Cystic fibrosis in adults

Cystic Fibrosis in Adults 275

Clinical Reviews in Allergy & Immunology Volume 25, 2003275

*Author to whom all correspondence and reprintrequests should be addressed. E-mail: [email protected].

Clinical Reviews in Allergy & Immunology© Copyright 2003 by Humana Press Inc.

1080-0549/03/275–288/$25.00

Cystic Fibrosis in Adults

Current and Future Management Strategies

Brian M. Morrissey,*,1 Bettina C. Schock,2 Gregory P. Marelich,3

and Carroll E. Cross1

1Adult Cystic Fibrosis Clinic and University of California Davis School of Medicine, Sacramento, CA;2Queen’s University of Belfast School of Medicine Respiratory Research Group, Belfast, Northern Ireland;

3Kaiser Permanente, Sacramento, CA

Over 30,000 individuals in the United States of America are living with cystic fibrosis (CF).Despite incremental advances in care and understanding of its pathophysiology, CF remains asignificantly life-limiting disease. Readily accessible newborn screening, genetic testing, andan improved awareness have increased the early recognition of CF, atypical presentations ofCF, and the CF-related diseases. Improvements in medical management have led to continu-ally improving life expectancy for patients with CF. Despite improved management strate-gies, severe lung disease remains the commonly life-limiting pathology. We review thepathophysiology, diagnosis, and management of the respiratory-tract manifestations of CFthat represent the life-limiting aspects of the condition and summarize upcoming and possiblefuture therapies for patients with CF.

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Index Entries:Cystic fibrosis; CF; adult; CFTR.

IntroductionCystic fibrosis (CF), the most common auto-

somal recessive disorder in Caucasians with afrequency of 1/2500 live births, was first recog-nized in 1936 as a disorder separate from the“coeliac syndrome” (1). The term “cystic

fibrosis of the pancreas” was coined 2 yr later(2). In 1964 a therapeutic plan for patients withCF was described that stressed the importanceof airway clearance, nutrition, and the treat-ment of infection (3). During this same decade,the CF Foundation accredited comprehensivecystic fibrosis centers based on their clinicalcare, teaching, and research activities. In the fol-lowing decades, the number of patientsreceiving care in CF centers increased, as didtheir median age of survival.

276 Morrissey et al.


In the 1990s, the population of adult CFpatients expanded and the CF Foundation for-mulated strategies for the accreditation of com-prehensive Adult CF Programs. Teams of CFcaregivers consisted of pulmonologists withtraining in CF; nurse clinicians; social workers;nutritionists; and respiratory therapists; withback-up specialists in ear, nose, and throat; gas-troenterology; diabetes; infectious diseases;reproductive urology; and transplant surgery.According to the National Institutes for Health(NIH) Heart, Lung and Blood Institute esti-mates in 2002, about 30,000 U.S. citizens haveCF, of which 23,732 were registered with theCF Foundation. Forty percent of these are overage 18. Within the current decade, over one-half of the CF population will consist of adults.It is clear that primary-care physicians shouldbe generally familiar with CF management.

This review discusses pathophysiologicallybased strategies for the management of adultCF patients with progressive and often severepulmonary disease. Focus is on the acute orpersistent respiratory problems that dominatethe clinical features of adult CF patients andthat account for over 95% of the morbidity andmortality in these patients. Comprehensivedescriptions of “adult” CF-related complica-tions in hepatobiliary, pancreatic, gastroin-testinal, reproductive, and metabolic systemsand the standards expected by the CF Founda-tion are well-documented (4,5). In July 1999,the CF Foundation published the “CF AdultCare Consensus Conference Report.” Thishighlights the standard of care expected inaccredited Adult CF Centers.

CFTR

Deficiency or dysfunction of the cysticfibrosis transmembrane regulatory (CFTR)protein results in CF. Over 1000 mutations ofthe CFTR gene on chromosome 7 have beendescribed so far. CFTR mutations are groupedinto six classes (5,6): I: no full-length CFTR pro-tein is produced at all owing to a premature

stop codon; II: defective processing and abnor-mal trafficking, leading to premature degrada-tion (the most common example beingdelta-F508del caused by deletion of phenylala-nine at position 508); III: CFTR reaches the cellsurface but has defects in regulation; IV: CFTRreaches the cell surface but channel/or conduc-tion is defective; V: CFTR reaches the cell sur-face but is present at abnormally low levels;and VI: CFTR reaches the cell surface but resultsin abnormal regulation of other channels. Iden-tification of these classes has led to an increasedunderstanding of genotype/phenotype correla-tions and to new rationales for the develop-ment of potential therapies. Delta 508del, themost common worldwide mutation, varies infrequency among ethnic groups; it appears in82% of CFTR mutations in Denmark, but onlyin 32% of mutations in Turkey (5).

It is increasingly clear that membrane-transport proteins do not function in isolationbut often interact with a variety of neighboringtransport and regulatory proteins. CFTR itselfis recognized to regulate/modulate a numberof other cellular functions including severalother membrane channel-conductive path-ways (7). In the normal respiratory tract, a cru-cial downregulation of apical sodium-channelactivity (ENaC) results in decreased sodiumabsorption. Normal CFTR anion-channel activ-ity also allows for transcellular movements ofATP into airway lining fluids, resulting in acti-vation of purinergic-receptor of outwardlyreflecting chloride channels, providing for aug-mented transcellular transports of chloride ion.When CFTR function is compromised, both ofthese effects contribute to a decreased nettransepithial movements of water into airway-surface fluids. The coupling of CFTR airwayepithelial ion channels to common physiologicregulation gives rise to the concept that CFTR-related mechanisms contribute to the initiationand progression of CF-related respiratory-tractdisease. In aggregate, these lead to decreasedpericiliary water, thick mucus, impaired muco-ciliary clearance of microorganisms, accumu-



lation of inflammatory cell debris, and secre-tions, causing CF lung disease.

Phenotypic Considerations

Although in some cases, specific CFTRmutations relate to the severity of subsequentlung disease, especially in the milder CFTRgenotypes, in the majority of CF cases withvery low or dysfunctional CFTR there is noclear relationship between the CFTR mutationsand the severity of disease (8). Thus, in patientshomozygous for delta-F508del, CF-related res-piratory-tract disease varies across the spectraof development, rate of progression, and sever-ity. This implicates strong modifying roles forenvironmental factors and genes other than theCFTR gene, including epigenetic factors relatedto inflammatory mediators, the immune sys-tem, and lectins (9). It can be safely predictedthat polymorphisms in many genes capable ofmodulating inflammatory-immune processeswill eventually be shown to affect many differ-ent aspects of the CF respiratory-system phe-notype (10). Patients with CFTR abnormalitieswithout any overt CF lung disease offer insightinto CFTR genotype-phenotype relationships.Examples of patients with moderate decreasein CFTR function who have isolated sinus dis-ease (11) and possibly patients with allergicbronchopulmonary aspergillosis (12) suggest ahierarchy of functional sensitivities to CFTRdysfunction. Further understandings of themechanisms modifying CF phenotypic expres-sion should lead to the identification of newtherapeutic targets for CF.

Pathophysiology

The most serious life-limiting organ changesassociated with CFTR mutations occur prima-rily in the respiratory tract. Secretory cells ofthe nasal and airway epithelium, and espe-cially the glandular epithelium, produceabnormal respiratory tract-surface fluids withsubsequent chronic respiratory infections witha select group of microbes, most notably Pseudo-

monas aeruginosa but also Staphylococcus aureus,Haemophilus influenzae, and Stenotrophomonasmalthophilia (13). An overly zealous inflamma-tory-immune response may even antedate theestablishment of the chronic airway infection;it is difficult to unequivocally establish whichcomes first in the first months of life (13). Link-ages between the defect in CFTR and thedevelopment of infections and concomitantheightened inflammatory-immune airwayresponses are still both controversial andincomplete (14,15).

The current paradigm that describes thepathophysiology of CF starts with abnormalfluid and electrolyte transports to airway sur-faces (16). This altered airway-surface environ-ment is believed to impair mucociliary transportof impacted inhaled or aspirated microbes, fur-thering their multiplication within the airways,heightening airway inflammatory-immuneprocesses, and stimulating oversecretion ofmucus. The progressive decline in pulmonaryfunction is attributable to vicious cycles of air-way infections and inflammatory-immune sys-tem responses dominated by neutrophilinfluxes and proinflammatory cytokines such asinterleukin-8 (IL-8) and tumor necrosis factor-a (TNF-a) (17,18). By the time most CF patientsreach adulthood, P. aeruginosa dominates andmost patients harbor mucoid strains. Once P.aeruginosa is present, patients often have an ac-celerated decline in pulmonary function. Thisdecline is higher in females than in males,accounting for the thus-far unexplainable gen-der gap in life expectancy in females comparedto males (19).

Many hypotheses have attempted to linkabnormal CFTR ion-channel defects to otheraspects of the undeniable classical CF airwaypathophysiology. These are based on the rec-ognition that CFTR may regulate other mem-brane-cellular processes, such as the epithelialsodium channel, and affect various other cel-lular processes. These include defective inflam-matory-immune defense processes; reducedsialyation of CF epithelial-cell glycoconjugates,



which could relate to altered bacterial-adhesion processes; defective respiratory-tractdefensins; and nitric oxide (NO) functions (20),which could relate to defective airway antimi-crobial capabilities, and to an exaggerated, sus-tained host immune response (21). The highlyactivated inflammatory-immune processes arebelieved to play a key role in the progressionof the lung disease. These processes probablyinclude a role for phagocytic oxidation,nitrosation, and proteolysis process, whichmay be broadly applicable to the treatment ofCF (20,22–25). It remains a mystery just howCFTR defects relate to many of these proposedaltered cellular processes. The various hypoth-esis are more fully discussed elsewhere (7).

DiagnosisMost adults with CF were diagnosed in

infancy or early childhood. Typical suggestivesymptoms include: persistent respiratory symp-toms; failure to thrive/malnutrition; abnormalstools with steatorrhea or intestinal obstruc-tion; including meconium ileus; rectal pro-lapse; electrolyte imbalance; nasal polyps/sinus disease; hepatobiliary disease; and/or apositive family history/amniocentesis or screen-ing activity. However, in approx 5% of cases,the diagnosis is not made until adulthood, usu-ally on a basis of persistent respiratory symp-toms and findings that typically predate theage of diagnosis by many years. Highly sug-gestive chest X-rays show diffuse upper lobe-predominant airway and parenchymal changes.Other suggestive findings are pansinusitis,nasal polyps, digital clubbing, and persistentairway infection with mucoid strains of pseudo-monas. Evidence of CFTR dysfunction and anappropriate clinical scenario offer definitivediagnosis. A sweat chloride greater than 60mM usually indicates abnormal CFTR func-tion. Alternatively, nasal potential differenceor rectal potential difference in specialized cen-ters will assess CFTR function. Genotyping forthe most common CFTR mutations to confirm

diagnosis is widely available. Despite testing,a few patients remain without a definitivediagnosis, highlighting the inadequacies ofconsidering CF as an all-or-nothing disease.Patients with a less-than-convincing diag-nostic test for CF, but who phenotypicallyresemble CF, should be managed as if theyhave CF, even though issues may arise regard-ing health insurance and genetic counseling. Inother instances of atypical CF presentations,patients may never develop classical CF com-plication and will not need standard therapy.

Pulmonary Disease: AirwayClearance, Antibiotics,and Nutrition

Within the past several decades, augmentedclearance of mucus, vigorous antibiotic admin-istrations, and aggressive nutritional repletionshave become the pillars of conventional CF res-piratory-tract therapies.

The defective mucociliary clearance, evenin those patients with normal spirometry, rep-resents perhaps the initiating clinical hallmarkof CF (26). The resultant retention of mucus,impacted inhaled bacteria, and degrading res-piratory-tract epithelial and inflammatory celldebris, contribute to the increased viscosity ofsecretions. Numerous strategies exist forenhancing mucociliary and cough clearance(27,28). In adult CF patients, who typicallyhave severe bronchiectasis, therapy includesthe administration of bronchodilators and useof expiratory retard-positive expiratory pres-sure (e.g., PEP) techniques, including thosethat use an oscillatory maneuver (e.g., Flut-ter®, Acapella®), or techniques using a percus-sive vest. There is a high incidence of bronchialhyperactivity in CF. Although this high inci-dence is not usually related to atopy, bron-chodilator strategies are a helpful adjuvanttherapy and often a necessity in CF patientswho may also suffer from allergic asthma (29).Mucolytics, such as hypertonic saline andrecombinant human deoxyribonuclease (DNase)



are widely used. There is little evidence to dateto support the use of reduced thiol compoundssuch as glutathione and N-acetyl-cysteine(NAC), which are themselves irritating to air-ways. However, use of less-irritating thiol com-pounds such as the lysine salt of NAC (30)seems to modulate pro-oxidant-mediated pro-inflammatory processes in some cell systemsand thus have a possible therapeutic potentialin inflammatory lung disease such as CF (31).Exercise routines, which result in an increaseventilatory depth and rate, are believed to con-tribute to airway clearance, although do notrepresent a substitute for formal airway-clear-ance routines.

Although eradication of bacteria from adultCF airways remains an unobtainable goal,widespread antibiotic use attempts to reducethe burden of organisms and should decreaseinflammatory-immune stimuli of the airwaymilieu. However, the downside of persistentantibiotic treatment is the emergence of resis-tant and more virulent microbial airway micro-organisms. There is no universally acceptedstrategy for routine administrations of antibi-otics for their antimicrobial effects alone. Thereis general acceptance in 2003 that inhaledtobramycin twice daily every other month rep-resents an efficacious treatment of CF patientsharboring strains of pseudomonas. In suchpatients, 2–3 wk courses of oral ciprofloxacinare useful adjuncts for subtle exacerbations.Interesting recent data has supported the con-cept that macrolides may have antiinflamma-tory activities that may account for at leastsome of their efficacies in treating chronic air-way diseases such as bronchiectasis and dif-fuse panbronchiolitis (DPB) (32). Aggressiveroutine periodic use of parenteral antibioticsrepresents an approach yet to be tested in con-trolled perspective clinical trials.

The last two decades have seen an increas-ing awareness of the interrelationshipsbetween the infective, inflammatory, pulmo-nary-function manifestations of CF disease

progression and nutritional considerations.This has resulted in more aggressive approachestoward nutritional issues such as deficienciesof pancreatic exocrine and endocrine dysfunc-tion; the necessity of accounting for increasedenergy needs to allow for some degree of mal-digestion and malabsorption (e.g., the fat-soluble vitamins A, D, E, and K, and othermicronutrients such as carotenoids); and thenegative protein balance, muscle wasting, andincreased respiratory work of those patientswith advancing CF lung disease (33). Earlyinsulin therapy for those with abnormal glu-cose tolerance tests, aggressive use of high-calorie supplements, optimization of pancreaticenzyme supplementation, and early interven-tions with strategies such as nocturnal G-tubefeedings are routinely used. These measuresunderscore the importance of the multi-disciplinary approaches adult CF centers usein engaging the issue of preserving pulmonaryfunction in CF patients.

Pulmonary ExacerbationsThe airways of CF patients are continually

colonized and frequently infected. A CFpatient’s quality of life is affected adversely bythe number of infectious exacerbations he orshe experiences. However, there will also beperiods of more intense inflammatory-immunesystem activations with accompanying clinicalsymptoms and signs. These include changes inthe amount, color, or viscosity of respiratory-tract secretions; increased breathlessness; fever;chest discomfort; appearance of new patho-gens on sputum culture; weight loss; and pul-monary-function decline. Chest X-ray changesare also used to identify periods of acute exac-erbation and in the selected patient, high-resolution computed tomography (HRCT) cancontribute to the delineation of specific CF-related bronchopulmonary pathologies andappropriate management. An acute decrease inFEV1 and weight are frequently seen, alongwith objective evidences of increased inflam-



matory-immune responses, such as increasedleukocytosis in peripheral blood.

Therapeutic strategies to interrupt the viciouscycle of infection, inflammation, and airwaydamage include intensification of all modes oftherapy, including aggressive targeted sys-temic antibiotic administrations, more vigor-ous chest physiotherapy, and aggressivenutritional supports with temporary and judi-cious use of antiinflammatory agents. Suscep-tibility testing of P. aeruginosa isolates in CF isnot closely related to parenteral antibioticeffectiveness and clinical outcome (34) andrecent strategies emphasize a possible role forsynergy testing among the various antipseudo-monal antibiotics. It is important to rememberthat the pharmacokinetics of many drugs arealtered in CF patients and that effective two-drug therapy should be routinely used in thetreatment of the majority of CF patients har-boring P. aeruginosa.

Adult patients with CF invariably encoun-ter more complicated pulmonary aspects oftheir disease, the most common of which arereviewed in the following sections.

Burkholderia cepaciaBurkholderia cepacia (formerly classified as a

P. cepacia) is a potentially highly virulentorganism that is recognized to cause acceler-ated progressive airway disease in CF patients.A major problem in combating B. cepacia infec-tions is the organism’s resistance to a widerange of antibiotics, including antimicrobialpeptides. Although B. cepacia colonization isassociated with an accelerated decline in CF,specific genomovars are not predictive of rapiddecline. In some cases B. cepacia-infected patientsmay develop B. cepacia syndrome, with symp-toms that include intense inflammatory-immune system activations, invasion of theorganism into parenchymal lung tissues, andeven bacteremia, impressive leukocytosis, andrapid clinical deterioration. The B. cepacia geno-movan III strain is considerably more virulent

in this regard and along with the level of FEV1

reduction represents one of the strongest pre-dictors of survival in adult CF populations.Cross-infection of CF patients harboring thisorganism is of concern for CF centers and alongwith resistant pseudomonas have changed theperspective of infection-control policies rel-evant to CF patients (35). Further studies areneeded to unravel the virulence factors andtreatment strategies that could be effective inthe treatment of this potentially devastatingcomplication.

Resistant PseudomonasAlthough various bacterial airway infec-

tions wax and wane during childhood years,most adult CF patients eventually becomeinfected with P. aeruginosa, which becomestheir dominant organism. Moreover, the earlyhost airway-defense systems have usuallyactivated stress responses in the organism,which have forced its mutation into mucoidvariants of the colonizing strain. As in patientswith non-CF-related bronchiectasis, persistentairway P. aeruginosa colonization is detrimen-tal and leads to accelerated rates of pulmonary-function decline. Although no current therapyeffectively eradicates this organism (or termi-nate the elicited inflammatory response), themagnitude of the airway colonization can beinfluenced by effective antibiotic administra-tions. However, continued progressive infec-tion and aggressive antibiotic administrationsselect progressively resistant organisms. Resis-tant strains point out the need for improvedantibiotics and prevention of epidemic spreadamong patients.

Better understandings of the mechanism ofP. aeruginosa resistance and complex biology inprotective aggregated microcolonies (biofilmcommunities) in the lungs of CF patients holdthe key to the development of new and noveltherapies for this resistant infection. Theseunderstandings are expected to be availablesoon as a result of the complete uncoding of



the pseudomonas genome (36), which hasintensified research activities of pathogenicmechanisms of this organism (37,38).

MRSAStaphylococcus aureus is not infrequently

cultured from CF patients’ sputum and inadults it is frequently methicillin-resistant(MRSA). Because most of these patients haveassociated P. aeruginosa airway infections, it isdifficult to clearly ascribe the specific patho-logical significance of MRSA. There is somedata suggesting that patients with concurrentP. aeruginosa and MSRA infection are likely tohave a more rapid decline in pulmonary func-tion (39). Although there are reports of success-ful aggressive treatment with vancomycin;linezoid; or prolonged treatment with oralagents including rifampin, antibiotic nasalointments, and skin decontamination mea-sures, in most cases the MRSA remains chroni-cally present. There is a paucity of dataregarding not only the efficacy of treatmentstrategies but also the precise contribution thatthis organism makes to lung-function deterio-ration in CF.

Environmental MycobacteriaPatients with chronic airway disease are

susceptible to airway colonization by environ-mental mycobacteria, which are ubiquitous inthe environment and have a predilection forwater supplies, including hot tubs. Theseorganisms are not infrequently cultured fromthe respiratory tract of adult CF patients. Theprevalence of such species as M. avium com-plex (including M. avium and M. intracellulare),M. abscessus, M. fortuitum, and M. kansasii, aswell as various untyped organisms, seems tobe increasing, probably owing to the increas-ing survival in CF, increasing awareness of thesignificant contribution their presence makesto CF lung disease progression, and the use ofmore sophisticated diagnostic techniques(40,41). The challenge is to distinguish between

their presence in the airway secretions andtheir pathogenic infection of airway and paren-chymal tissues. In up to 10–15% of adults withCF, the issue will need to be repeatedlyaddressed (41). Late-stage CF patients morecommonly have their airways colonized bythese organisms and this represents a risk fortheir developing early and late intrathoracicdisease following lung transplantation.

CF sputum samples should be periodicallystained and cultured for acid-fast organisms. Ifsuch organisms are found, increased vigilancethat they may be contributing to the CF lungdisease is appropriate. Parameters such as per-sistence of the organism in the sputum; increas-ing symptoms, including unexplained fevers,increasing sputum color, or volume; decreasingpulmonary functions; or radiographic evi-dence of infection including nodularity, cysts,or cavities or tree-in-bud infiltrates on HRCTscanning, suggest the need for treatment (40).If there is no other reason for clinical deteriora-tion in CF patients, it is important to considerthe possibility of environmental mycobacterialdisease and to start appropriate diagnosticmeasures and treatment.

As for tuberculosis, drug susceptibilities ofthe environmental mycobacterial strain areimportant. Some strains may have multidrugresistance (MDR) (especially M. abscessus andM. fortuitum), and it is often problematic toeradicate multiresistant organisms. Once spe-cific choices of drugs are chosen, attentionmust be given to correct drug dosing based ondrug levels both initially and periodicallyafterwards, and with careful attentions to aller-gic sensitization and to toxicities. Useful drugsfor the treatment of these organisms includeclarithromycin or azithromycin, cefoxitin,aminoglycosides, and kanamycin. Unfortu-nately, some of the drug regimens have to beadministered intravenously. Treatment dura-tion should be continued for up to a year fromthe sputum becoming negative for acid-fastorganisms, and these patients may harbor dif-



ferent acid-fast species over time, not all ofwhich will represent true infection (41).

Allergic BronchopulmonaryAspergillosis (ABPA)

ABPA develops in 10–20% of CF patientswhen high levels of aspergillis spores andhyphal fragments in the CF respiratory tractlead to the production of specific IgE andrelated proinflammatory cytokine productionand corresponding enhanced airway pro-inflammatory responses (40,41). It is manifestby a history of atopy or wheezing, pulmonaryinfiltrates, airway fibrosis, or a rapid decline inpulmonary function not attributable to anotheretiology. The specific diagnosis of ABPA in CFis often difficult and delayed because, like thecase for environmental strains of mycobacteria,many of the diagnostic presentations overlapwith other common manifestations of CF. Labo-ratory criteria include elevated total serum IgE,elevated specific IgE and IgG antibodies to A.fumigatus, positive cultures, and suggestivenew pulmonary infiltrates on chest X-ray thatimprove in response to steroids (42). Treatmentconsists of systemic steroids to attenuate theactive inflammatory-immune processes anditraconazole to decrease the antigenic stimulusand fungal burden. In the management ofchronic recurrent ABPA, increasing attentionis being given to the latter strategy because ofthe predisposition of patients with CF to haveco-existing diabetes and/or osteoporosis. AConsensus Conference report has recentlybeen issued on this topic by the CF foundation(42a).

Pneumothorax and HemoptysisPneumothorax is a common complication

in CF patients, increasing with age and moreadvanced disease. It remains a significantcause of serious morbidity, with an incidenceof approx 15%. These patients typically havesevere CF lung disease with low FEV1s, chronicpseudomonas infections, suboptimal nutrition

with low body mass indexes (BMIs), and notinfrequently indwelling lines for iv antibiotics.On occasion, asymptomatic pneumothoracescan be noted on chest X-rays, and conservativetreatment is often successful in those cases (43).

Symptomatic pneumothorax usuallyrequires an invasive procedure. This raises adilemma with regards to management strate-gies, in that aggressive pleurodesis may com-promise future lung transplantation. Althoughiatrogenic pneumothorax can be successfullytreated by chest tube-drainage alone, there is ahigh rate of recurrence in spontaneous pneu-mothorax in CF patients without pleurodesis.Although rigorous comparative data is lacking,in patients with moderately advanced CF lungdisease video-assisted thorascopic surgery(VATS) under general anesthesia with limitedthorascopic doxycycline or talc poudrage fol-lowed by immediate suction represents a pru-dent management strategy. On infrequentoccasions, CF patients can die acutely as a con-sequence of pneumothorax.

Blood-tinged sputum, often present inpatients with CF, increases in patients withsevere-stage disease and during infective exac-erbations. Medical treatment of more acutehemoptysis includes correction of any coagu-lation defects (with vitamin K and fresh-frozenplasma) and aggressive antibiotic treatment ofongoing infection. In massive hemoptysis(>240 mL/d), treatment includes attempts tolocalize the site of bleeding by history (thepatients often experience a sensation of gur-gling in a particular part of the chest and thismay be a reliable guide) (44). Alternatively, thesite of bleeding can often be approximated bychest X-ray and, if in doubt, by bronchoscopy.The affected lung should be kept dependentand selective intubation considered for patientswhose bleeding cannot be otherwise managed.Bronchial artery embolization is a definitivetreatment with a low risk of complications,which include chest pain, bronchial necrosis,and very rarely paraplegia (44).



Critical Care, Dying, and Death IssuesWhen the need of intensive care arises for

individual patients with CF, it is often difficultto determine whether this is appropriate(45,46). For clear-cut partially or wholly revers-ible issues, such as management of acute exac-erbation, hemoptysis, and pneumothorax, it isclearly indicated. However, many critically illpatients with CF have end-stage disease and itwould be inappropriate to extend the dyingprocess, especially if lung transplantation isnot a possibility.

Noninvasive ventilation strategies areincreasingly being used for those patients withsubacute presentations in respiratory failure(47), which may have some reversible compo-nent with more intensive antibiotic, physio-therapy, and nutritional treatments. Theintroduction of noninvasive ventilation strate-gies in the management of outpatients withprogressive degrees of hypercapnia on O2

therapy is also finding increasing application,maintaining patients to transplantation inthose accepted into transplant programs, andin others offering long-term stabilization of res-piratory failure and possibly improving sur-vival. It is beneficial for decisions as to theappropriate aggressiveness of in-hospital treat-ment strategies be made in a milieu of trustingrelationships between patients, their relatives,and the managing CF care team. As with allpatients, open discussions of dying and deathissues need to be addressed with both the CFcare team and the CF patient and his/her sup-port system.

Lung TransplantationProgressive severe pulmonary disease rep-

resents by far the primary cause of mortality inCF. CF is the second most common indicationfor lung transplantation (48). Identification ofappropriate patients with CF who are candi-dates for lung transplantation remains com-plex, largely because the identification ofpatients with CF most likely to benefit from

lung transplantation is not precise. It is likelythat individual assessment criteria that extendbeyond absolute values of FEV1 and individualaverage rates of decline will be eventuallyclosely predictive of either 2-yr mortality or theoptimal time of lung-transplantation listing(49). The unpredictable survival, nonlinearprogression, MDR infection issues with suchorganisms as P. aeruginosa and B. cepacia andmarginal nutritional status, and 2-yr waitinglists make it a challenging decision for physi-cian, families, and patients (48,50). However,for the foreseeable, future lung transplanta-tion remains the only definitive option for theseverely advanced CF patient (51). Not surpris-ingly, lung transplantation-related deaths havebecome the second most common cause ofdeath in CF patients (48).

Newer Therapies on the HorizonNovel Antibacterial Approaches

Chronic persistent airways infection remainsthe major clinical challenge in CF in spite of theever-increasing spectrum of antibiotics becom-ing available to CF clinicians. Approachesdesigned to prevent early infection (such aspseudomonas vaccination); to modify meta-bolic pathways leading to increased antimicro-bial resistance; to modify adherence, mucoidtransformation, and biofilm formation; and toincrease bacterial killing by utilizations of newclasses of antimicrobial therapeutic agents,such as defensins, are activity being pursued.This research is greatly assisted by the avail-ability of genomic data (6).

Antiinflammatory AgentsA great deal of emphasis is currently being

placed on research and clinical translation onthe inflammatory aspects of diseases of the air-ways, including asthma and chronic obstruc-tive pulmonary disease (COPD), and certainlyCF warrants inclusion. There exists much evi-dence that overly zealous inflammatory-immune responses to the abundant organisms



residing in CF airways contribute to the pro-gressive airway and parenchymal lung-tissueinjury and remodeling characteristic of CF lungdisease (17,18). CF-related pancreatic diseaseand the attendant high incidence of diabetesmellitus and CF-related osteoporosis (in partowing to steroid use to treat severe exacerba-tions and ABPA) also play a role. Nonsteroidalantiinflammatory drugs (NSAIDs) have beenadvocated but require monitoring of blood lev-els and potentially contribute to the alreadyprevalent gastrointestinal (GI) tract manifesta-tions of CF. Leukotriene and PDE4 inhibitorsand compounds that modify chemokine andcytokine via specific receptor and/or signal-transduction pathways represent novelapproaches for treating inflammatory-immuneaspects of airway diseases, but have yet to berigorously studied in CF (6,52,53).

Antioxidants and AntiproteasesThe chronic persistent respiratory-tract

infections and overly exuberant activation ofhost inflammatory-immune processes, whichrepresent the paramount pathobiological fea-tures in CF, are accompanied by overproduc-tions of reactive oxygen species (ROS), nitricoxide (NO), proteases, and defensins, whichare helpful in airway antimicrobial defenses,but under conditions of excess are believed toinjure the lungs. There is abundant evidencefor oxidative stress at CF airway surfaces (54–57). This altered redox milieu is widely believedto cause not only oxidative damage to macromo-lecular tissue constituents, but also to potentiallybe transduced into intracellular compartments.This may alter signal-transduction pathways,such as the NF-kB pathway and activation ofapoptotic pathways. Because respiratory-tractepithelial cells are exposed to a higher oxygentension than the cells of other organ systems, ithas repeatedly been argued that they shouldrequire a more active protective antioxidantsystem.

Although attentions toward treating thecausative infection and the overexuberant

inflammatory responses are paramount(17,21,58,59), systemic and/or local airwaydeliveries of antioxidant and antiproteasetherapeutic approaches have yet to be rigor-ously evaluated. However, because alpha-tocopherol (vitamin E) deficiency results inexcessive phagocytic responses while repre-senting a most important lipophilic membraneantioxidant (60), it seems prudent to at leastmaintain normal plasma levels of this antioxi-dant micronutrient with supplements.

Because inflammatory reactions are univer-sally associated with pro-oxidative stresses, thepotential for an effective antioxidant-enzymetherapy to reduce the consequences of inflam-matory-airway diseases has been recognizedsince the discovery of superoxide dismutase(SOD). Although the major contributor toinflammation-based oxidative stress remainsactivated phagocyte NADPH oxidases, the rec-ognition that this family of membrane-associ-ated proteins are responsible for generatingROS (e.g., superoxide ion and hydrogen per-oxide) in a wide variety of other cells, largelyfor purposes of cell signaling, complicatestheoretical constructs that augmentations ofindubitable evidences of oxidative stress atsuch sites (24).

The goal of reducing undesired conse-quences of inflammation by the antioxidantenzymes and their modified constructs and“mimics” has remained thus far elusive forclinical research. Nonetheless, there are severalanimal models of inflammatory lung damagethat have been ameliorated by the administra-tion of such agents (61,62). The observation thatglutathione (GSH) is reduced in bronchoalveolarlavage (BAL) fluids and plasma (63) but not redblood cells (RBCs) (64), and that CFTR anionicchannels may play a role in cellular GSH secre-tion (e.g., GS–) (65), has kindled interest inadministrations of thiols in these patients (66).Although it is true that intracellular GSH playsan important role in detoxification pathways(including some products of lipid peroxidation)and is a major regulator of cellular thiol-



disulfide redox state, its role in extracellularfluids such as the airway-surface fluids ispoorly characterized. To date, there is little evi-dence that intracellular levels of GSH arereduced in CF (64,65).

Because the pro-oxidative environment inthe endoplasmic reticulum (ER) and the relatedformation of disulfide bonds is critical for theproduction of correctly folded secretory andmembrane proteins (such as CFTR), it is notaltogether clear whether creation of supernor-mal intracellular GSH concentrations would behelpful in CF. In addition, airway surfacesalready are coated with great excesses of thiolsvia the large amounts of mucus glycoproteins,which themselves represent a potent antioxi-dant substance (67). Furthermore, the alginatesecreted by mucoid strains of Pseudomonasrepresent another potential antioxidant at theairway surface of CF patients and may be pro-tecting the microbe from the oxidant-generat-ing antimicrobial activity of phagocytes.

The possible redox activation of the “free”iron known to be present in CF airway secre-tions, and the possible further activations ofalready hyperactive inflammatory-immuneprocesses, represent other possible concerns intherapeutic attempts to augment airway-sur-face “antioxidants” in CF. Nonetheless, therecurrently is a lack of a substantive theoreticalconstruct and insufficient evidence supportingstrategies focused on increasing antioxidantsubstances, including thiols, in the extracellu-lar airway-lining compartment. It is clear thatmore basic and clinical research is neededbefore widespread uses of antioxidant thera-peutic strategies are universally instituted inCF patients.

In theoretical constructs of the pathogen-esis of inflammation-related respiratory-tractinjury, it is important not to overlook the neu-trophil nonoxidative mechanisms of damagingairway epithelial cells (68).

For example there is abundant evidence ofproteolytic stress at CF airway surfaces(22,23,25). However, as is the case for antioxi-

dants, there are no rigorously controlled trialsdocumenting the therapeutic efficacies of aug-mentation of antiprotelytic pathways in CF.

As for defensins, most of the CF literaturehas focused on the possible role of defensininactivity in CF (69,70). However, at the site ofintensive inflammation, there is the possibilitythat overabundances of defensins, known tomodulate inflammatory-immune processes,could injure host tissues (71,72).

Modulations of the Airway-Surface FluidIon Transport

Therapeutic strategies designed to directlystimulate airway chloride-ion secretion, via stim-ulations of membrane-bound CFTR or bystimulation of other potentially available chlo-ride-transport pathways, are being currentlytested, as are strategies to inhibit excessiveairway absorptions of sodium ion (6). Oneintriguing approach has been to use the anti-biotic anion channel forming squalamine toincrease cell chloride ion transports (72a).Osmotically active sugars and hypertonic sa-line are other modifiers of airway surface fluidcomposition and may increase mucociliarytransport in CF.

Nongenomic Modulationsof CFTR Function

Discovery of CFTR and its cellular traffick-ing has opened new avenues for pharmaco-logical interventions designed to modulatepathways which would have the overall effectof increasing airway-cell CFTR functions, suchas CFTR correctors, which move CFTR frominside the cell to the cell surface, or CFTRpotentiators, which open up defective CFTR.In Class I defects, which do not make anyCFTR, it has been shown that gentamicin pos-sess the ability to bind to rRNA and skip overthe stop mutation, leading to translation ofnative CFTR. Administrations of this amino-glycoside have been shown to increase respira-tory-tract CFTR in human airways by bothimmunocytochemical and functional tech-



niques (73,74), in CF patients with Class I butnot with other classes of mutation. Clinical tri-als using this strategy are ongoing. Severaldifferent approaches aimed at increasing thetrafficking of the Class II misprocesseddeltaF508del up to apical-cell surfaces are under-way, facilitated by the development of a rapid-screening method (6). Flavonoids such asgenistein, apigenin, and benzoflavone, selectedxanthines, and IBMX are among the com-pounds under study (75). These approaches arealso undergoing testing in CFTR proteins withdefects in the other classes.

Gene- and Cell-Replacement TherapyAlthough given a great boost by the discov-

ery of the CF gene for CFTR over a decade agoand successful experimental CFTR gene trans-fer into tissue-culture cells and even humanrespiratory-tract epithelial cells (6), medicalscience is a long way from translating thesebasic findings into the safe and efficacioustreatment of CF patients. Major problems includethe targeting of the gene-transfer unit to theappropriate respiratory-tract epithelial cellsdeficient in CFTR, the known inflammatory-immune response that is probably elicited bymany of the vectors used to carry the gene intothe cell, the possibility that misplacedinsertions into the genome could induce can-cer, the seemingly prohibitive potential costsof repeated CFTR gene applications into respi-ratory-tract epithelial cells with active cell turn-over, and the practicalities of assessing notonly parameters of successful molecular trans-fer but also clinical efficacy. The field of stem/progenitor cell biology and the use of stem cellsto repopulate the cells of different organs,including respiratory-tract epithelial cells (76)represents another challenging basic researchstrategy that may someday find a therapeuticapplication in CF (77).

References1. Franconi, G., Uehlinger, E., and Knauer, C. (1936),

Wien Med Wochenschr 86, 753–756.

2. Anderson, D.H. (1938), Am J Dis Child 56, 344–399.3. Matthews, L.W., Doershuk, C.F., Wise, M., et al.

(1964), J Pediatr 65, 558–575.4. Yankaskas, J. and Knowles, M.R. (1999), in Cystic

Fibrosis in Adults. Yankaskas, J. and Knowles, M.R.,eds. Lippincott-Raven, Philadephia.

5. Ratjen, F. and Doring, G. (2003), Lancet 361, 681–689.6. Davies, J.C. (2002), J R Soc Med 95(Suppl 41), 58–67.7. Sheppard, D.N. and Welsh, M.J. (1999), Physiol Rev

79(1 Suppl), S23–S45.8. McKone, E.F., Emerson, S.S., Edwards, K.L., and

Aitken, M.L. (2003), Lancet 361, 1671–1676.9. Merlo, C.A. and Boyle, M.P. (2003), J Lab Clin Med

141, 237–241.10. Hurme, M., Pessi, T., and Karjalainen, J. (2003), Ann

Med 35, 256–258.11. Friedman, K.J., Heim, R.A., Knowles, M.R., and

Silverman, L.M. (1997), Hum Mutat 10, 108–115.12. Miller, P.W., Hamosh, A., Macek, M., Jr., et al.

(1996), Am J Hum Genet 59, 45–51.13. Khan, T.Z., Wagener, J.S., Bost, T., et al. (1995), Am

J Respir Crit Care Med 151, 1075–1082.14. Poschet, J.F., Boucher, J.C., Tatterson, L., et al.

(2001), Proc Natl Acad Sci USA 98, 13,972–13,977.15. Schroeder, T.H., Lee, M.M., Yacono, P.W., et al.

(2002), Proc Natl Acad Sci USA 99, 6907–6912.16. Guggino, W.B. (1999), Cell 96, 607–610.17. De Rose, V. (2002), Eur Respir J 19, 333–340.18. Li, J., Johnson, X.D., Iazvovskaia, S., et al. (2003),

Am J Physiol Lung Cell Mol Physiol 284, L307–L315.19. Parad, R.B., Gerard, C.J., Zurakowski, D., et al.

(1999), Infect Immun 67, 4744–4750.20. Kelley, T.J. and Drumm, M.L. (1998), J Clin Invest

102, 1200–1207.21. Witko-Sarsat, V., Sermet-Gaudelus, I., Lenoir, G.,

and Descamps-Latscha, B. (1999), MediatorsInflamm 8, 7–11.

22. Birrer, P. (1995), Respiration 62, 25–28.23. Bruce, M.C., Poncz, L., Klinger, J.D., et al. (1985),

Am Rev Respir Dis 132, 529–535.24. Cross, C.E. (2003), Pediatr Res 53, 365–368.25. O’Connor, C.M., Gaffney, K., Keane, J., et al. (1993),

Am Rev Respir Dis 148, 1665–1670.26. Regnis, J.A., Robinson, M., Bailey, D.L., et al. (1994),

Am J Respir Crit Care Med 150, 66–71.27. Hardy, K.A. (1994), Respir Care 39, 440–455.28. Houtmeyers, E., Gosselink, R., Gayan-Ramirez, G.,

and Decramer, M. (1999), Eur Respir J 14, 452–467.29. Escotte, S., Tabary, O., Dusser, D., et al. (2003), Eur

Respir J 21, 574–581.30. App, E.M., Baran, D., Dab, I., (2002), Eur Respir J 19,

294–302.31. Antonicelli, F., Parmentier, M., Drost, E.M., et al.

(2002), Free Radic Biol Med 32, 492–502.32. Gorrini, M., Lupi, A., Viglio, S., et al. (2001), Am J

Respir Cell Mol Biol 25, 492–499.33. Dowsett, J. (2000), Nutrition 16, 566–570.34. Smith, A.L., Fiel, S.B., Mayer-Hamblett, N., et al.

(2003), Chest 123, 1495–1502.



35. Jones, A.M., Govan, J.R., Doherty, C.J., et al. (2003),Thorax 58, 525–527.

36. Stover, C.K., Pham, X.Q., Erwin, A.L., et al. (2000),Nature 406, 959–964.

37. Lambert, P.A. (2002), J R Soc Med 95(Suppl 41), 22–26.38. Tsang, K.W., Shum, D.K., Chan, S., et al. (2003), Eur

Respir J 21, 932–938.39. Wilson, K., Schuster, D., Rosenbluth, D., and

Ferkol, T. (2003), Am Resp Crit Care Med 167, A918.40. Olivier, K.N., Weber, D.J., Lee, J.H., et al. (2003), Am

J Respir Crit Care Med 167, 835–840.41. Ebert, D.L. and Olivier, K.N. (2002), Clin Chest Med

23, 655–663.42. Skov, M., Koch, C., Reimert, C.M., and Poulsen,

L.K. (2000), Allergy 55, 50–58.43. Curtis, H.J., Bourke, A.D., and Gascoigne, A.D.

(2003), J Cystic Fibrosis 2, S49.44. Brinson, G.M., Noone, P.G., Mauro, M.A., et al.

(1998), Am J Respir Crit Care Med 157, 1951–1958.45. Sood, N., Paradowski, L.J., and Yankaskas, J.R.

(2001), Am J Respir Crit Care Med 163, 335–338.46. Thomas, S., Evans, T., and Geddes, T. (2000), Pediatr

Pulmonol 20(Suppl), 292.47. Madden, B.P., Kariyawasam, H., Siddiqi, A.J., et al.

(2002), Eur Respir J 19, 310–313.48. Liou, T.G., Adler, F.R., Cahill, B.C., et al. (2001),

JAMA 286, 2683–2689.49. Mayer-Hamblett, N., Rosenfeld, M., Emerson, J., et

al. (2002), Am J Respir Crit Care Med 166, 1550–1555.50. Yankaskas, J.R. and Mallory, G.B., Jr. (1998), Chest

113, 217–226.51. Noone, P.G. and Egan, T.M. (2002), Am J Respir Crit

Care Med 166, 1531–1532.52. Conway, S.P., Etherington, C., Peckman, D.G., and

Whiteheah, A. (2003), J Cystic Fibrosis 2, 25–28.53. Eidelman, O., Srivastava, M., Zhang, J., et al. (2001),

Mol Med 7, 523–534.54. van der Vliet, A., Eiserch, J., Marelich, G.P., et al.

(1996), Pharmacology 38, 491–513.55. Brown, R.K., Wyatt, H., Price, J.F., and Kelly, F.J.

(1996), Eur Respir J 9, 334–339.56. McGrath, L.T., Mallon, P., Dowey, L., et al. (1999),

Thorax 54, 518–523.57. Morrissey, B.M., van der Vliet, A., Eiserch, J., and

Cross, C.E. (2003), in Redox-Genome Interactions inHealth and Disease. Fuchs, J., Podda, M., and Packer,L., eds. Marcel Dekker, New York, pp. 261–283.

58. Konstan, M.W, and Berger, M. (1997), PediatrPulmonol 24, 137–142.

59. Grisham, M.B. (2000), Trends Pharmacol Sci 21,119–120.

60. Cachia, O., Benna, J.E., Pedruzzi, E., et al. (1998), JBiol Chem 273, 32,801–32,805.

61. Kinnula, V.L. and Crapo, J.D. (2003), Am J RespirCrit Care Med 167, 1600–1619.

62. Gao, B., Flores, S.C., Leff, J.A., et al. (2003), Am JPhysiol Lung Cell Mol Physiol 284, L917–L925.

63. Roum, J.H., Buhl, R., McElvaney, N.G., et al. (1993),J Appl Physiol 75, 2419–2424.

64. Mangione, S., Patel, D.D., Levin, B.R., and Fiel, S.B.(1994), Chest 105, 1470–1473.

65. Gao, L., Kim, K.J., Yankaskas, J.R., and Forman, H.J.(1999), Am J Physiol 277, L113–L118.

66. Hudson, V.M. (2001), Free Radic Biol Med 30,1440–1461.

67. Cross, C.E., Halliwell, B., and Allen, A. (1984), Lan-cet 1, 1328–1330.

68. Lee, W.L. and Downey, G.P. (2001), Am J Respir CritCare Med 164, 896–904.

69. Smith, J.J., Travis, S.M., Greenberg, E.P., andWelsh, M.J. (1996), Cell 85, 229–236.

70. Ko, Y.H., Delannoy, M., and Pedersen, P.L. (1997),FEBS Lett 405, 200–208.

71. Yang, D., Biragyn, A., Kwak, L.W., and Oppen-heim, J.J. (2002), Trends Immunol 23, 291–296.

72. Ganz, T. (2002), J Clin Invest 109, 693–697.72a. Jiang, C., Lee, E.R., Lane, M.B., et al. (2001), Am J

Physiol Lung Cell Mol Physiol 1281, 1164–1172.73. Wilschanski, M., Famini, C., Blau, H., et al. (2000),

Am J Respir Crit Care Med 161, 860–865.74. Clancy, J.P., Bebok, Z., Ruiz, F., et al. (2001), Am J

Respir Crit Care Med 163, 1683–1692.75. Caci, E., Folli, C., Zegarra-Moran, O., et al. (2003),

Am J Physiol Lung Cell Mol Physiol 285, L180–L188.76. Krause, D.S., Theise, N.D., Collector, M.I., et al.

(2001), Cell 105, 369–377.77. Hochedlinger, K. and Jaenisch, R. (2003), N Engl J

Med 349, 275–286.

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