLenL cough
AP8
8ronchlecLasls and obsLrucuve lung dlsease
uesnon 4
Medlcal Lherapy for all pauenLs wlLh Cl who are
older Lhan 6 years lncludes:
1. CorucosLerolds
2. Macrollde anubloucs
3. Plgh-dose lbuprofen
4. rhunase (dornase alpha)
Cysnc I|bros|s u|monary Gu|de||nes
Alrway Clearance 1echnlques. 8esp Care 2009, 34: 322-37
1reaLmenL of ulmonary Lxacerbauons. Am ! 8esp CrlL Care Med
2009, 180:802-808
Chronlc Medlcauons for MalnLenance of Lung PealLh. Am ! 8esp
CrlL Care Med 2007, 176:937-969
ulmonary Compllcauons: PemopLysls and neumoLhorax. Am !
8esp Crluc Care Med 2010, 182: 298-306
A8A ln Cl. Clu 2003,37(Suppl 3),S223-64
Lung 1ransplanLauon ln Cl. ChesL 1998,113,217-226
Culdellnes for ulagnosls, nuLrluon, lnfecuon ConLrol also avallable
Management of CI
CurrenLly focused prlmarlly on mlugauon of
downsLream eecLs ln resplraLory and oLher organ
sysLems
llume A. 8MC Medlclne 2012, 10:88
Management
Clearance of alrway secreuons recommended for all
pauenLs wlLh cysuc brosls for clearance of spuLum,
malnLenance of lung funcuon, and lmproved quallLy of
llfe
ChesL physloLherapy
lorced explraLory Lechnlques
Mechanlcal vesLs
lluuer valves
none proven superlor Lo oLhers
Aeroblc exerclse recommended as an ad[uncL

Management
8ronchodllaLor Lherapy
auenLs wlLh aL leasL 10 lmprovemenL ln lLv1
rlor Lo C1 and lnhalauonal Lherapy
?lmprove mucoclllary clearance (salmeLerol may resLore
chlorlde secreuon)
82 agonlsLs recommended for all pauenLs > 6 years of age Lo
lmprove lung funcuon
Management
8educe vlscoslLy of secreuons
rhunase l (dornase alpha)
All pauenLs >6
Csmouc 1herapy
lnhaled hyperLonlc sallne
All pauenLs >6
Annb|onc 1herapy
lour modallues
Chronlc prophylaxls Lo prevenL speclc lnfecuon
Converslon Lo culLure negauvlLy upon deLecuon of
new speclc paLhogens
alllauon of acuLely elevaLed slgns and sympLoms of
lnfecuon
Chronlc suppresslon of esLabllshed lnfecuons
Annb|onc 1herapy
arenLeral Lherapy for 14-21 days for acuLe
exacerbauons
CephaloLhln or nafclllln for sLaph, anupseudomonal
Lherapy for Lhose colonlzed
use mosL recenL culLures Lo gulde Lherapy
noL enough daLa Lo recommend lnhaled anubloucs
over parenLeral Lherapy
Chronlc lnfecuon wlLh pseudomonas
rolonged course LhaL eradlcaLes organlsm may
delay chronlc lnfecuon and lung funcuon decllne
Lradlcauon more feaslble early, before mucold sLralns
wlLh blolm develop
Slngle course (4 weeks) wlLh repeaL only wlLh
recurrenL culLure adequaLe
nebullzed amlnoglycosldes used ln documenLed
chronlc lnfecuon
2009 Cochrane revlew conrms lmproved lung
funcuon and decreased hosplLallzauons

Ann-Inammatory 1herapy
neuLrophll predomlnanL lnammauon
auenLs have abnormal basal and lnduclble alrway
lnammauon
rlmarlly endobronchlal
lnLracellular slgnallng paLhways a key componenL
lnammaLory response prolonged and lnvolves
helghLened oxldauve and proLeolyuc sLress
Ann-Inammatory 1herapy
SysLemlc SLerolds
8eneclal eecLs on lung funcuon ouLwelghed by adverse
eecLs
8ecommended only for asLhma or A8A
Lack of daLa on lnhaled CS--- also recommended only for
A8A or asLhma
Ann-Inammatory 1herapy
lbuprofen
lnhlblL mlgrauon of neuLrophlls
Slows decllne of lung funcuon ln hlgh doses
uependenL on adequaLe serum levels- musL be
lndlvldually dosed and monlLored
Cl loundauon recommends for chlldren 6-12 wlLh
moderaLe-severe lung dlsease
AlLhough reglsLry daLa reveal LhaL lL ls under-uullzed
(only 6)
Ann-Inammatory 1herapy
Macrolldes
lnhlblL neuLrophll mlgrauon and elasLase producuon
Long-Lerm use of azlLhromycln assoclaLed wlLh lmproved
lung funcuon and reducuon ln exacerbauons
Cl loundauon recommends 1lW Lherapy for pauenLs wlLh
long-Lerm pseudomonas lnfecuon and moderaLe-severe
lung dlsease
Ann-Inammatory
lnvesugauonal agenLs
AnuoxldanLs (nAC, aerosollzed gluLaLhlone)
CyLoklne regulauon
lnLerrupL lnLracellular slgnallng paLhways
AnuproLeases (lnhaled A1A1)
New 1herap|es
Cene Lherapy (alrways presenL barrlers)
CorrecLors" LhaL can promoLe proper foldlng
vx-809, vx-661
Cl18 modulaLors/augmenL channel funcuon
lvacaor (Cl18 poLenuaLor) approved for Lhose wlLh
C331u muLauon, noL eecuve ln l308del-Cl18
lnduce alLernauve lon channels
newer anubloucs
lnhaled azLreonam luA approved Lhls pasL year
lron chelaLors Lo prevenL formauon of blolms
u|monary Comp||canons
PemopLysls
neumoLhroax
non-Luberculous mycobacLerlal lnfecuon
A8A
8esplraLory fallure, cor pulmonale
1ransp|antanon |n CI
Cenerally good candldaLes
1ransplanLed lung does noL develop defecL
8equlres bllaLeral lung LransplanLauon
lndlcauons
ueLerlorauon desplLe aggresslve Lherapy, lLv1 <30
predlcLed,
llfe-LhreaLenlng compllcauons (lCu sLay)
ulmonary hyperLenslon
ConLralndlcauons
CLher organ fallures, noncompllance, psychosoclal
lnsLablllLy, profound malnuLrluon, acuve asperglllus, n1M
or 8otkbolJetlo cepoclo Complex
rognos|s |n CI
Medlan survlval 20 years ln 1970, 37 by 2007,
chlldren born Loday wlll survlve lnLo slxLh decade of
llfe
When lLv1 decllnes Lo < 30 predlcLed, 2-year
survlval ls <30
Medlan lLv1 ercenL redlcLed vs. Age, 1990 and 2009
Cl loundauon auenL 8eglsLry Annual 8eporL 2010
NCN-CI 8kCNCnILC1ASIS
Chronlc lnfecuon
wlLh resplraLory
paLhogens
lnammauon
wlLh lnLense
Mn lnlLrauon
Lyuc enzymes
released by
bacLerla or
Mns
rogresslon of
alrway damage
n.lofoeozoe
l.oetoqlooso
5.loeomooloe

*5.ooteos otyplcol
C|ass|hcanon
Cyllndrlcal
varlcose
Cysuc
All Lhree may coexlsL
lolllcular
1yplcally follows chlldhood lnfecuon
Cysnc 8ronch|ectas|s
C||n|ca| Man|festanons
More common ln women, 6Lh decade
Cough, chronlc dally spuLum, dyspnea
8hlnoslnuslus and faugue also common
Crackles and wheezlng
CbsLrucuve venulaLory pauern, lmpalred dluslng
capaclLy
40 wlll have AP8
Lno|ogy -Ioca| 8ronch|ectas|s
Mechanlcal obsLrucuon
lorelgn body asplrauon
LxLernal compresslon
SLenosls
CongenlLal bronchlal aLresla
necrouzlng pneumonla
Lno|ogy -- D|use
CenLral redomlnance
Allerglc bronchopulmonary asperglllosls (A8A)
Carulage declency syndromes
Mounler-kuhn's Syndrome
Wllllams-Campbell Syndrome
Lno|ogy -- D|use
erlpheral predomlnance-upper lung
Cysuc llbrosls
Sarcoldosls
osL-radlauon brosls
Lno|ogy -- D|use
erlpheral predomlnance-lower lung
ldlopaLhlc
osL-lnfecuous
Chronlc asplrauon
llbrouc lung dlsease (Lracuon bronchlecLasls)
osL-LransplanL re[ecuon
Pypogammaglobullnemla/Plv

Lno|ogy -- D|use
erlpheral predomlnance-mlddle lobe and llngular
ALyplcal mycobacLerlal lnfecuon (MAl)
lmmoule cllla syndrome
D|agnosnc Lva|uanon
PlsLory
Age aL onseL
PlsLory of frequenL
alrway lnfecuons
Smoklng hlsLory
revlous lung surgery
Chlldhood lnfecuons
(perLussls, measles,
pneumonla)
18 or MAC
ALopy or asLhma
C1u
8lsk for Plv
lnferullLy
8eux SympLoms
D|agnosnc 1esnng
ln mosL pauenLs
C8C, lgC, lgA, lgM, splromeLry, P8C1
As dlrecLed by hlsLory
8l, lgL, asperglllus preclplLans, alpha-1 anuLrypsln, spuLum
culLures for mycobacLerla and fungl, sweaL chlorlde Lesung
Clllary Lesung lf hx of frequenL upper resplraLory lnfecuons
or ouus
D|agnosnc 1esnng
8ronchoscopy
focal obsLrucuon
LM for cllla
8AL for n1M
8lopsy for dluse bronchlollus
kad|ograph|c I|nd|ngs
8ouune Cx8
1ram Lracks
Pyperlnauon
8lng shadows
P8C1
lnLernal bronchus dlameLer wlder Lhan ad[acenL arLery
lallure of bronchl Lo Laper
Lxcesslve wall Lhlckenlng
lmpacLed mucus
1ram 1rack|ng
13 y]o CI A8A
8arker A. N Lng| I Med 2002,346:1383-1393
n|gh-keso|unon Computed 1omograph|c Images of Lungs w|th
8ronch|ectas|s
1herapy for 8ronch|ectas|s
1reaL underlylng dlsease where posslble
8ronchodllaLors
Alrway clearance Lechnlques
Mucolyuc agenLs
uornase alpha nC1 recommended ln non-Cl
pauenLs
PyperLonlc sallne and mannlLol may be of beneL,
used commonly, buL noL recommended rouunely
Lxerclse Lralnlng
neumococcal and lnuenza vacclnauon
MeLersky ML. 1her Adv 8esplr uls 2010, 4: 93-99
asLeur MC eL al. 81S Culdellne for non-Cl bronchlecLasls. 1horax 2010, 63:1-38
1herapy for 8ronch|ectas|s
Anubloucs
AcuLe exacerbauons, prevenL exacerbauons, reduce
bacLerlal burden
auern of colonlzauon relauvely sLable over ume
Slmllar Lo pauenLs wlLh Cl, chronlc pseudomonas lnfecuon
has been lndependenLly assoclaLed wlLh morLallLy
Small Lrlals/81S Culdellnes supporL regular lnhaled
amlnoglycosldes for pseudomonas
may be assoclaLed wlLh lncreased bronchospasm
no good evldence for use wlLh oLher paLhogenlc
organlsms

Ann-Inammatory Agents
lnhaled corucosLerolds
Lspeclally ln Lhose wlLh AP8
lmprove sympLoms, CCL, spuLum volume
no eecL on lung funcuon
Cral corucosLerolds
ShorL course only for exacerbauons
nSAluS occaslonally used
LeukoLrlene recepLor anLagonlsLs may lnhlblL
neuLrophll medlaLed lnammauon
Ann-Inammatory Agents
Macrolldes, older smaller Lrlals suggesLed LhaL
May reduce spuLum producuon
May lmprove lung funcuon
May reduce spuLum lnammaLory markers
May reduce cllnlcal sympLoms, lmprove survlval
Macro||des |n Non-CI 8ronch|ectas|s
3 recenLly publlshed Lrlals suggesL beneL
8LLSS, 8A1 and LM88ACL (eryLhromycln,
azlLhromycln)
8educed exacerbauons
lmproved lung funcuon ln Lwo of Lhe Lralls
1rend Lowards lmproved CCL
no evldence of Lhe emergence of new paLhogens
lncreased macrollde reslsLance for some organlsms
wlLhouL cllnlcal consequence
Macro||des |n Non-CI 8ronch|ectas|s
All Lrlals enrolled pauenLs wlLh frequenL
exacerbauons
need Lo check for n1M prlor Lo LreaLmenL
MonlLor llver funcuon, C1C and hearlng
Serlsler u!. !AMA 2013, 309:1260-1267
AlLenburg !. !AMA 2013, 309:1231-1239
Wong C. LanceL 2012, 380:660-667
Summary of key o|nts
nocardla and acunomycosls share many feaLures
8oLh are oen noL suspecLed
Plgh lndex of susplclon ln aL-rlsk populauon
8ronchlecLasls common
SysLemauc approach Lo exclude LreaLable condluons
Medlcal managemenL slmllar Lo LhaL of Cl
auenLs wlLh Cl llvlng longer
ManagemenL of pulmonary dlsease paramounL