Cystic Fibrosis

INTRODUCTION

Cystic fibrosis (CF) is a multisystem disorder affecting children and, increasingly, adults.1 CF is characterizedchiefly by chronic airways obstruction and infection and by exocrine pancreatic insufficiency with its effects on gas-trointestinal function, nutrition, growth, and maturation.This condition is the most common life-threatening genetictrait in the white population.2 Numerous mutations of asingle gene are responsible for the CF syndrome and forvariations in its severity. The gene encodes a membraneprotein called the cystic fibrosis transmembrane regulator(CFTR). CFTR functions in many tissues as a kinase-regulated Cl- channel. In some tissues, CFTR also regulatesthe activity of other ion channels. Typically, mutations inCFTR affect both of these functions.

Cystic fibrosis is an important medical problem for anumber of reasons. It is the major source of severe chroniclung disease in children and has become an important causeof morbidity and mortality from chronic lung disease inyoung adults. CF is responsible for most cases of exocrinepancreatic insufficiency in childhood and early adulthoodand for many cases of nasal polyposis, pansinusitis, rectalprolapse, nonketotic insulin-dependent hyperglycemia, andbiliary cirrhosis in these age groups. Therefore, CF entersinto the differential diagnosis of many pediatric and youngadult patients. Finally, research advances have introducedthe challenge of designing pharmacologic and gene trans-fer therapies to combat the broad range of manifestationsand complications.

Central to CF diagnosis and care is a carefully integratedand closely monitored network of approximately 115 refer-ral centers in the United States sponsored by the CysticFibrosis Foundation. The Foundation also supports asmaller number of multidisciplinary research centers aimedat elucidating the molecular pathophysiology and improv-ing the quality of life for patients with CF. Similar care and research centers are found in Canada and in many European countries.

HISTORICAL PERSPECTIVES

Cystic fibrosis was first described as a distinct clinical entityin the late 1930s. However, numerous references to infantsand children with meconium ileus and characteristic pan-creatic and lung diseases are sprinkled throughout the lit-erature from as early as 1650. Of interest are references inEuropean folklore to the association of salty skin and earlydemise.3 Dorothy Andersen, a pathologist at Babies Hospi-tal in New York City, is usually credited with the first com-prehensive description of CF in 1938.4 She coined the termcystic fibrosis of the pancreas. In 1945, Farber suggested thatCF is a disease of exocrine glands, characterized largely byfailure to clear their mucous secretory product.5 He intro-duced the term mucoviscidosis, which was used for a numberof years. Chronic infection of the lungs was recognized earlyas a major contributing factor, and antibiotics were first usedfor the treatment of CF in the 1940s. At the same time, an autosomal-recessive inheritance pattern for CF was

38

IntroductionHistorical PerspectivesEpidemiologyGenetic BasisPathology

Lung PathologyOther Respiratory Tract PathologyNonrespiratory Pathologic Features

PathophysiologyCystic Fibrosis Transmembrane Regulator Protein:

Structure, Metabolism, and FunctionAbnormal Airway Mucosal Salt and Water TransportActive Ion Transport Properties of Airway EpitheliaMucin Macromolecule Secretion in the Cystic Fibrosis

AirwayPathophysiology of Infection

Clinical ManifestationsLower Respiratory Tract DiseaseUpper Respiratory Tract DiseaseComplications of Respiratory Tract DiseaseGastrointestinal ManifestationsPancreatic DiseaseHepatobiliary DiseaseGenitourinary Tract AbnormalitiesSweat Gland Dysfunction

DiagnosisTreatment

Ambulatory CareHospital Therapy

Course of the Disease and PrognosisSummary

1217

Cystic FibrosisRichard C. Boucher, M.D., Michael R. Knowles, M.D.,

James R. Yankaskas, M.D.

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1218 Section J • OBSTRUCTIVE DISEASES

suggested by Andersen and Hodges.6 In 1953, di Sant’Ag-nese and colleagues investigated salt depletion in childrenwith CF during a summertime heat wave and concludedthat excessive loss of salt occurred via sweat.7 Subsequently,they documented that sodium and chloride levels in sweatare elevated in virtually all (>98%) persons with CF. Thisobservation led to a description by Gibson and Cooke ofthe pilocarpine iontophoresis method for sweat testing,8 amethod that remains the diagnostic standard to this day. Bythe late 1950s, CF was reported occasionally in older chil-dren and young adults. Soon thereafter, comprehensive andaggressive approaches to the care of patients were institutedin many treatment centers, and these approaches have beencredited with the survival into adulthood of a steadilyincreasing number of patients with CF. In the past 40 years,a markedly refined description of the CF syndrome and themany related complications has emerged.

Several recent observations have resulted in partial under-standing of CF pathogenesis at a molecular level. In theearly 1980s, epithelial physiologists described abnormalitiesof both sodium and chloride transport by CF respiratoryepithelia9 and the chloride impermeability of sweat glandducts in patients with CF.10 These observations focusedattention on a pathogenetic role for abnormal electrolyteand water movement across CF epithelia. From 1985 to1987, geneticists, using restriction fragment length poly-morphism analysis, located the CFTR gene on the long armof chromosome 7.11–14 Shortly thereafter, the CFTR genewas isolated, cloned, and sequenced,15 and the major muta-tion of this gene was characterized.16 Transfer of a wild-type(normal) gene into CF cells corrected the chloride trans-port defect.17,18 The product of the CF gene, the CFTR,was studied and found to be both a Cl- channel19–21 and aregulator of other channels.22,23 Studies of the metabolismof CFTR suggested that mutations could lead to abnormalfolding and mislocation of the protein.24–26 Knockout of theCFTR gene in transgenic mice has provided an animalmodel that possesses several physiologic and clinical simi-larities to human CF.27–30 These observations provided adetailed understanding of CFTR structure and function andhave laid the groundwork for development of more specifictherapeutic interventions, including gene therapy.

EPIDEMIOLOGY

Cystic fibrosis is recognized in approximately 1:250031 and1:17,00032 live births in white and black populations,respectively, in the United States. The range of reportedincidence figures worldwide varies from 1:56933 in a confined Ohio Amish population to 1:90,000 in an Asianpopulation of Hawaii.34

Generally, mutations of the CF gene are most prevalentin northern and central Europeans and in persons whoderive from these areas. An intermediate incidence is likelyalthough less well documented in non-European whites. CFis considered rare in American Indians, Asian populations,and black natives of Africa. It has been suggested that therelatively low frequency in populations living in tropical andsemitropical geographic locations is related to adverse con-sequences in the past from excessive salt loss in heterozy-gotes as well as homozygotes for the CF gene. In white

populations, 2% to 5% are carriers of a CF gene mutation.These people have no clinical stigmas of CF. Although anumber of chemical or physiologic alterations have beendescribed in heterozygotes, these alterations can be identi-fied only on a statistical basis.

GENETIC BASIS

Cystic fibrosis is an autosomal-recessive trait resulting frommutations at a single gene locus on the long arm of chro-mosome 7.2,31 This locus spans approximately 250 kB ofDNA, contains at least 27 exons, and codes for a largeprotein that has several transmembrane domains, two cyto-plasmic nucleotide (ATP) binding folds, and numerousphosphorylation sites containing a cytoplasmic regulatory(R) domain (Fig. 38.1). The primary and secondary struc-ture of the protein product of the CF gene resembles othermembrane proteins that act as pumps [e.g., the ATP-binding cassette (ABC) transporters].15

The predominant CFTR mutation is a 3-bp deletion thateliminates the phenylalanine of CFTR at position 508, theso-called DF508 mutation.16 This deletion has been detectedin 66% of more than 20,000 CF patient chromosomes analyzed worldwide,2,31,35 but its prevalence varies consider-ably from population to population (Table 38.1). Ingeneral, DF508 is more prevalent in northern Europeanthan southern European or in Middle Eastern popula-tions.31 More than 1000 other mutations of the CF genehave been reported but all at a relatively low frequency. The occurrence of known mutations accounts for only 90%of all CF gene abnormalities.31 CFTR mutations includeother deletions, missense mutations, nonsense mutations,frameshift mutations, and introduction of new splice sites.31

Correlations between genotype and phenotype are begin-ning to emerge. For example, homozygosity for the DF508mutation almost always confers exocrine pancreatic insuffi-ciency.32 A severe phenotype, including meconium ileus andliver disease, is strongly associated with the presence of two“severe” (i.e., pancreatic exocrine insufficiency) alleles.36–38

A region on human chromosome 19q13 has recently beenidentified as a modifier locus for meconium ileus.39 Con-flicting data exist on whether DF508 homozygosity versusother severe alleles is associated with a more severe form of

Table 38.1 Frequency of the DF508 Mutation

Cystic Fibrosis Population Chromosomes (%)

North American Caucasians 76

North American Hispanics 46

United Kingdom 74

Spain 49

Italy 43

Ashkenazi Jews 30

From Leinna WK, Feldman GL, Kerem B, et al: Mutation analysis forheterozygote detection and the prenatal diagnosis of cystic fibrosis. N Engl J Med 322:291–296, 1990.

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chronic lung disease.33 On the other hand, “mild” muta-tions with some residual CFTR function and preservationof pancreatic exocrine function have been identified that areassociated with normal concentrations of sweat chloride,exocrine pancreatic sufficiency, or both.40,41 Moreover, vari-able phenotypes with “mono-organ” disease are also emerg-ing; for example, idiopathic pancreatitis and congenitalbilateral absence of the vas deferens are associated withmutations in the CFTR gene.42–44 In summary, it is nowclear that CF is indeed a syndrome caused by many combi-nations of mutations at a single gene locus, each of whichmay confer a slightly different phenotype.45 The ultimatephenotype of each person with CF is undoubtedly also influ-enced by genetic background (i.e., “modifier genes”46) aswell as postnatal environmental factors.

Deoxyribonucleic acid (DNA) analysis can now be usedto confirm the diagnosis, make prenatal diagnoses, andscreen for carrier status in selected cases. For example,probes for 28 of the most common CF mutations in NorthCarolina provided definitive diagnostic information in fewerthan 90% of persons with CF. Screening for CF carriersusing the DF508 probe identifies only 50% to 60% ofcouples at risk of having a CF child.47

The high frequency of CF gene mutations in many pop-ulations has been ascribed to an unknown heterozygoteadvantage. Some evidence suggests a reproductive advan-tage for the carrier state.48,49 Others have postulated thatreduced capacity to generate a secretory diarrhea inresponse to cholera infection because of diminished intes-tinal chloride transport may have provided a historical survival advantage to heterozygotes.50–52

PATHOLOGY

Soon after the original description of the CF syndrome,Farber pointed out the prominent accumulation of mucusin the respiratory and gastrointestinal tracts.5 Subsequently,mucus stasis has been described in numerous sites, includ-ing the conducting airways of the lung,53 paranasal sinuses,mucus-secreting salivary glands, apocrine sweat glands,small intestine, appendix, pancreas, biliary system, uterinecervix, and wolffian duct structures. However, the eccrinesweat gland, which figures prominently in the pathophysi-ology of CF, is morphologically normal at all ages. Patho-logic changes in the lung, which is the primary site of organdysfunction, also reflect chronic infection.

LUNG PATHOLOGY

It is clear that disease of the conducting airways in CF isacquired postnatally. The airways of children with CF whohave died within the first days of life display only subtleabnormalities. The earliest macroscopic pathologic lesion is reported to be mucus obstruction of bronchioles.53

However, the numbers and distribution of mucus-produc-ing goblet cells and the numbers and size of submucosalglands appear to be within normal ranges at birth. A carefulmorphometric analysis of CF airways early in life demon-strated dilation of submucosal gland acinar and ductallumens before reaction to chronic infection would beexpected.54 This finding suggests that either hypersecretionor, more likely, failure to clear secretions at an early ageaccounts for mucus accumulation in bronchial regions,

121938 • Cystic Fibrosis

R domain

Outside

NH2NBD1

DF508 Mutation

Chargedside chains

Protein kinase C

Protein kinase A

NBD2 CO2H

N-linkedcarbohydrate

Calculated net charge on the CFTR isindicated by color intensity. The darkestpurple is +12 and the darkest gray is –6.

NBD = Nucleotide Binding Domain

ATP bindingdomains

0 +6 +12–6

Figure 38.1 Proposed structure for the cystic fibrosis transmembrane regulator (CFTR) protein. Two repeat segments each consist ofsix transmembrane spans followed by a nucleotide-binding fold (NBF). The segments are joined by a highly charged region thatcontains multiple phosphorylation sites, the R domain. Much of the CFTR is intracytoplasmic. Glycosylation occurs on an extracellularloop of the second motif.

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whereas the mucus retention in bronchioles presumablyreflects the failure to clear mucus secreted by surface secre-tory (goblet) cells. Failure to clear secretions from theairway lumens likely initiates infection.

With the progression of lung disease, evidence for bron-chiolitis and bronchitis becomes more prominent, the submucosal glands hypertrophy, and goblet cells not onlybecome more numerous but also propagate into the bron-chioles. Small airways may be completely obstructed bysecretions (Fig. 38.2).55 Bronchiolectasis and thenbronchiectasis are consequences of persistent obstruc-tion–infection cycles. Bronchiectasis had been thought tomanifest in the second decade of life but now is beingdetected earlier in life with increased use of computedtomography (CT) scans. Pneumonia, when present, gener-ally assumes a peribronchial pattern.

Detailed pathologic descriptions of lung disease are basedon examination of lungs at autopsy or lung transplant, andthey reflect advanced changes.56–59 Bronchiectatic cystsoccupy as much as 50% of the cross-sectional area of thelate-stage CF lung.60 In general, bronchiectasis is moresevere in upper lobes than in lower lobes. In addition todilation of the small airways, bronchioles may be stenoticor even obliterated. The extent of obliterative bronchiolitisappears to be directly correlated with age at death.57 Autop-sied lungs also show extensive overinflation of air spaces.Small amounts of destructive emphysema are seen in manypatients, especially those who have lived for two to threedecades.57 Absence of more extensive alveolar wall destruc-tion can be explained by the confinement of chronic infec-tion to conducting airways. Several patterns of interstitialpneumonia have also been described in autopsied lungs,including usual interstitial pneumonitis, interstitial pneu-monitis with organizing pneumonia, and diffuse alveolardamage.61 Fibrosis is extensive in peribronchiolar and peri-bronchial regions and may contribute to the restrictive lungfunction pattern that is superimposed on obstruction inend-stage lung disease.62 Subpleural cysts often occur on themediastinal surfaces of the upper lobes and are thought tobe related to the frequent occurrence of pneumothorax in

patients with advanced lung disease.63 The bronchial arteries become large and tortuous,64 contributing to apropensity for hemoptysis in ectatic airways. The pulmonaryarteries display varying degrees of change reflecting pul-monary hypertension.

OTHER RESPIRATORY TRACT PATHOLOGY

Hypertrophy and hyperplasia of secretory elements, mucusaccumulation, and chronic inflammatory changes are alsofeatures of the paranasal sinuses and the nasal passages. Acommon feature of nasal pathology is inflammatory edemaof the mucosa with subsequent pedunculation and forma-tion of polyps.65

NONRESPIRATORY PATHOLOGIC FEATURES

Most of the nonpulmonary pathology in CF occurs in thegastrointestinal tract and related organs. Striking changesare seen in the exocrine pancreas.66 Obstruction of ducts byinspissated secretions is an early feature, followed by dila-tion of secretory ducts and acini and flattening of the epithe-lium. Loss of acinar cells is widespread, and areas ofdestruction are replaced by fibrous tissue and fat. Intra-luminal calcifications may occur and may be recognizedroentgenographically. Small cysts are common and gener-ally represent dilated ducts. Inflammatory changes are notprominent. The islets of Langerhans are spared until laterperiods of life. Changes in the islets include disruption byfibrous tissue bands that may provide a barrier betweenhormone-secreting cells and the vascular spaces.67 Patho-logic changes in the pancreas are used occasionally to makea postmortem diagnosis in atypical or missed cases of CF.

The pancreas is abnormal in almost all patients with CFand is virtually destroyed in approximately 90% of CFpatients studied at autopsy. Liver changes are not as fre-quent or consistent.68 In 25% or more of all autopsies,islands of relatively normal parenchymal cells are divided byfibrotic bands, creating a distinctive multilobular appear-ance. Microscopically, this focal biliary cirrhosis is

A B

Figure 38.2 A, Hypertrophied submucosal gland in the trachea of an 18-year-old woman with cystic fibrosis is shown. Mucus-containing acini are distended. The gland occupies almost the entire thickness of the tracheal wall. B, Large and small bronchioles inthe lungs of a 21-year-old man with cystic fibrosis. These airways are completely obstructed with secretions and display chronicinflammation of the walls and surrounding tissues. Peribronchiolar fibrosis also can be demonstrated with appropriate stains. Airspace enlargement is prominent (right), but more normal-appearing peripheral lung architecture is present (left). (A, B: Hematoxylinand eosin stain; ¥42.)

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characterized by inspissation of secretions within the bileductules, bile duct proliferation, inflammatory reaction, anda paucity of evidence for bile stasis. Approximately 30% ofpatients also display fatty infiltration of the liver, whichcannot always be ascribed to malnutrition. In approximately25% of cases, the gallbladder is hypoplastic and contains agelatinous mucus-like material. Cholelithiasis is an increas-ingly frequent observation.

Changes in the intestinal tract itself are less prominent.69

Brunner’s glands of the duodenum are hypertrophied, withdilated ducts and acinar lumens filled with mucus. There islittle if any primary change of the small intestinal tractmucosa. The appendix frequently displays goblet cell hyper-plasia of the epithelium and accumulation of secretionswithin crypts and in the lumen, changes that may be diag-nostic of CF. A number of investigators have claimed theability to diagnose CF by rectal biopsy based on goblet cell hyperplasia and accumulation of mucus in the crypts.However, subsequent studies have demonstrated that thesefindings are not consistent in the rectal mucosa of patientswith CF.70

Reproductive abnormalities are frequent and characteris-tic.71 In a large majority of male patients with CF, the vasdeferens, the tail and body of the epididymis, and seminalvesicles are obliterated by fibrous tissue or are completelyabsent. Women with CF have mucus-distended uterine cer-vical glands and plugging of the cervical canal with tena-cious mucus secretions. Endocervicitis is a frequent finding.

Non-mucus-secreting glands, such as the sweat glandsand the parotid salivary glands, have normal gross and his-tologic appearances. Mucus-secreting salivary glands areusually somewhat enlarged, contain prominent mucus-secreting cells, and display a varied amount of mucus plug-ging in duct lumens.

PATHOPHYSIOLOGY

CYSTIC FIBROSIS TRANSMEMBRANE REGULATORPROTEIN: STRUCTURE, METABOLISM, AND FUNCTION

The CFTR is a single peptide chain that contains 1480amino acids. The calculated molecular weight is 170 kD, butCFTR migrates in its mature form as an approximately 180-kD glycoprotein due to variable N-glycosylation.31,72 Figure38.1 demonstrates the domain structure of CFTR, with tworepeat motifs, each consisting of six transmembrane span-ning segments followed by a consensus nucleotide-bindingfold (ATP-binding region). These two segments are linkedby a highly charged region, the R (regulatory) domain,which contains multiple phosphorylation sites.15 The N andC termini contain important motifs that mediate protein–protein interactions that position CFTR within specializedcellular domains.73 The CFTR structure closely resemblesthat of a number of other solute transport proteins and placesthe CF gene product in the ABC superfamily of proteins.74

CFTR mRNA expression is largely restricted to epithelialcells and is found at moderate levels in human pancreas, sali-vary glands, sweat glands, intestine, and the reproductivetract.15,72 In the lung, CFTR mRNA is expressed at lowlevels in the surface epithelium of the airways and perhapsat higher levels within certain regions of submucosal

glands.75 These sites of CFTR mRNA expression are con-sistent with locations of tissue dysfunction in patients withCF. Biochemical and immunohistochemical studies describean apical membrane location for CFTR in most epithelia,although CFTR may also be inserted into the basolateralmembrane of sweat ductal epithelia.76

Most studies indicate that a central feature of the molecu-lar pathophysiology of CF is that mutated CFTR (e.g.,DF508) is not normally folded and processed; hence it doesnot reach the Golgi or apical plasma membranes (Fig.38.3).24,77 The abnormal CFTR DF508 trafficking is temperature-sensitive, and some degree of normal process-ing and delivery of CFTR DF508 to the plasma membranecan be detected when temperatures are lowered.78 Most(>80%) of the other identified CFTR mutations also producea protein that is not normally processed.79 Some studies sug-gested that abnormal folding of DF508 may not occur in allaffected tissues in vivo, including the airways and colonicepithelia.80,81 However, more recent studies indicate that theprocessing defect is likely a feature of these epithelia in vivo.82

Abnormal processing is not characteristic of all CFTRmutations.79,83 Mutant CFTR may reach the plasma mem-brane but be refractory to regulatory influences or exhibitconduction abnormalities as a consequence of several typesof CFTR gene mutations.84

The CFTR protein appears to have multiple functions(Fig. 38.3). It serves as a Cl- channel,20,21 modulates theactivity of other plasma membrane channels,22,23 and perhapsregulates exocytotic and endocytotic events.85,86 AlthoughCFTR resembles known solute pumps, as yet CFTR has notbeen shown to function as a pump. Its chloride channelactivity (open probability, or Po) is regulated through cyclicadenosine monophosphate (cAMP)-dependent kinase,


Lumen

Blood

Golgi

RER

Nuclei

cAMP

Otherchannel(s)

Cl-CFTR +/–

+

Normal cell

CFTR

Otherchannel(s)

Cystic fibrosis cell

Figure 38.3 Schema of biogenesis of CFTR in a normal cell (L)and a DF508 CF cell (R). In the normal cell, the mature CFTRpolypeptide has been synthesized in the rough endoplasmicreticulum (RER), glycosylated in the Golgi, and localized to theapical membrane to function as a cAMP-regulated Cl- channeland regulator of other channels, e.g., as an inhibitor of theepithelial Na+ channel (ENaC). In the CF cell, the DF508 CFTRpolypeptide has misfolded and been degraded by intracellularproteolytic airways. Hence, it is not positioned in the apicalmembrane to act as a cAMP-regulated Cl- channel or to inhibitENaC.

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C-kinase, and tyrosine kinase pathways.87–89 Phosphorylationof R-domain serine residues and ATP binding and hydroly-sis by the nucleotide binding folds are necessary, independ-ent steps in the activation of chloride conductance.90,91

ABNORMAL AIRWAY MUCOSAL SALT AND WATER TRANSPORT

Cystic fibrosis is a disease that affects the epithelia liningvarious organs of the body. Because the native functions ofaffected epithelia in these organs vary widely—some are salt-absorbing but not volume-absorbing (sweat duct), some are volume-absorbing (airways), and others are volume-secreting (pancreas)—it is not surprising that the physio-logic consequences of mutant CFTR in these epithelia differwidely.

In the lung, airway but not alveolar epithelia are primarilyaffected. It is not yet clear whether the predominant patho-physiology of CF in the airway occurs in the superficial

epithelium or the glandular elements in the airway wall. Thebest studied defects in CF airway epithelia are the Na+ andCl- transport abnormalities identified in the superficialepithelia covering nasal and tracheobronchial surfaces.9,92

The likelihood that the superficial epithelium may be themore important affected epithelium in the lung is suggestedby data indicating that the earliest functional manifestationin the CF lung is airflow obstruction in the bronchioles, aregion that contains no glands.93 For discussion of the speci-ficity of tests of function in the small airways, see Chapter 24.

A classic premise of CF research has been that abnor-malities of Cl- and likely Na+ transport lead to abnormalregulation of airway surface liquid (ASL) volume, that is,depletion of both salt and water (volume) on the CF airwaysurface (Fig. 38.4). As a result of ASL volume reduction,mucus clearance mechanisms are impaired, which causesairflow obstruction and ultimately bacterial infection. Asecond hypothesis linking abnormal Na+ and Cl- trans-port to CF pathogenesis focused on differences in salt

7 µm

7 µm

Basal state

Cystic fibrosis

Basal state

MCT

NaCl + waterabsorption

NaCl + waterhyperabsorption

Cystic fibrosis

MCT

Figure 38.4 Schema describing the mucociliary transport (MCT) apparatus in normal and cystic fibrosis airway epithelia. In normalairways (upper left panel), the volume and composition of airway surface liquids (stars between cilia) are adjusted so the extendedcilium can transmit energy to the mucus layer that rests on the surface of the periciliary liquid layer. The height (volume) and thecomposition of this liquid layer are regulated by the superficial epithelial cells. The low-power electron micrograph (upper rightpanel) shows the 7 mm deep periciliary liquid layer on the surface of a cultured normal airway epithelium that exhibits mucustransport.98 In cystic fibrosis airways (lower left panel), hyperabsorption of volume in response to excessive Na+ transport depletesthe height (volume) of the airway surface periciliary layer. It is postulated that this depletion of liquid contributes to slower airwayclearance in cystic fibrosis by impacting mucus on cilial shafts and by altering cough clearance properties of mucus. The low powerelectron micrograph (lower right panel) shows the depleted periciliary layer on the surface of a CF airway epithelial culture that haslost the ability to perform mucus transport.98 Other composition abnormalities of the periciliary secretory layer also may be importantbut are as yet unidentified.

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concentration and activity of antimicrobial factors (e.g.,defensins) in CF versus normal ASL.94,95 This hypothesissuggests that airway epithelia regulate the ionic concentra-tion, not volume, of ASL, and NaCl concentrations are pre-dicted to be low (<50 mmol/L) in the airway surface liquidsof normal individuals and “high” in CF (>100 mmol/L).Defensins are active in low-salt ASL, whereas they are inac-tive in high-salt ASL. The result of inactive defensins in CFwould be chronic infection. Table 38.2 describes the ASLcomposition in normal subjects and CF subjects prior toinfection.143,398 These data do not support a difference inASL NaCl composition as central to the initiation of CFlung disease. Furthermore, defensins are found in very smallquantities in both normal and CF ASL.96

As discussed in Chapter 12, the role of active ion systemsin the pulmonary epithelium can be reviewed on two levels:(1) the requirement of pulmonary epithelium to coordinateintrapulmonary surface liquid volume during “axial” (i.e.,surface) flow between different pulmonary regions, such asalveolar and airway surfaces; and (2) the requirement toregulate the surface-liquid volume in local microenviron-ments to mediate efficient mucus transport. Recent studieshave increased the level of understanding of how airwayepithelia normally regulate ASL volume under a variety ofconditions and how CF airway epithelia fail to do so. Forexample, confocal microscopy studies of well differentiatedhuman bronchial epithelial cultures that exhibit rotationalmucus transport have revealed that the mucus and peri-ciliary liquid (PCL) layers are both transported axially,imposing a requirement for volume absorption as ASL istransported cephalad in vivo.97 Further studies with thissystem revealed that net volume hyperabsorption is a featureof CF airway epithelia and abolishes mucus transport, bothby depletion of the 7 mm PCL layer and concentration ofmucins in the mucus layer.98 The depletion of PCL is a“severe” lesion, as it is predicted to hinder both cilial-dependent and cough-dependent mucus clearance. Consis-tent with this prediction, the evidence that mucociliary andparticularly cough clearances are depressed in CF patientsin vivo is mounting.99,100

ACTIVE ION TRANSPORT PROPERTIES OF AIRWAY EPITHELIA

Normal airway epithelia exhibit the capacity to activelyabsorb Na+ and actively secrete Cl- ions. Each of these

processes is electrogenic, and they are coordinately regu-lated.101 The relative physiologic role of each process variesdepending on the volume of liquid on airway surfaces.

A parameter that describes the overall airway transportactivity of airway epithelia is the transepithelial electricpotential difference (PD). The transepithelial PD can beanalyzed simply as the product of the active ion transportrate [short-circuit current (Isc)] and the ionic resistance ofthe epithelium (Rt). A diagnostic hallmark of CF airwayepithelia is a raised PD. A series of in vivo ion substitutionstudies,9 complemented by in vitro isotopic flux studies ofexcised tissues,9,92,102 revealed that the raised PD in CFairway epithelia reflects contributions of both increased iontransport (Na+ absorption) and increased epithelial resist-ance (due to decreased cellular Cl- permeability). Indirectevidence from studies measuring the effects of amiloride, aNa+ channel blocker, in vivo indicates that the elevated Na+

absorptive rate rather than the defective Cl- conductancedominates the resting electric abnormalities of the superfi-cial epithelium of CF airways.

Abnormalities of Superficial Epithelial Cl- Transport

In vivo PD,9 Ussing flux chamber,102 and microelectrodestudies103–107 all agree that CF airway epithelial cells exhibitan abnormally low apical membrane conductive Cl- perme-ability. Studies utilizing double-barreled Cl--selectivemicroelectrodes indicate that the basolateral membrane Cl-

conductance and Na+/K+/2Cl- cotransport activities of CFcells are not different from those of normal cells.105,106,108

The abnormality in the resting apical membrane Cl- con-ductance of airway epithelia reflects the absence of tonicCFTR function at this site. Like other affected epithelia, CFairway epithelia do not respond with Cl- secretion to agentsthat raise cellular cAMP (e.g., beta-agonists), whereasnormal airway epithelia do, if the apical membrane Na+ per-meability is blocked.88,92,109–112 This abnormal response inCF airway epithelia does not reflect dysfunction of adeny-lyl cyclase or cAMP-dependent protein kinase activities.Rather, CF airway epithelial cells fail to secrete Cl- due to the absence of CFTR in the apical membrane or to intrinsic defects in mutant CFTR.

Unlike normal airway epithelia, CF airway epithelia alsodo not respond with Cl- secretion to activators of proteinkinase C (PKC).88,111,113,114 Studies with the expressed CFTRprotein have indicated that the CFTR Cl- channel is directly


Table 38.2 Composition of Airway Surface Liquid in Normal Subjects and Uninfected Cystic Fibrosis Patients

Region/Phenotype Study No. Na+ (mmol/L) Cl- (mmol/L) K+ (mmol/L)

Normal nose Knowles143 8 109 ± 5 126 ± 5 29 ± 3Hull398 10 106 ± 4 115 ± 4 ND

CF nose Knowles143 8 110 ± 6 132 ± 5 28 ± 3Hull398 10 116 ± 7 125 ± 4 ND

Normal lower airway Knowles143 11 91 ± 7 81 ± 6 17 ± 3Hull398 7 85 ± 10 108 ± 5 ND

CF lower airway Knowles143 8 87 ± 4 77 ± 6 21 ± 2Hull398 5 78 ± 16 77 ± 7 ND

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regulated by PKC phosphorylation.115 Thus, the failure ofCF airway epithelia to respond to PKC also reflects absenceor dysfunction of the mutated CFTR Cl- channel itself. Anarea of intense interest at present is how CFTR is func-tionally and physically associated with regulatory kinasesand phosphatases in the apical domains of epithelialcells.116,117

Recent studies have placed in perspective the function ofdefective CFTR-mediated Cl- transport in airway epithelia.In normal airway epithelia, the maintenance of a normalASL volume depends on both the regulation of Na+ trans-port rates (see later) and the ability to secrete Cl- (Fig.38.5). Specifically, as ASL volume diminishes to about

7 mm, Na+ absorption is inhibited and CFTR-mediated Cl- secretion is initiated. In CF, the absence of CFTR-dependent Cl- secretion contributes to the failure to main-tain an adequate ASL volume on airway surfaces.

The CF airway epithelial cells retain their normal capac-ity to secrete Cl- in response to elevations in intracellularCa2+.118,119 Data derived from studies of cultured monolay-ers impaled with double-barreled Cl- selective microelec-trodes indicate that elevation of intracellular Ca2+ withcalcium ionphores (e.g., ionomycin) initiate Cl- secretion in both CF and normal cells. The Cl- channel activated byraised Ca2+ must be molecularly distinct from CFTR, as evi-denced by retention of this activity in gene-targeted (“CF”)

A

High/NormalASL Volume

Na+ Cl-

Na+ Na+ 2Cl-K+

K+

H2OAbsorption

Secretion

~

ENaC CaCCCFTR

Va = ~-30 mVDFaCl- = 0 mV

Low ASL Volume

Na+Cl-

Na+ Na+ 2Cl-K+

K+

H2O

~

ENaC CaCCCFTR

Va = -35 mVDFaCl- = -5 mV

B

High/NormalASL Volume

Na+ Cl-

Na+ Na+ 2Cl-K+

K+

H2O

Absorption

~

ENaC CaCC

Cl-CFTR

Low

Na+

K+K+ K+

~K+

Na+ Cl-

Na+ Na+ 2Cl-K+

K+

H2O

~

ENaC CaCC

Cl-CFTR

Na+

K+

~K+

Figure 38.5 A, Normal human airway epithelia can switch between absorptive and secretory ion transport modes. Left. When excessairway surface liquid is present, epithelial Na+ channel (ENaC)-mediated Na+ absorption is dominant. Cl- is projected to be absorbedpassively via the paracellular path, reflecting the fact that there is no electrochemical driving force (DFa

Cl-) favoring Cl- exit from thecell. In contrast, both the negative apical membrane potential (Va) and low intracellular Na+ activity (-20 mM) favor Na+ entry intothe cell. Water is absorbed in response to the osmotic gradients generated by combined NaCl absorption. Right. When the ASL volumeis low, ENaC is inhibited, the apical membrane potential becomes more negative, and a driving force for Cl- secretion is generated.NaCl and water are thus secreted. B, CF airway epithelia exhibit accelerated ASL volume absorption under “high/normal” ASL volumeconditions and cannot switch to a secretory mode during low ASL volume conditions. Left. Routes of raised Na+, Cl-, and H2Oabsorption and cellular mechanisms for raised Na+ transport in CF airway epithelia under high/normal ASL volume conditions. Right.The absence of CFTR from the apical membrane eliminates regulation of the Na+ channel (ENaC) and limits capacity for Cl- secretion.

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mice.120 This Ca2+-activated Cl- channel (CaCC), however,has still not been adequately described biophysically withsingle-channel (patch electrode) techniques. It has also not been resolved whether CaCC responds to raised Ca2+

itself or requires participation of a kinase (e.g., a Ca2+

calmodulin-dependent kinase).118,119,121,122

The observation that Ca2+-regulated Cl- secretion can betriggered in CF airway epithelia has therapeutic implications.In a search for compounds that interact with receptors onthe lumen of airway epithelial cells that regulate intracellularCa2+ levels, it was discovered that the triphosphatenucleotides [ATP and uridine triphosphate (UTP)] werehighly effective in initiating Cl- secretion in CF and normalairway epithelial cells.123–126 Triphosphate nucleotidesincrease intracellular Ca2+ by interacting with purinoceptors(P2Y2) that, via activation of phospholipase C, increase inos-itol triphosphate levels. In vivo studies found that ATP andUTP were effective Cl- secretagogues in the nasal mucosa ofCF subjects.125 Indeed, an intriguing finding was that thetriphosphate nucleotides were more effective in initiating Cl-

secretion in CF than in normal subjects. These observationshave led to the clinical testing of analogues of UTP that byvirtue of being resistant to hydrolysis in CF airways may havea long duration of action.127,128

Abnormalities of Superficial Epithelial Na+ Transport

Abnormalities in Na+ transport in CF appear to be confinedto epithelia that are involved in volume absorption. Thus,data have been reported that accelerated Na+ absorption isa feature of the proximal tubule of the kidney,129,130 thejejunum and the ileum of the small intestine,131–133 and theairways of CF patients.92 Interestingly, the mechanisms ofNa+ hyperabsorption may differ in the three affected epithe-lia. Na+-coupled solute movements may be the majoraffected pathways in the intestine, whereas defective regu-lation of the epithelial Na+ channel (ENaC) is the majorabnormality in the lung.

Studies of freshly excised airway specimens establishedthat the raised PD that characterizes CF airway epitheliareflects in part an accelerated basal rate of active Na+ absorp-tion.103 These studies also identified a defect in acute regu-lation of Na+ transport rates in CF.103 Beta-agonists andother reagents that raise intracellular cAMP paradoxicallyraise the already accelerated basal rate of Na+ transport inCF tissues but do not affect Na+ transport rates in normaltissues.103

Studies with microelectrodes in freshly excised tissuesindicated that the principal abnormality in the Na+ trans-port path in CF airway epithelia resided in the apical mem-brane Na+ conductance.103 Studies of cultured airwayepithelia with double-barreled Na+ selective microelectrodesshowed that the apical membrane Na+ permeability in CFwas twofold to threefold higher than in normal cells.134,135

Thus, these studies placed a second ion permeability abnor-mality in the CF apical membrane and strongly suggestedthat the Na+ transport abnormality was not secondary to the changes in the electrochemical driving forces for Na+

entry consequent to the absence of apical membrane Cl-

permeability.The effects of the CF defect on the regulation of Na+

transport rates at the single-channel level are not under-

stood. The available evidence indicates that the fraction oftime the Na+ channel is capable of conducting ions (Po) isapproximately threefold greater in CF than in normalcells.136–138 This finding suggests that the defect responsiblefor accelerated Na+ transport in airway epithelia reflects anabsence of the tonic inhibition of ENaC provided by wild-type CFTR.

A key issue with respect to the Na+ transport defect relatesto its role in the pathogenesis of airway infection. As dis-cussed above, recent data indicate that both regulation ofNa+ transport rates as a function of the available volume onan airway surface and the capacity to secrete Cl- are requiredfor ASL volume homeostasis (Fig. 38.5). Furthermore,these studies have shown that CF airways fail to normallyregulate Na+ absorption, and this defect contributes toabnormally low ASL volumes on CF airway surfaces. Forexample, in vitro studies of cultured CF bronchial epitheliahave shown that in CF Na+ hyperabsorption persists despitelow ASL volume, and that this defect contributes to PCLdepletion and mucus stasis (Fig. 38.6). Further evidence forthe role of increased Na+ absorption in the pathogenesis ofCF has emerged from in vivo studies of mice with airway-specific overexpression of ENaC. These mice exhibitedincreased Na+ absorption and a lung phenotype that resem-bles CF (e.g., mucus obstruction, neutrophilic inflamma-tion, and defects in bacterial clearance).139 The recentreports that nucleotides also slow Na+ transport in CFairways140,141 suggest that data from therapeutic trials withthese agents may be informative with respect to the role ofNa+ absorption in CF lung disease.

Ion Transport Defects of Glandular Epithelium

CFTR may be expressed at high levels in certain regions ofproximal airway glands. In situ hybridization studies indi-cate that lung CFTR is expressed at the highest level insome serous cells contained in submucosal gland acini anda minor cell type in the ductal epithelium, the so-calledoncocyte.142

In vivo studies of nasal gland secretion have suggested asimilar capacity for gland acini to secrete liquid volume inCF and normal subjects in vivo.143 Furthermore, thesestudies raised the possibility that submucosal gland ductsmodify the gland secretion so it is hypotonic (i.e., has areduced NaCl concentration). Unlike the sweat duct, butsimilar to the parotid duct, the functions of the ductalepithelium in nasal glands of CF patients appear similar tothose in normal subjects.

In vitro studies indicate that cultured CF bronchial glandacinar cells, unlike the superficial airway epithelium of CFsubjects, do not respond to raised intracellular Ca2+ with Cl-

secretion, whereas normal glandular cells do. Thus, thebronchial glands could have a Cl- transport phenotype thatis more similar to gastrointestinal epithelia than the super-ficial airway epithelium.133,144,145 Studies of bronchial glandshave more recently been performed on freshly excisedpreparations from lung transplant procedures. CF airwaygland acini, like superficial airway epithelia, do not secreteCl- in response to beta-agonists, whereas glands fromnormal subjects exhibit moderate responses.144,145 Interest-ingly, both normal and CF glands secrete Cl- in response to cholinergic agents, suggesting that Ca2+-regulated Cl-


38.qxd 1/25/05 2:47 PM Page 1225


secretion is preserved in freshly excised gland preparations.The predicted functional correlate of these data is that CFglands fail to secrete sufficient volume to normally hydratemucins secreted by glands or, possibly, hydrate the airwaysurface. The relative role of the gland defect in CF ASLvolume depletion is presently unknown, but at a minimumthis deficiency would serve to exacerbate the ASL volumedefect generated by the CF superficial epithelium.

MUCIN MACROMOLECULE SECRETION IN THE CYSTICFIBROSIS AIRWAY

Following Farber’s report5 of mucus obstruction in manyexocrine glands, a search was initiated for abnormal macro-molecules that might change the physical properties of CFexocrine secretions. Particular emphasis was placed onanalysis of mucin glycoproteins, the high-molecular-weightglycoconjugates that are the determinants of the viscoelas-tic properties of mucus.146 One of the difficulties in com-paring these substances sampled from CF and controlairways is that they are susceptible to proteolytic andperhaps other degradative enzymes to which they areexposed in vivo. In addition, these glycoproteins displayextensive microheterogeneity of carbohydrate constituentsand, therefore, are difficult to compare from subject tosubject as well as patient group to control group.

Overall, purified mucins from CF patients and controlsubjects show considerable similarity. Early suggestions thatthe fucose content of CF glycoproteins was elevated and thesialic acid content decreased appears to reflect the effects ofchronic infection and inflammation and is not a CF-specificdefect.147 In addition, several investigators have reportedthat CF mucus glycoproteins from both respiratory and gas-trointestinal sources contained increased numbers of sul-fated sugars.148–151 Goblet cells in the bronchial epitheliumof patients with CF have an elevated sulfur content,152

which, if present as sulfate, could reflect increased sulfationof secretory glycoconjugates. However, again, most evi-dence suggests that increased sulfation likely is a reflectionof chronic infection rather than a consequence of CFTRmutations.147

There is also no convincing evidence that CF epithelialcells hypersecrete mucin macromolecules before the onset ofairway injury.153 However, hypersecretion of mucus doesoccur in response to proteases, oxidative metabolites, and other products of chronic infection and inflammation.This induced hypersecretion, coupled with goblet cell

A

pO2

B

pO2

C

pO2

Figure 38.6 A, Failure of mucus transport coupled withpersistent mucin secretion over time produces adherent mucusmasses/plugs. The raised epithelial QO2 required to fuelaccelerated CF Na+ absorption generates steep oxygen gradients(red Æ blue stippling in bar) in thickened mucus masses. B, Pseudomonas aeruginosa deposited on mucus masses growsand adapts to hypoxic niches within these masses asmacrocolonies (biofilms). C, The thickened mucus, coupled withmacrocolony growth, resists secondary defenses, includingneutrophils, setting the stage for chronic infection. Thepresence of increased macrocolony density and, to a lesserextent, neutrophils renders these mucopurulent masses franklyanaerobic (blue bar).

38.qxd 1/25/05 2:47 PM Page 1226

hyperplasia, likely significantly exacerbates the mucus accu-mulation and obstruction that is initiated by ASL volumedepletion.154

In the future, an important area of research will focus on the behavior of mucins in reduced (“low”) ASL volumeenvironments. Of particular interest are studies on thenature of the adhesive interactions that may occur when a“thickened” (concentrated) mucus layer comes into contactwith cell surface (tethered) mucins in the absence of PCL(Fig. 38.2). Elucidation of the mechanism of this interac-tion may lead to therapies to reverse this adhesion and allowclearance of adherent mucus plaques.

Analyses of other macromolecular secretory productsfrom patients with CF have failed to uncover substantialabnormalities. These macromolecules have included alpha-amylase, ribonuclease, and lysozyme from salivary secretionsand pancreatic enzymes, including chymotrypsin, trypsin,carboxypeptidase, amylase, and lipase.

PATHOPHYSIOLOGY OF INFECTION

Failure of the airways to clear mucus normally is likely theprimary pathophysiologic event in CF (Fig. 38.6). Adher-ent mucus plaques and plugs are the sites of the chronicbacterial infection of CF airways.155 These bacteria areusually found in macrocolonies that appear to represent thebiofilm type of growth characteristic of CF infections. Ingeneral, biofilms represent a type of bacterial growth inwhich bacteria form and become enmeshed in an extensiveextracellular matrix. Bacterial cellular physiology maychange in this environment, and the matrix may provide abarrier to antimicrobial agents and inflammatory cells,thereby promoting bacterial persistence. Generation ofthese immobile mucus surfaces thus provides the nidus forthe chronic respiratory tract infection that is the major con-tributor to the loss of lung function and eventual demise ofpatients with CF.

The chronic infection of the CF lung usually is localizedto endobronchial regions, and the bacterial species mostcommonly cultured are Staphylococcus aureus andPseudomonas aeruginosa. Once established, infection of theCF lung is rarely eradicated. Bacterial infection extendingbeyond the airways, however, is distinctly uncommon.Therefore, local airway defense mechanisms, rather thangeneralized host or pulmonary defense mechanisms, appearto be impaired in CF.

As reviewed above, the old concept that a generalizedfailure of mucus clearance from airways is the principal airwaydefense mechanism degraded in CF has been supplementedwith new clinical and laboratory data. For example, studies of airway mucus transport velocity had found that clearanceof inhaled radiotracers from the central airways is usuallyreduced.100 More recent studies of mucus clearance from themore peripheral airways, the site of early disease in CF, havefound that clearance is routinely reduced in this region.156

Virtually all studies agree that ciliary morphology and beatfrequency in CF airway epithelia are normal.157,158 In con-trast, data from model systems indicate that the volume ofliquid on CF airway surfaces is severely reduced.98 Thus, it islikely that ASL volume depletion, by both removing the PCLand concentrating the mucus layer, leads to failure of bothmucociliary and cough clearance. The resulting mucus stasis,

adhesion, and obstruction likely are responsible for thesevere, unrelenting lung infections (Fig. 38.6).

Staphylococcus aureus and P. aeruginosa are infrequent res-piratory tract pathogens of children and adults, except inCF. The role played by these organisms in endobronchialinfection has prompted suggestions that surface propertiesof CF airway epithelia are altered in a fashion that promotestheir adherence. S. aureus does not preferentially adhere toCF airway epithelial cells,159 and studies of respiratory cellinteractions with P. aeruginosa also have not demonstratedconsistent differences between CF and normal cells.160,161 Inan opposite formulation, recent studies have suggested thatthe wild-type CFTR expressed on normal epithelial cellsbinds Pseudomonas and mediates bacterial internalization,which ultimately kills the microorganism. CF cells report-edly fail to perform this function.162 Although intriguing,there is little pathologic evidence for P. aeruginosa inter-nalization in normal well differentiated airway epithelialcells, and this hypothesis does not account for infection inCF patients who express mutant CFTR in the apical mem-brane (e.g., G551D CFTR).

As noted above, there is increasing evidence that CFairway infection reflects an infection of the mucus layer,forming biofilms of bacteria that are resistant to the host’sdefense.155 No differences in bacterial binding to CF versusnormal mucins have been detected for Staphylococcus orPseudomonas.159 Rather, it is likely that it is increased bac-terial mucus adherence due to nonspecific increases in“tackiness” of the mucins concentrated by ASL volumedepletion that accounts for the presence of these bacteria inmucus. In addition, there may be a unique interactionbetween P. aeruginosa and concentrated mucus that pro-motes biofilm-type growth.163

An important new concept is that the mucus adherent toairway surfaces may be hypoxic and even frankly anaerobic(Fig. 38.6).164 Prior to infection, the increased oxygen con-sumption by CF airway epithelia (required to fuel increasedNa+ absorption), coupled with increased diffusion distancesfor oxygen through mucus plaques, can create relativelyhypoxic zones near the epithelial surface. As it has recentlybeen shown that P. aeruginosa can adapt to and grow in ahypoxic environment, this environment may exert a subtlepressure that favors P. aeruginosa acquisition in CF. Perhapsmore importantly, as bacterial densities in CF mucus reach106 CFU/mL or more, the bacteria consume the remain-ing oxygen in the environment. Indeed, direct measure-ments of PO2 in vivo with oxygen electrodes have recordedPO2 of less than 2 mm Hg in infected CF mucus.164

This observation has two important implications for CFtherapy. First, P. aeruginosa sensitivities to antimicrobialschange in oxygen-depleted versus oxygen-rich environ-ments; for example, macrolides become more effective inoxygen-depleted environments. Thus, clinical testing ofPseudomonas isolates for antimicrobial sensitivity mayrequire studies under anaerobic conditions. Second, P.aeruginosa physiology differs under anaerobic and aerobicconditions.165 Identification of essential genes for anaerobicgrowth may represent novel therapeutic targets.

Once bacterial infection of mucus has occurred, bacteriarelease products that diffuse to the underlying epithelial cellsand stimulate up-regulation of mucin production166,167 andcytokine responses,168 and they mediate cell damage. The


38.qxd 1/25/05 2:47 PM Page 1227


infection may be worsened after cell damage by bacteriabinding to the injured cells (but not the uninjured cells).169

Pulmonary immunology in CF has been investigatedextensively. There is little reason to believe that a primaryimmunologic deficiency state exists in CF. Although CFsubjects tend to have low levels of serum immunoglobulinG (IgG) in the first decade of life, these levels increase dramatically as chronic infection is established.170 Secretoryantibody levels appear to be normal or enhanced.171 Anti-body responses specific for infecting organisms in the res-piratory tract are brisk.172,173 The number of B lymphocytesand plasma cells that differentiate into immunoglobulin-secreting cells are not depressed.174 T-lymphocyte numbersare adequate, and these lymphocytes proliferate in responseto nonspecific mitogens.175 With advancing severity of pul-monary disease, lymphocytes of CF patients may proliferateless briskly in response to P. aeruginosa and other gram-negative organisms.176 This acquired dysfunction can bereversed in some patients by intensive antibiotic treatment,but this may contribute to subsequent resistance of end-stage lung disease to antimicrobial therapy.

Polymorphonuclear leukocytes and macrophages areplentiful in CF airways. CF pulmonary macrophages func-tion normally when removed from their usual environ-ment.177 Polymorphonuclear cells also function normallyoutside the host environment. These observations suggestthat potential phagocytic defects in vivo could reflect infec-tion-induced degradation of opsonins (e.g., IgG and com-plement) and possibly defective leukocyte migrationthrough thickened, adhesive mucus.178

Much recent work has focused on the magnitude of theinflammatory response to airways infection in CF and theregulatory systems that modulate this response.179 Studiesfrom lung lavage fluid from CF neonates indicate that themagnitude of the neutrophil response normalized to bacte-rial counts in lavage fluid is increased in CF compared tothat of non-CF infants with lung infections.180 Otherworkers have suggested that the cytokine interleukin-10(IL-10), which normally serves to dampen epithelial cell IL-6 and IL-8 responses to luminal bacterial infection, is notproduced at normal levels in CF airway epithelia.181,182 It isimportant to learn whether the increased neutrophil influxreflects persistent failure to kill bacteria growing in biofilmswithin thickened mucus plaques, failure of an epithelial regulatory mechanism for neutrophil influx, epithelial com-pensation to a chronic stimulus, or a combination thereof.

The mechanisms by which progressive obstructive lungdisease and destruction of airway walls occur in CF havereceived attention recently. The role of proteinases in thisprocess in particular has been intensively studied.183 Leuko-cytes and bacteria produce large quantities of elastase thatexceed the neutralization capacity of airway antiproteinases.Both leukocyte and bacterial elastases generate C5a non-immunologically in CF secretions.184 High levels of thischemotactic factor stimulate further polymorphonuclearleukocyte recruitment, increasing the burden of free elas-tase in the airway lumen. Ultimately, proteolytic injury toairway walls contributes to their destruction with the devel-opment of widespread bronchiolectasis and bronchiecta-sis.185 The fact that destructive emphysema is not aprominent feature of CF lungs, especially early in the course of lung disease, can be attributed to confinement of

infection to endobronchial spaces in mild to moderate lungdisease. Other mechanisms of conducting airway tissueinjury undoubtedly exist but have not yet been described indetail.

CLINICAL MANIFESTATIONS

Cystic fibrosis presents in many ways and mimics a numberof other clinical entities. Usual presentations include earlyonset of respiratory tract symptoms, particularly persistentcough and recurrent or refractory lung infiltrates. Usualgastrointestinal presentations include meconium ileus inapproximately 15% of patients and failure to thrive withsteatorrhea. A surprising number of people with CF escapedetection in the first decade or two of life, often becausesymptoms are unusual, subtle, or even absent. Patients with“mild” mutations may present in childhood or later in life.35

unusual presentations are compiled in Table 38.3, and presentations that may be expected at adolescence or earlyadulthood are indicated. Recognition of the protean mani-festations of CF and a high index of suspicion are requiredto detect all cases, either in childhood or later in life.

LOWER RESPIRATORY TRACT DISEASE

The earliest manifestation of CF lung disease is generallycough. At first it is intermittent, coinciding with episodes ofacute respiratory tract infection and persisting longer thanexpected. With time, the cough becomes a daily event. It isoften worse at night and especially on arising in the morning.

Table 38.3 Unusual Presentations of Cystic Fibrosis

RespiratoryBronchiolitis/asthmaPseudomonas aeruginosa or Staphylococcus aureus colonization

of the respiratory tract*Staphylococcal pneumoniaNasal polyposis*Nontuberculous mycobacterial infection*

GastrointestinalMeconium plug syndromeRectal prolapseRecurrent abdominal pain and/or right lower quadrant mass*Hypoproteinemic edemaProlonged neonatal jaundiceBiliary cirrhosis with portal hypertension*Vitamin deficiency states (A, D, E, K)Acrodermatitis enteropathica-like eruption with fatty acid and

zinc deficiencyRecurrent pancreatitis*

GenitourinaryMale infertility*Female infertility*

OtherHypochloremic, hyponatremic alkalosis

Mother of a child with cystic fibrosis*

* Presentations that may occur in adolescents or adults with cysticfibrosis.

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With progression of lung disease, the cough becomes pro-ductive and then paroxysmal, with associated gagging andemesis. Sputum is usually tenacious, purulent, and oftengreen, reflecting P. aeruginosa infection. Hyperinflation ofthe lungs is noted early in the progression of lung disease. Infact, it is unusual to see CF respiratory tract disease withoutat least a moderate increase in lung volume. Asthmatic orbronchiolitic-type wheezing is most common during thefirst 2 years of life but may be encountered at any age.Wheezing may occur with or without evidence of atopy,which is probably not more frequent in patients with CF.186

Lung sounds are often unremarkable for extended periods oftime, sometimes for years. Not infrequently, diminution inthe intensity of breath sounds may be the only abnormalitynoted, correlating with the extent of hyperinflation. Adven-titious lung sounds are usually heard first over the upperlobes, and they often are localized to the right side.

Cystic fibrosis patients may have only mild bronchiticsymptoms for long periods of time, in some cases for adecade or two, but eventually these periods of stability arepunctuated with exacerbations of symptoms, includingincreased intensity of cough, tachypnea, shortness of breath,decreased activity and appetite, and weight loss. It has beenassumed that these exacerbations are triggered by acute res-piratory infections, perhaps of viral or mycoplasmal origin,although studies differ concerning evidence for these infec-tions during periods of increased lung symptoms.187–192

Environmental factors, including cigarette smoke,193 alsomay evoke more respiratory symptoms. Intense antibiotictherapy and assistance with clearance of mucus are usuallyrequired to reduce lung symptoms and improve lung func-tion. Exacerbations characteristically occur with increasingfrequency. Frank limitation of activity or disability is associ-ated with end-stage lung disease and heralds a sequence ofterminal events, including substantial hypoxemia, pul-monary hypertension, cor pulmonale, and death.

Microbiology

The airways of patients with CF are colonized early withbacteria; and once established, infection is rarely if ever

eradicated. S. aureus and Haemophilus influenzae are oftenthe first organisms detected.194 P. aeruginosa characteristi-cally is cultured from respiratory secretions months to yearslater, although this organism is present at diagnosis withincreasing frequency. Age at acquisition of P. aeruginosa,shown in Figure 38.7, is dependent in part on genotype,with earlier acquisition occurring in persons homozygousfor DF508.33 The possibility of nosocomial acquisition of P.aeruginosa has been raised.195 With progression of lungdisease, P. aeruginosa is often the only organism recoveredfrom sputum, and it may be present in several types ofcolony, usually with different antibiotic sensitivity patterns.Typically, one of these types is mucoid due to elaborationof large amounts of alginate. These mucoid organisms arefound in microcolonies of pseudomonads embedded andgrowing in biofilms of alginate.196 Mucoid properties arethought to inhibit opsonic and nonopsonic phagocytosis,enhance adherence properties, and decrease sensitivity toantibiotics and toxic, reactive intermediates produced byleukocytes.155,197–199 The recovery of P. aeruginosa, particu-larly the mucoid form, from the lower respiratory tract of achild or young adult with chronic lung symptoms is virtu-ally diagnostic of CF, although it may also occur in patientswith primary ciliary dyskinesia.200

Recently, other species have been recovered from CFlungs with increasing frequency, particularly Burkholderiacepacia. This organism has become prevalent in a few CFcare centers and is particularly difficult to treat because it isusually resistant to most antimicrobial drugs. Evidence forpatient-to-patient spread is strong and has led to recom-mendations for stringent infection control measures in CFcare settings.201,202 Colonization has been linked to the rapiddemise of a small percentage of patients203 with what iscalled the “cepacia syndrome.” Molecular analyses have dis-tinguished genomovars of B. cepacia, some of which com-prise distinct species.204–207 Genomovars II (Burkholderiamultivorans) and III (Burkholderia cenocepacia) have beenassociated with the cepacia syndrome, and genomovar IIIincludes the highly transmissible strain that may be linkedto expression of the cable pilus.206–208 Occasionally, othergram-negative rods are present in sputum, including


Per

cent

80

70

60

50

40

30

20

10

00-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 36+

OverallPrevalence

61.9%58.2%

FemalesMales

Age (years)

Figure 38.7 Prevalence of Pseudomonas aeruginosainfection by age and sex in cystic fibrosis patientsenrolled in the U.S. Cystic Fibrosis Foundation Registry,1991, based on an analysis of 16,417 patients.(Courtesy of Dr. S. FitzSimmons.)

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mucoid Escherichia coli, Stenotrophomonas maltophilia,Alcaligenes xylosoxidans, Klebsiella, and Proteus. Anaerobeshave been recovered from CF lung tissue; they may beundetected pathogens and are found in large abscess cavities on rare occasions.209

Sputum bacteriology correlates reasonably well with spec-imens obtained directly from the lower respiratory tract.Oropharyngeal swab cultures that yield S. aureus or P.aeruginosa are modestly predictive of results from bron-choscopic specimens, but negative pharyngeal cultures donot rule out the presence of these organisms in lowerairways.210 Quantitative bacteriology may be particularlyuseful for determining the relative contributions of organ-isms isolated.

A large number of sputum specimens contain yeast andAspergillus fumigatus. Neither organism has been consid-ered a serious pathogen, although the latter causes symp-toms of allergic bronchopulmonary aspergillosis in a smallpercentage of patients.211,212 Colonization of lungs withrapidly growing mycobacteria has been documented withincreasing frequency. Up to 20% of adult patients in someclinics are colonized by nontuberculous mycobacteria, occa-sionally prompting treatment with agents directed againstthese organisms.213–217 Mycobacterium tuberculosis infectionhas been seen in only very sporadic cases.

Radiology

The earliest radiographic change is usually hyperinflation ofthe lungs, reflecting obstruction of small airways. Thedegree of hyperinflation generally increases with age. Asbronchitis progresses, peribronchial cuffing becomesincreasingly prominent. Mucus impaction in airways may be seen as branching finger-like shadows. Evidence ofbronchiectasis, such as enlarged ring shadows and cysts, iscommon by 5 to 10 years of age. Frequently, peripheralrounded densities are noted during acute exacerbations;they may disappear with treatment, leaving residual cysts.Subpleural blebs often become evident during the seconddecade of life and are most prominent along the mediasti-nal border. For reasons that remain unexplained, the rightupper lobe usually displays the earliest and most severechanges. With advancing disease, the pulmonary artery seg-ments become more prominent. A relatively small, verticalcardiac shadow is typical, but the heart enlarges with onsetof cor pulmonale. Hilar adenopathy is rarely prominent.Lobar or segmental atelectasis is uncommon but is mostoften seen in infants or small children. Chest roentgeno-graphic scoring systems have been introduced and may beuseful for clinical studies and to chart the course of lunginjury.218

Roentgenographic improvement with intensive treatmentis not readily appreciated because of the fixed nature of theairway changes. The most striking improvement often isreduced inflation of the lungs, a change that tends to makethe fixed lung markings more prominent.

Computed tomography of the chest has not been usedroutinely for monitoring the course of CF lung changes.The cost is high, and resolution for young patients was initially poor. With the advent of rapid scanning, however,mild bronchiectasis and mucoid impaction can be observedat all ages.219,220 CT scanning detects these lesions, even

when the chest roentgenogram is nearly normal. The sever-ity of bronchiectasis can be graded in older patients.221 Theindications for CT scanning in place of routine chestroentgenography are not established. One indication maybe the evaluation of a patient considered for lobectomy.Magnetic resonance imaging (MRI) also defines peri-bronchial thickening, mucoid impaction, and bronchiecta-sis but has no well documented advantage over CT scans in these areas of imaging.222 MRI may be superior for dis-tinguishing hilar adenopathy and prominent pulmonaryvessels.223

Lung Function

Newborns with CF are thought to have normal lung func-tion. However, within weeks to months, many infants withCF show evidence of increased airway resistance, gas trap-ping, and diminished flow rates.224 When children reach anage that makes cooperation possible, more complete testingfirst demonstrates airway obstruction, which presumablyoccurs in small airways, as indicated by reduced maximummidexpiratory flow rates, reduced flows at low lungvolumes, and elevation of the residual volume to total lungcapacity ratio (RV/TLC).225–227 Other sensitive indicators oflung pathology include an increased alveolar-arterial oxygengradient, frequency dependence of dynamic compliance,reduced response of flows to a helium-oxygen mixture, elevated slope of phase III of the single-breath nitrogenwashout, and an elevated physiologic dead space.224 Teststhat are used most often to follow the course of pulmonaryfunction include spirometry, lung volume measurements,and measures of oxygenation. In general, patients progressfrom initial reductions in maximum midexpiratory flowrates to reductions in FEV1/FVC and then to diminishedvital capacity and total lung volumes. This progression fromperipheral airway obstruction to more generalized obstruc-tion and then to acquisition of a restrictive component isillustrated in Table 38.4. These tests are described and evaluated in Chapter 24.

By the time a diagnosis is made, many children with CFshow mild decrements of arterial PO2. Oxygenation declinesslowly throughout life. As a rule, patients who maintain satisfactory oxygenation do well, independent of the extentof the obstructive impairment. When arterial PO2 values dipbelow 55 mm Hg on a sustained basis, symptomatic pul-monary hypertension should be expected.228,229 Exaggeratednocturnal desaturation experienced by patients with CF may be a contributing factor to pulmonary hypertension.230

Hypoxemia generally is not accompanied by polycythemia,at least in part due to an expanded plasma volume and, insome persons, to suppressed erythropoiesis secondary tochronic infection. Elevation of arterial PCO2 generallyoccurs with FEV1 volumes less than 30% of those predictedand constitutes an end-stage event for most patients. Lessthan 50% of patients with FEV1 less than 30% of predicted,arterial PCO2 greater than 50 mm Hg, or arterial PO2 lessthan 55 mm live for 24 additional months.231

Airway hyperreactivity is a frequent feature of CF lungdisease and can be demonstrated by exercise testing, hista-mine challenge, or response to bronchodilators. Up to 68%of the CF population demonstrate decreased flows after histamine, and flows improve in as many as 40% with

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aerosolized bronchodilators.232 In contrast to cross-sectional studies, repeated tests every 1 to 3 months for ayear have demonstrated bronchodilator responsiveness atleast once in 95% of subjects.232 Responsiveness is unrelatedto the severity of pulmonary disease or indices of atopy butseems to be more prevalent during winter than duringsummer months. Responsiveness diminishes with exacerba-tions of lung disease but returns as lung function improvesover 2 weeks of intensive in-hospital therapy. Several inves-tigators have noted that occasional patients with CF have aparadoxical response to bronchodilators, perhaps due tofurther loss of tone in bronchiectatic airways. The patho-genesis of bronchial hyperreactivity in CF is unclear. Airwayhyperreactivity is discussed in Chapter 37.

Exercise tolerance is related to the severity of the airwayobstruction.233,234 Most patients with CF maintain adequateoxygen saturation, even with maximal exercise. However, inone study, 12 of 29 patients with an FEV1 less than 50% offorced vital capacity (FVC) had arterial oxygen saturationbelow 90% at peak exercise, compared with no drop forpatients with higher FEV1 values.235 Persons with CF havehigher than expected ventilatory muscle endurance, and thisendurance can be further improved with inspiratory muscletraining. However, improved inspiratory muscle strengthand endurance do not augment exercise performance.236

Exercise does improve cardiorespiratory fitness but does notimprove standard pulmonary function test results. Variedweight training, however, in one study increased weight and

muscle size and, in addition, reduced the RV/TLC by12%.237 Another study demonstrated that adults with CFand advanced lung disease improve with exercise, but thosewith only moderate lung disease have decreased end-expiratory lung volumes after graded exercise on a cycleergometer.238 Maximum oxygen consumption during exer-cise appears to be a better predictor of survival than routinepulmonary function testing.239 The physiology of exerciseand exercise testing are discussed in Chapter 25.

Resting energy expenditure is variably elevated in patientswith CF. Although some have claimed that there are genet-ically determined increases in energy expenditure (e.g.,increased ATP hydrolysis) related to certain CFTR muta-tions,240 others have found increased work of breathing tobe a more plausible explanation.241

UPPER RESPIRATORY TRACT DISEASE

Virtually all patients with CF have roentgenographic opaci-fication of the paranasal sinuses242 and intermittent symp-toms of increased upper airway secretions and moderateairflow obstruction.243 Nasal polyps occur in 15% to 20% ofpatients and are most common toward the end of the firstdecade and during the second decade of life.65 Manifesta-tions include severe or complete nasal airflow obstruction,rhinorrhea, and occasionally widening of the bridge of thenose. Despite the presence of roentgenographic abnormal-ities, acute or chronic symptoms of sinusitis occur in fewerthan 10% of children244 and in about 24% of adults.245,246

COMPLICATIONS OF RESPIRATORY TRACT DISEASE

Lobar and segmental atelectasis occurs in about 5% ofpatients.247 This complication is most prevalent in the first 5years of life and thereafter has a diminishing frequency. Theright lung is the site of atelectasis in the majority of patients.Many episodes occur in conjunction with an exacerbation ofclinical symptoms, but silent atelectasis is common. Occa-sionally, volume loss is associated with allergic aspergillosisand endobronchial mucus plugs. However, in mostinstances, a discrete plug is not evident on bronchoscopy.

Pneumothorax is a more frequent complication and iscaused by rupture of subpleural blebs. The overall incidenceis about 1% per year and increases with age and diseaseseverity, so less than 20% of CF adults experience at leastone pneumothorax.248 Pneumothorax occurs equally inboth sexes and is more frequent in the right chest. A smallasymptomatic pneumothorax may be discovered at the timeof routine chest roentgenographic examination. More com-monly, patients develop acute onset of shortness of breath,chest pain, and/or hemoptysis. The incidence of tensionpneumothorax is probably higher in patients with CF thanin those with less severe or no lung disease; and under thesecircumstances, the accumulation of pleural air may becomea life-threatening event. Simultaneous bilateral pneumoth-oraces have been described and constitute an urgent situa-tion. Recurrent pneumothoraces are very common.

Hemoptysis is a common event in older CF patients. It cor-relates with clinical and radiologic evidence of bronchiecta-sis and is usually due to airway inflammation rather thanvigorous activity or trauma to the chest. Blood streaking inthe sputum (“minor hemoptysis”) is common, and massive


Table 38.4 Representative Pulmonary Function Test Resultsfrom Three Young Adult Males with Mild, Moderate, andSevere Lung Disease*

Patient with Patient withPatient with Moderate SevereMild Lung Lung Lung

Test Disease Disease Disease

FVC 98 72 48

FEV1 92 46 34

FEV1/FVC (0.81) (0.70) (0.64)

MMEF 83 15 6

Vmax50 91 19 11

Vmax25 52 10 5

FRC 162 112 75

RV 189 200 120

TLC 131 105 62

RV/TLC (0.29) (0.45) (0.50)

PaO2 (room air) [87] [74] [48]

* Values are percent predicted, except those in parentheses, which aresimple ratios, and those in brackets, which are millimeters of mercury.Patient with mild disease coughs several times a day; the cough isoccasionally productive. He shows no restriction of activity. Patientwith moderate disease coughs frequently, expectorates moderatelylarge amounts of mucus, but is able to jog 3 miles daily and is a full-time student in a professional school. Patient with severe disease haschronic right heart failure but is able to work daily as a hair stylist.

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hemoptysis (>240 mL of blood in 24 hours) occurs inapproximately 5% of patients.249 There is a strong correlationbetween the occurrence of both small- and large-volumehemoptysis and the exacerbation of lung infection. Patientswith relatively large-volume hemoptysis may be able to local-ize the site of bleeding by describing a bubbling or gurglingsensation in one area of the chest. Any lobe may be involved,and localization is difficult in most patients. Even emergentbronchoscopy often does not detect the location of blood inthe airways. In the past the immediate mortality with massivehemoptysis may have been as high as 10%, but with propertreatment most patients with massive hemoptysis have aprognosis that is not much different from that for theremainder of the CF population.250

About 1% to 10% of patients develop allergic bron-chopulmonary aspergillosis (ABPA) at some time in theirlives.251 In one study, more than 50% of patients with CFhad precipitating antibodies to Aspergillus fumigatus intheir serum, and this organism can be recovered from thesputum with a similar frequency.252 New lung infiltrates,increased cough, respiratory distress, wheezing, and theexpectoration of rusty brown plugs of sputum containingmany eosinophils suggest this diagnosis. Atelectasis due toplugging of a lobar or segmental bronchus with hyphae-laden mucus may occur. Chronic airway colonization withA. fumigatus (or other species) is common, and diagnosisof ABPA requires new clinical findings plus skin hypersen-sitivity and elevated levels of IgG and IgE antibodies againstA. fumigatus or other fungi.211,212

Pleural effusions and empyema are uncommon in patientswith CF, but pleuritic symptoms and signs may accompanyexacerbations of lung disease. Staphylococcal andpseudomonal empyemas have been described, but respira-tory tract infections usually spare the pleural space.253

Digital clubbing occurs in virtually all patients with CF andis usually present early in the course of symptomatic lungdisease. The cause of clubbing is unknown, but its severitygenerally correlates with the severity of lung disease.254

Hypertrophic pulmonary osteoarthropathy occurs in as manyas 15% of older adolescents and adults.175,255 If roentgeno-graphic evidence for periostitis is used as the definition, theincidence is 8%. The most common sites are the distal aspectsof the tibia, fibula, radius, and ulna. Signs and symptomsinclude pain, bone tenderness, swelling, and warmth overthe involved areas. Effusions in nearby joints may occur.There is often discomfort with ambulation. Hypertrophicpulmonary osteoarthropathy frequently becomes moresymptomatic with pulmonary disease exacerbations andtends to subside when control of pulmonary symptoms isachieved. There are rare instances of cutaneous vasculitis due to CF, which causes a self-limited, painless, palpablepurpura, typically involving the lower extremities.255

Respiratory failure leads to death in more than 90% ofCF patients. Hypoxemia often develops during exertion256

or sleep257 and progresses over years. Hypercapnia reflectssevere airway obstruction and increases with disease sever-ity and acute exacerbations. Hepatic congestion and periph-eral edema caused by pulmonary hypertension and corpulmonale may develop in the last year of life,258 particu-larly if hypoxemia is not adequately treated. Occasionally,infections such as respiratory syncytial virus or influenzacause acute respiratory failure that is fully reversible.259

GASTROINTESTINAL MANIFESTATIONS

Meconium ileus occurs in at least 15% of newborns with CFand is virtually diagnostic for CF.69 These infants fail to passmeconium in the first day or two of life, develop abdomi-nal distention, and proceed to bilious emesis. Occasionally,perforation occurs, and peritonitis accompanied by shockintervenes. Flat and upright abdominal films reveal multi-ple dilated loops of intestine and air-fluid levels. The lowerabdomen often takes on a granular appearance, represent-ing accumulated meconium containing small air bubbles. Abarium enema demonstrates a small colon; and if contrastmaterial can be refluxed into the ileum, the point of ilealobstruction can be identified. In utero, ileal perforationresults in peritoneal and scrotal calcification. Occasionally,obstruction occurs lower in the intestinal tract and causesonly delayed passage of meconium. This condition has beentermed the meconium plug syndrome and is much less spe-cific for CF.260 Meconium ileus is also a prominent featureof transgenic mice with a disrupted CFTR gene.27

Beyond the newborn period, intestinal obstruction mayoccur for a variety of reasons. Perhaps the most common(occurring in 20% of patients) is called the meconium ileus equivalent or the distal intestinal obstruction syn-drome.36,69,261 As with meconium ileus of the newborn,obstruction occurs in the terminal ileum and is usually asso-ciated with voluminous, sticky, incompletely digested intes-tinal contents. In some instances, a partial obstructionoccurs, accompanied by intermittent abdominal pain. Com-plete obstruction is associated with failure to pass stools,abdominal distention, and vomiting. A mobile right lowerquadrant mass may be palpable. Obstruction beyond theimmediate newborn period is also characteristic of the CFmouse model. Other causes of abdominal pain associatedwith obstruction include intussusception, intestinal adhe-sions from previous abdominal surgery (a particularproblem in patients with CF), low-grade appendicitis (par-tially suppressed by antibiotic therapy) and periappendicealabscess.262 Nonfilling of the appendix with contrast enemais frequent in patients with CF, even in the absence ofappendicitis.263 Duodenal irritation, caused by failure tobuffer gastric acid, may underlie radiographic changes inthis area and recurrent epigastric pain.264

Rectal prolapse occurs in nearly 20% of children but is aninfrequent event for adults with CF.265 In fact, CF is said tobe the most common cause of rectal prolapse in the UnitedStates. Factors contributing to rectal prolapse include thepresence of bulky, sticky stools that adhere to rectal mucosa,loss of the perirectal fat that normally supports the rectum,and increased frequency of high intra-abdominal pressuredue to paroxysmal coughing. Pneumatosis coli has beenreported in association with rectal prolapse in an 18-year-old with CF.

PANCREATIC DISEASE

Pancreatic exocrine insufficiency is present from birth in thelarge majority of patients with CF.266 It has been estimatedthat only 5% to 10% of patients have significant pancreaticenzyme release. Exocrine pancreatic sufficiency has beenassociated with several mutations, including 3789 + 10 KbC to T, R117H, R334W, R347H, R347P, A455E, P574H,

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and Y563N. Enzyme deficiency results in fat and proteinmaldigestion, producing a distended abdomen and fre-quent, bulky, greasy, foul-smelling stools. Uncorrectedmaldigestion results in failure to gain weight and ultimatelyfailure of linear growth. However, poor growth also may beassociated with increased expenditure of energy to accom-plish the work of breathing, a point that is often overlookedin the assessment of patients who are short or excessivelythin.267 Fat loss in stools may be as high as 50% to 70% oftotal intake. Nitrogen malabsorption is roughly comparableor perhaps somewhat less severe. In general, carbohydratesare adequately absorbed in CF. Deficient absorption of fat-soluble vitamins occasionally produces symptoms. Sympto-matic vitamin A deficiency, initially a prominent part of the CF syndrome, is rare and occurs only in patients whodo not take supplementary vitamins or pancreatic enzymes.Increased intracranial pressure, xerophthalmia, and nightblindness may result. Rickets due to vitamin D deficiency israrely seen. However, bone demineralization is common in CF patients.268–271 Vitamin E deficiency is common inunsupplemented patients but only rarely causes symptomsor signs, including increased red blood cell destruction andneuroaxonal dystrophy. Vitamin K-dependent coagulationfactors may also be deficient, resulting in a hemorrhagicdiathesis. Although severe hemorrhagic problems occurmostly in young children, associated symptoms such ashemoptysis are occasionally seen in older patients.

It is now recognized that symptoms of pancreatitis areencountered in less than 1% of identified adolescent or adultCF patients and are limited to those who have retainedsome exocrine pancreatic function.272 However, recurrentpancreatitis has recently been reported to be associated withmutations in CFTR and is becoming more frequently rec-ognized as a presenting symptom in adults with CF.43,273,274

Pancreatic calcifications are occasionally seen roentgeno-graphically but do not seem to correlate with symptomaticpancreatitis.

HEPATOBILIARY DISEASE

Focal biliary cirrhosis is characteristic of CF but producessymptoms in less than 5% of CF patients and causes deathin about 2%.37,275 Hepatic abnormalities can present ashepatosplenomegaly or as persistent elevation of hepaticenzymes (particularly alkaline phosphatase). Rarely, patientspresent with esophageal varices and hemorrhage due toportal hypertension. Fatty liver is more common and mayimprove with adequate nutrition. Gallbladder disease iscommon in adults with CF. Altogether, 10% to 30% ofpatients have dysfunctional gallbladders276 or gallstones.277

Common bile duct stenosis secondary to CF is rare.278

GENITOURINARY TRACT ABNORMALITIES

More than 99% of male patients with CF have obstructiveazoospermia due to obstruction of the vas deferens.44 Rel-atively high incidences of inguinal hernia and hydrocele alsohave been noted. Failure of reproductive function does notbecome an issue until well into the second decade of life.Semen analysis may be required to identify the 1% of maleCF patients who are fertile. The volume of ejaculate isusually one third to one half of normal. There usually is

complete absence of spermatozoa, and a number of chem-ical abnormalities of semen that reflect absence of secretionsfrom the seminal vesicles can be demonstrated.279

Female infertility in CF may be as high as 20%.279 Somewomen with CF are anovulatory because of chronic lungdisease and malnutrition. Another obstacle to conceptionmay be the presence of thick, tenacious cervical mucus,which is difficult to dislodge from the os. This mucus isdehydrated and has abnormal electrolyte concentrations,preventing the usual ferning at midcycle and perhapsimpeding normal sperm migration.280 Endocervicitis iscommonly noted.

More than 600 pregnancies in CF females have beenreported. A longitudinal study of 325 pregnant women withCF demonstrated 258 live births (79%) and 67 therapeuticabortions.281 Compared to 1142 age- and severity-matchedcontrols, pregnancy in a woman with CF did not have anindependent negative effect on pulmonary status or mor-tality over 2 years.282 However, it is essential that CF femalesconsider their own health and expected life span in thecontext of family planning. Women with CF can breast-feedsuccessfully.283

SWEAT GLAND DYSFUNCTION

Sweat chloride is elevated in most CF patients due to abnor-mal NaCl reabsorption in the sweat ducts.284 Excessive loss ofsalt in the sweat predisposes young children to depletionepisodes, especially at times when there is additional salt lossdue to vomiting or diarrhea. These children present withlethargy, anorexia, and hypochloremic alkalosis, a presenta-tion that is more common in warm arid zones. Suchhypochloremic alkalosis is rare in older children and adults.285

DIAGNOSIS

The diagnosis of CF is based on carefully defined clinical cri-teria and laboratory evidence of CFTR dysfunction, includ-ing abnormal sweat Cl- levels.284,286 Accepted diagnosticcriteria are listed in Table 38.5. Any one of these clinical fea-tures, if accompanied by a sweat chloride level greater than60 mEq/L, is sufficient to make the diagnosis. Characteris-tic nasal epithelial bioelectric abnormalities can also serve as laboratory evidence of CFTR dysfunction and be used to diagnose CF when phenotypic clinical features arepresent.284,287 Many diagnoses are verified by identifying amutation in CFTR on both alleles. At this time, however, asubstantial number of patients have unidentified mutations.A few persons with sweat chloride values persistently in thediagnostic range but without clinical features of CF or afamily history have been identified. So long as they remainsymptom-free and mutations of both CFTR genes are notidentified, the diagnosis of CF cannot be made. Other clin-ical entities may be accompanied by elevated sweat chlorideconcentrations (Table 38.6). None of these disorders iseasily confused with CF. It is now recognized that a smallpercentage of persons with CF have sweat values in an inter-mediate (40–60 mEq/L) or even normal range.35,288,289

For the 1% to 2% of patients with compatible clinical fea-tures of CF but normal sweat chloride levels, severalapproaches to the diagnosis are available. Clinical criteria for


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diagnosing CF in the presence of a normal sweat chloridevalue were proposed prior to modern diagnostic options.288

The discovery that bioelectric potential differences acrossrespiratory epithelia are abnormal in patients with CF9,102,287

offers a quantitative diagnostic test that has been useful forevaluating atypical patients. Also, DNA analysis techniquesare now available for detecting CF gene mutations, partic-ularly in clinical variants. For example, a single mutation of

the CFTR gene, 3789 + 10 Kb C to T, is associated withmany of the suspected cases of CF whose sweat chloridevalues are in the normal range.35,40

Although DNA analysis is becoming a standard of care inCF, the sweat test remains the diagnostic standard. Onlyone method is recognized by the Cystic Fibrosis Founda-tion as adequate for a definitive diagnosis of CF. This testinvolves collection of sweat by pilocarpine iontophoresiscoupled with chemical determination of the chloride con-centration.290,291 The procedure must be carried out in ameticulous fashion to avoid errors that frequently con-tribute to misleading values. As many as 40% of patientsreferred to CF centers have been inaccurately diagnosedelsewhere because of false-positive or false-negative sweattest results. In addition to frequent laboratory errors, faultyvalues can be obtained if the sweat rate is not sufficientlyhigh. At least 50 mg of sweat must be collected in a 30-minute period. Potential pitfalls in interpretation includethe presence of hypoproteinemic edema, failure to considerage-related effects, and concurrent administration of corti-costeroids. Although using a chloride threshold of 60 mEq/Lin sweat appears to distinguish nearly all adults with CFfrom those with other lung conditions,292 normal values ofsweat chloride do increase with age, and some investigatorsinsist on documentation of sweat chloride levels in excess of70 mEq/L for the diagnosis of CF in adults.

Newborn screening for CF is carried out on all infants inseveral states. The test used is an assay of immunoreactivetrypsin in dried blood spots collected on filter paper in thefirst several days of life. Experience thus far suggests thatmany, but not all, newborns with CF may be identified withthis test.293 The test has an acceptable rate of false-positiveresults. Screening for gene mutations is currently precludedby the large number of mutations. If screening were basedon DF508 alone, fewer than half of all newborns with CFwould be identified. If parents were to be screened by DNAanalysis, only 70% of carriers or 50% of carrier couples wouldbe detected. At present, routine newborn screening cannotbe strongly recommended, largely because there is not yeta specific highly efficacious therapy for this condition thatdemands early intervention. However, studies of newbornswith CF discovered by screening have detected nutritionaldeficits, which suggests that early identification and treat-ment may be useful for protecting against loss of lung func-tion.294–297a In addition, pharmacologic and gene transfertherapies, currently at an experimental stage, are theoreti-cally most effective early in life; if their efficacy is docu-mented, newborn screening can play an important role.

Antenatal diagnosis can now be carried out, especiallywhen the genotype of parents is established. A recentNational Institutes of Health Consensus Statement recom-mended that genetic testing for CF be offered to couplescurrently planning a pregnancy.298

TREATMENT

The primary objectives of CF treatment are to control infec-tion, promote mucus clearance, and improve nutrition.299

In addition, experience has repeatedly demonstrated thatattention to preventive aspects of lung care and psychoso-cial factors are important. The efficacy of a number of

Table 38.5 Criteria for the Diagnosis of Cystic Fibrosis

Phenotypic Clinical FeaturesChronic Sinopulmonary DiseaseChronic cough and sputum productionPersistent infection with characteristic pathogens

(Staphylococcus aureus and Pseudomonas aeruginosa)Airflow obstructionChronic chest radiographic abnormalitiesSinus disease; nasal polypsGastrointestinal and Nutritional AbnormalitiesPancreatic exocrine insufficiency; recurrent pancreatitisMeconium ileus; distal intestinal obstruction syndromeObstructive Azoospermia in Males

Laboratory Evidence of CFTR DysfunctionElevated sweat Cl-

Mutation in the CF gene on both allelesCharacteristic bioelectric abnormalities (potential difference)

in nasal epithelium in vivo

CFTR, cystic fibrosis transmembrane conductance regulator.Adapted from Rosenstein BJ, Cutting GR: The diagnosis of cysticfibrosis: A consensus statement; Cystic Fibrosis Foundation ConsensusPanel. J Pediatr 132:589–595, 1998.

Table 38.6 Conditions Other Than Cystic Fibrosis Associatedwith Elevated Sweat Chloride Levels

Adrenal insufficiency

Anorexia nervosa

Atopic dermatitis

Pseudohypoaldosteronism

Hypothyroidism

Hypoparathyroidism

Nephrogenic diabetes insipidus

Ectodermal dysplasia

Glycogen storage disease (type I)

Mucopolysaccharidosis

Fucosidosis

Malnutrition

Mauriac’s syndrome

Familial cholestasis syndrome

Prostaglandin E1 administration

Hypogammaglobulinemia

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currently used and new approaches is being tested in con-trolled multicenter clinical trials.

AMBULATORY CARE

At diagnosis, most patients are introduced to a care programthat includes postural drainage with chest percussion, admin-istration of antibiotics as indicated, and a nutritional regimenincluding pancreatic enzymes and fat-soluble vitamins.Other therapeutic modalities are prescribed as indicated.

Airway Clearance

The use of postural drainage with chest percussion to clearmucus is based on the concept that cough clears mucusfrom large airways, but chest vibrations are necessary tomove secretions from the small airways, where expiratoryflow rates are low. The most compelling argument for theuse of this therapeutic modality comes from a study of olderchildren with mild to moderate airflow limitation.300 Whenpatients were receiving chest physical therapy on a regularbasis, the only immediate effect documented was an increasein peak expiratory flow rate 30 minutes after therapy.However, after 3 weeks without chest physical therapy, bothFVC and flow rates were significantly reduced. The diminu-tion in lung function could be reversed with renewal ofregular chest physical therapy. A recent meta-analysis of 35studies concluded that standard chest physical therapyincreases sputum production and improves expiratoryairflow (FEV1).301 Most care centers prescribe this therapyone to four times a day, depending on the severity of illness.A variety of mechanical percussors are available to assist,especially for patients who perform their own therapy.Several studies in the literature suggest that repeated forcedexpiratory maneuvers,302 use of positive expiratory pres-sure,303 and vigorous exercise304–306 may substitute for chestphysical therapy. The advisability of chest physical therapyfor patients who have minimal cough and no apparentsputum production is open to question. Study results arenot available to answer this question. Theoretically, chestphysical therapy might prevent or delay inspissation ofmucus in small airways, which is the earliest lesion. In addi-tion, caregivers have found that many patients who do notreceive chest physical therapy on a regular basis are unlikelyto initiate this therapy when pulmonary exacerbations arise.

Antibiotics

Lung infection is the major source of morbidity and mor-tality in CF. Therefore, antibiotic therapy is the mainstay of therapy designed to control progression of disease. Ingeneral, antibiotic therapy should be predicated on the pres-ence of symptoms and guided by the identification of organ-isms from the lower respiratory tract. There is evidence thatearly, vigorous use of antibiotics produces better results thandelaying the administration of antibiotics until symptomsare well developed or advanced.307 Similarly, P. aeruginosainfection has been treated by regularly scheduled courses ofintravenous antibiotics.308 Data justifying these approachesare lacking.

Another principle of antimicrobial therapy in CF is thatdosages need to be higher than for non-CF-related chest

infections. Both total body clearance and volume of distri-bution are considerably greater for CF patients than forother patients.309 In addition, large doses are needed toachieve therapeutic levels in the infected and mucus- or pus-filled endobronchial space. Sputum levels achieved arehighly varied but usually are less than half of the levels meas-ured in serum.310 Experience also has led many caregivers ofCF patients to use longer than usual courses of antibiotics,continuing for at least 2 weeks and frequently 3 to 4 weeks.

The choice of antibiotics is optimally based on the resultsof sputum culture and sensitivity testing. For patients withnonproductive cough, specimens are best obtained by har-vesting secretions with a throat swab placed just above theglottis during repetitive coughing. Nasopharyngeal culturesare not useful as a guide for selecting antibiotics. If S. aureusis present or expected, the choice may include a semisyntheticpenicillin, a combination of ampicillin and clavulanic acid, acephalosporin, or clindamycin. Suggested drugs and dosesare given in Table 38.7. Haemophilus infections are besttreated with ampicillin, trimethoprim-sulfamethoxazole,cefuroxime, or cefaclor. In the majority of cases, these antibi-otics eradicate S. aureus and H. influenzae from the airwayson a temporary basis. In older children and adults, tetracy-clines may provide useful empirical therapy. Ciprofloxacinappears to control symptoms and reduces numbers ofPseudomonas organisms in CF airways, but its usefulness islimited by rapid emergence of resistant organisms.311

Because of limited options for treatment of Pseudomonaswith oral antibiotics, parenteral preparations of aminogly-cosides or other antibiotics have been delivered to the lowerrespiratory tract by aerosol.312,313 Recent studies show clearshort-term benefit of aerosolized tobramycin (300 mg in anebulizer) taken twice daily.314 This treatment, taken inalternate months for three cycles, improved lung function,decreased the bacterial burden, and decreased the relativerisk for hospitalization. The rate of acquired tobramycinresistance was about 7% over 24 weeks in the treated group.

Azithromycin

Long-term macrolide antibiotics effectively treat diffusepanbronchiolitis and have been tested in CF. Randomized,controlled clinical trials in CF children in the UnitedKingdom,315 in adults who were chronically infected with P.aeruginosa in Australia,316 and in chronically P. aeruginosa-infected children and adults in the United States317 demon-strated clinical improvement (better pulmonary functionand fewer pulmonary exacerbations) with azithromycin. Asputum acid-fast bacillus (AFB) smear and culture shouldbe obtained prior to initiating chronic macrolide therapybecause of the risk that undiagnosed nontuberculousmycobacterial infection could develop macrolide resistance.For patients on chronic macrolide therapy, an AFB smearand culture should be obtained every 6 months.

Aerosolized Recombinant Human DNase

The lysis of viscous DNA with the recombinant enzymeDNase offers benefit to some patients with purulent airwaysecretions.318 When taken once daily, aerosolized DNasereduced the relative risk of respiratory exacerbations by 28%and improved the FEV1 about 6% above baseline over 6


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months. Not all patients had objective improvement in lungfunction, but symptomatic benefit occurred in many of thetreated patients without improved lung function. The long-term effect of DNase on lung function is currently beingevaluated in an open-label multinational study.

Other Aerosol Therapy

Other solutions given by aerosol have the objective of pro-viding a volume of liquid to hydrate inspissated mucus secre-tions. One frequently used solution is normal saline, but theefficacy of this approach has not been substantiated. Studiesfrom Australia suggest that aerosolized hypertonic saline(3–12%) may offer short-term benefit with acute improve-ment in lung function and mucociliary clearance.319,320,320a

Bronchodilators

As detailed in the clinical manifestations section, manypatients demonstrate bronchial lability, prompting frequentuse of bronchodilators,224 particularly beta-adrenoceptoragonists. Although their immediate effectiveness can be documented in the pulmonary function laboratory, overall

improvement or long-term benefit has not been established.Indications for the use of bronchodilators include trouble-some wheezing and a documented improvement in pul-monary function (e.g., at least 15% improvement of FEV1).Beta-agonists can be nebulized, administered by metered-dose inhalers, or given orally. Caution should be exercised con-cerning long-term therapy with these agents because animalstudies show that administration of large amounts of beta-adrenoceptor agonists cause submucosal gland hypertrophyand presumably a hypersecretory state.321 Theophylline prepa-rations also are effective in selected cases. However, CFpatients seem to be less tolerant of theophylline because of fre-quent gastrointestinal irritation.322 Ipratropium bromide is atleast as effective as beta-agonists in CF,323–325 although distalintestinal obstruction syndrome has been reported coincidentwith use of this agent.326 Cromolyn sodium has also been used;a single study failed to demonstrate efficacy.327

Corticosteroids

An initial double-blind controlled study of alternate-dayoral corticosteroid administration V. placebo demonstratedbetter maintenance of pulmonary function and fewer exac-

Table 38.7 Antimicrobial Agents Used to Treat CF Lung Infection

Dose

Route and PediatricOrganism Agent (mg/kg/day) Adult (g/day) Doses/day

OralS. aureus Dicloxacillin 50–100 2–4 4

Cefaclor 40 0.75–1.5 3Clindamycin 15–25 0.6–1.2 4Erythromycin 50 2 4Amoxicillin/clavulanate 40 1.5 3Azithromycin — 0.5 day 1, then 1

0.25 daily for 2–5 daysH. influenzae Amoxicillin 40–60 1.5 3

Trimethoprim-sulfamethoxazole 20* 0.32–0.64* 2–4P. aeruginosa Ciprofloxacin — 1.5–2.25 3

Ofloxacin — 0.8–1.2 2–3Empirical Tetracycline 50–100 2 3–4

IntravenousS. aureus Oxacillin 150–200 † 4

Vancomycin 40 2 2–4P. aeruginosa Gentamicin or 8–20 † 2–3

Tobramycin 8–20 † 2–3Amikacin 15–30 † 4–6Carbenicillin or 250–450 † 4–6Ticarcillin 250–450 † 4–6Piperacillin, mezlocillin, or 45–90 4 3–4

azlocillin ticarcillin/clavulanateimipenem/cilastatin

AerosolP. aeruginosa and Ceftazidime 150 4–6 3

B. cepaciaP. aeruginosa Gentamicin 40–600‡ 80–600‡ 2–4

Tobramycin 40–600‡ 80–600‡ 2–4

* Quantity of trimethoprim.† Usually dosed by milligrams per kilogram per day as with children.‡ Total dose in milligrams.

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erbations of lung disease requiring hospitalization over a 4-year period.328 However, a subsequent large multicenterstudy of corticosteroids administered in a dose of 1.0 or 2.0 mg/kg every other day failed to confirm efficacy andwas attended by an unacceptable rate of side effects, includ-ing growth suppression and hyperglycemia. Widespread useof corticosteroids cannot be advocated. They may, however,be used for specific indications such as allergic bronchopul-monary aspergillosis.

Anti-inflammatory Therapy With Ibuprofen

A recent study of high-dose ibuprofen over 4 years indicatesthat young CF patients (<13 years) with mild lung diseasehave remarkable slowing of the decline of lung function(eightfold) compared to placebo control subjects.329 Noeffect was documented in patients older than 13 years, evenamong patients with mild lung disease. There were few sideeffects, but most of the patients were taking antacids or H2-receptor blockers.

Other Respiratory Therapies

Mucolytics, expectorants, and cough suppressants havebeen used for relief of chest symptoms. In general, coughis an important mucus clearance mechanism for patientswith CF and should not be suppressed. Expectorants, whichassist in the elimination of airway secretions during cough,probably do not achieve that objective. Rather than beinghelpful, long-term administration of iodides to patients withCF has been associated with a high incidence of goiter andhypothyroidism.330 Mucolytics such as N-acetylcysteine areinjurious to respiratory epithelium and promote bronchitiswhen used regularly. Therefore, aerosol inhalation of thissubstance should be used selectively and only for shortperiods. Another experimental approach, delivery of elastaseinhibitors to airways by aerosol, is the subject of several clinical trials. Experimental studies implicate a cascadeinvolving epidermal growth factor receptor (EGFR) activa-tion in mucin production330a by a wide variety of stimuliincluding products of Pseudomonas bacteria,330b and selec-tive EGFR inhibitors may provide useful therapy for mucushyper secretion in CF.

Other experimental drugs include Na+ conductance inhi-bitors331,332 and triphosphate nucleotides.125,127,156 Both act toincrease salt and water availability at the epithelial surface ofthe airway and may improve mucus clearance properties.

Exercise is generally considered beneficial for patients withCF and should be encouraged for all but those with the mostsevere lung disease and hypoxemia.333 A 12-week exerciseprogram consisting of three 1-hour sessions a week, duringwhich jogging was used to produce a heart rate averaging70% to 85% of peak heart rate, has been shown to increaseexercise tolerance and cardiorespiratory fitness, probably by increasing respiratory muscle endurance.237 However,this program did not improve pulmonary function. Mostcaregivers of patients with CF believe that regular, vigorousexercise promotes a positive self-concept and increases theperception of wellness. In addition to cardiopulmonary con-ditioning exercises, isometric exercises such as weight liftingmay build abdominal and upper body muscle strength andin this way promote deep breathing and effective coughing.

Gene Transfer Technology

It is technically possible using genetically engineered viralvectors to transfer the wild-type CFTR gene to respiratoryepithelial cells in vitro, where it can be expressed for at leastdays to weeks.334 Systems for efficient targeted delivery andoptimal integration in vivo are being studied and contributeto the hope that genetic reconstitution will be a feasibleapproach to lung therapy in the future.

Nutrition

Approximately 90% of patients with CF require mealtimepancreatic enzymes, packaged as granules that are coatedwith acid-resistant material to promote delivery to the smallintestine. Capsules containing 4000 to 24,000 units of lipase are available. The number of capsules taken should beadjusted based on weight gain, the presence or absence ofabdominal cramping, and the character of the stools. Dosageshould be limited to current guidelines (about 2500 lipaseunits/kg/meal) because a large total daily dose of enzymeshas been associated with fibrosing colonopathy.335–338 Vita-mins A and D are generally supplied by a daily multiple-vitamin preparation. Also, 100 to 200 units of vitamin E dailyare recommended because serum levels are generally low inunsupplemented patients. Vitamin K is given sporadically totreat bleeding complications or to correct prolonged pro-thrombin times. Other vitamins and trace minerals may bedeficient and require supplementation on a selective basis.267

Many patients with CF have a higher than normal caloricneed because of the increased work of breathing. In general,patients should be encouraged to eat a balanced diet,including at least a moderate amount of fat. When theanorexia of chronic infection supervenes, there is failure togain weight or even weight loss. Further encouragement toeat high-calorie foods may be helpful. Supplementationwith elemental dietary preparations by mouth is unlikely tobe sustained over an extended period of time. Some CF carecenters administer supplementary elemental feedings noc-turnally by nasogastric tube or percutaneous duodenos-tomy.267,339 Although short-term benefits such as increasedweight gain can be achieved, long-term beneficial effects onpulmonary function have not been established.

Patients with CF who retain exocrine pancreatic functionand maintain good nutrition experience a slower rate ofdecline of pulmonary function than those with pancreaticdysfunction.340 This observation has been used as a ration-ale for emphasizing nutritional interventions. Although thisapproach may have merit, it is generally more efficacious tomaintain good nutrition by preventing progression of lungdisease than to maintain good lung function by emphasiz-ing nutritional therapy.

Psychosocial Factors

As with any chronic disease, compliance with therapy andthe ability to function fully are highly dependent on thepatient’s attitude. Therefore, approaches that promote apositive self-concept, foster the ability of patients to takecontrol of their medical management, and enable them toparticipate fully in life events are likely to promote well-being and perhaps longevity. Medical care that providescontinuity and fosters trust may pay large dividends.


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Personnel who specifically provide psychosocial support areimportant contributors to CF care teams.341

Immunization for Lung Pathogens

Rubeola, pertussis, and influenza infections are particularlyinjurious to CF lungs and may trigger a downward spiral oflung function. Adequate immunization early in life for per-tussis and measles is mandatory. In addition, patients of allages should be adequately immunized for influenza virusinfection on a yearly basis. The early use of amantadine foracute respiratory illnesses during epidemics of influenza Ainfections may further prevent adverse consequences of thisinfection. Other routine vaccines should be administered as for the general population. There is no evidence thatadministration of pneumococcal vaccine is useful.

HOSPITAL THERAPY

Indications for hospitalization and intensive pulmonarytherapy include increased cough or wheezing, respiratorydistress with decreased activity tolerance, weight loss, a sus-tained downward trend in pulmonary function, increasinghypoxemia, or one of the major pulmonary complicationsof CF. Although all the modalities of therapy can be inten-sified in the hospital, the major advantage of hospitalizationis the ability to administer intravenous antimicrobial agentsthat control Pseudomonas infection and intensify physicalmaneuvers to clear airway secretions.

Antibiotics for intravenous administration should beselected on the basis of respiratory tract cultures and sus-ceptibility studies. Two-drug treatment of Pseudomonasinfection is the rule. A third antibiotic may be added as necessary for control of S. aureus or other organisms. Drugsand dosages currently used for intravenous therapy are listedin Table 38.7. A clinical response is often not seen for 4 to7 days after initiation of therapy. In general, a 2-week courseprovides good improvement in pulmonary function342,343

and more sustained benefit than shorter courses. Withrefractory infection, treatment for 3 weeks or more is notunusual. Some advocate intensive therapy until pulmonaryfunction has returned to a previous baseline or untilimprovement has reached a plateau. Prolonged courses ofantibiotic therapy should include periodic monitoring ofrespiratory tract organisms and their antibiotic sensitivities,as shifts in either are common.

Aminoglycosides have been the mainstay of anti-Pseudomonas therapy for many years. A major advantage isthe ability to monitor and adjust blood levels. For gentamicinor tobramycin, two to three times a day dosage and achieve-ment of peaks in the range of 10 to 12 mg/mL and troughsless than 2 mg/mL seem to be optimal. Patients should bemonitored during aminoglycoside therapy for nephrotoxic-ity and ototoxicity. An aminoglycoside is usually paired withone of the penicillin derivatives or with ceftazidime.

Patients with CF, particularly those who are in school orholding full-time jobs, may opt to administer intravenousantibiotics at home for all or a portion of the treatmentcourse. This seems to work well in selected cases and maybe as effective as in-hospital treatment.344,345 For patientsrequiring frequent courses or long-term home antibiotictherapy, central intravenous catheters have been surgicallyplaced and used for prolonged periods.

One study suggested that intravenous infusion of immu-noglobulin (500 mg/kg) during a course of intravenousantibiotics enhances the pulmonary function response.346

Further studies are needed to confirm these observations.Interest in bronchial lavage as a therapeutic modality has

been tempered by the realization that long-term benefits areunlikely to accrue from this approach and that acute dete-rioration of lung function is a possible outcome.347 In fact,there is no evidence that bronchoscopy and lavage, whetherit be whole lung, lobar, or segmental, is superior to inten-sive antibiotic therapy and chest percussion.

Lung Complications

Hypercapnic and hypoxemic respiratory failure in CF areprimarily due to progressive obstructive airway disease withalveolar hypoventilation and ventilation/perfusion mis-matching. Treatment of airway infection and inflammationwith antibiotics as well as the airway clearance measuressummarized above is essential. Low-flow oxygen is effectiveat relieving nocturnal, exertional, and resting hypoxemiaand does not usually cause significant hypercapnia.348 Theuse of supplemental oxygen in children has been discour-aged349 because nocturnal oxygen did not improve survivalor prevent the development of cor pulmonale in one con-trolled trial.350 A larger study demonstrated that the devel-opment of pulmonary hypertension in adults with CF isstrongly correlated with hypoxemia and is associated withincreased mortality.351 Therefore, supplemental oxygen inaccordance with the guidelines established for chronicobstructive pulmonary disease352 is recommended.353

Diuretics, inotropic agents, and theophylline produce fewbenefits and are rarely used. Cor pulmonale is a late com-plication of airway obstruction, and no treatment optionsbeyond those for the primary disease processes are effective.

Ventilatory assistance is effective in CF patients with acuterespiratory failure caused by reversible insults,259 but it pro-duces few long-term benefits in patients with respiratoryfailure due to irreversible lung damage caused by CF bronch-iectasis.354 Assisted ventilation using nasal or face masks355 orendotracheal tubes356,357 can effectively treat patients awaitinglung transplantation. The airway disease generally progresses,however, and long-term ventilatory support is rarely feasible.

Atelectasis is best treated by vigorous standard therapy,including airway clearance and antibiotics. Corticosteroidsmay be helpful in the presence of reactive airways or severeairway inflammation. There is no evidence that bron-choscopy and lavage are effective in expanding collapsedsegments of lobes.247 ABPA responds to standard doses ofsystemic corticosteroids.358 Inhaled steroids359 and the oralantifungal agent itraconazole360 may prove to be useful.

Pneumothorax can be observed, allowing spontaneousresolution, if it is small and minimally symptomatic. A largepneumothorax (>20% of the hemithorax volume, compro-mising ventilation or causing hypotension) requires tubedrainage.229 Recurrences are very common and may requirethoracoscopic talc poudrage or surgical pleural abrasion.253

Hemoptysis requires treatment of airway infection andsupplemental vitamin K if the prothrombin time is pro-longed due to inadequate absorption. Massive hemoptysismay resolve with such conservative therapy and modestcough suppression for 1 to 2 days,249 but bronchial artery

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embolization250,361 provides more definitive control, whichusually persists for more than 6 months.

Gastrointestinal Complications

Meconium ileus can be relieved in a number of cases withenemas using meglumine diatrizoate (Gastrografin) orother contrast materials, which are refluxed into the termi-nal ileum under fluoroscopy. If this fails, or if there is evidence of perforation, surgical intervention is required.Distal intestinal obstruction syndrome also can be relievedwith contrast enemas that reach the terminal ileum.However, this approach has been largely supplanted byintestinal “flushes” with a balanced salt solution; 1 to 2 litersrapidly instilled into the stomach is usually effective. Occa-sionally, surgical intervention is necessary. Rectal prolapseusually can be reduced voluntarily by older patients usingabdominal, perineal, and gluteal muscles, but in small chil-dren rectal prolapse must be reduced manually by continu-ous gentle pressure with the patient in the knee-chestposition265; sedation may be helpful. Adequate pancreaticenzyme therapy, decreased fat in the diet, and control ofpulmonary infection usually prevent recurrences. A fewpatients may require surgical stabilization of the rectum.

Cirrhosis is generally focal and usually does not require spe-cific therapy. Localization of CFTR to bile ductule cells sug-gests that abnormal bile secretion may be germane to CF liverdisease. Ursodeoxycholic acid (URSO) is effective treatmentfor primary biliary cirrhosis.362 Early trials of URSO in CFpatients showed improved liver function test results, but thelong-term effect on liver function is not known.363,364 Thethresholds for initiating therapy and clinical outcomes areunder investigation. Bleeding esophageal varices that com-plicate cirrhosis often can be managed with banding or scle-rotherapy. In the past, significant bleeding has been treatedsuccessfully with portosystemic shunting.365 Splenorenal anas-tomoses have been most effective, and hepatic encephalopa-thy has not been a problem. The transjugular intrahepaticportosystemic shunt procedure366,367 can relieve portal hyper-tension and reduce bleeding episodes. Liver failure and ascitesare treated as in other patients. Liver transplantation has beensuccessfully performed, with the 2-year survival exceeding50%.368,369 Pancreatitis, when it occurs in adolescents oryoung adults with CF, is treated with standard measures.

Hyperglycemia as a complication of CF can occur at anyage, but it is generally a problem of the second and thirddecades of life.268 Ketoacidosis is rarely encountered. Whenblood glucose levels are only intermittently elevated andglycosuria is not present, no treatment is necessary. Withthe advent of sustained glycosuria, insulin treatment shouldbe instituted. Oral hypoglycemic agents, considered inef-fective in the past, may be helpful in selected patients.370

The development of significant hyperglycemia may notchange longevity.371,372 However, vascular disease affectingthe retina and kidneys has been documented in CF patientswho have had prolonged hyperglycemia.373,374 Therefore,careful control of blood sugar levels is desirable.

Surgical Therapy

Nasal polypectomy to relieve obstruction is the mostcommon surgical procedure in CF, and most patients get

symptomatic improvement.375 Recurrence of polyps iscommon,376 but the incidence of polyposis usually wanesafter the second decade. Gallstones are common, and symp-tomatic disease may require elective cholecystectomy in asmany as 5% of CF adults.377 Lobectomy is occasionally indi-cated for massive hemoptysis that is refractory to bronchialartery embolization. Partial lung resection has been advo-cated for apparently localized disease and recurrent severeexacerbations.378 However, the generalized lung diseasecontinues to progress; the limited probability of long-termbenefits dictates caution in patient selection.

Transplantation

See Chapter 89 for a full discussion of lung transplantation.Lung transplantation has become an accepted treatment

for respiratory failure secondary to CF.379 Heart-lung trans-plant has been largely replaced by sequential double-lungtransplant because of limited organ availability. Patientsshould be referred when their prognosis is about equal tothe waiting time for donor lungs, currently about 2 yearsafter acceptance as a lung transplant candidate. More than1600 lung transplants have been performed for CF aroundthe world. The transplanted lungs remain free of CF but aresubject to secondary infection, acute rejection, and chronicrejection (bronchiolitis obliterans syndrome). The 5-yearsurvival is 48%—as good as that of lung transplant re-cipients with other causes of lung disease. Living lobartransplantation is an effective alternative to conventionalcadaveric lung transplants.380 The lobe donors must havesufficiently large lungs that their lower lobe fills the recipi-ent’s hemithorax. Survival appears to be similar to that fol-lowing conventional lung transplantation.

COURSE OF THE DISEASE AND PROGNOSIS

Cystic fibrosis runs a highly varied course, ranging fromdeath due to complications of meconium ileus in the firstdays of life or death from severe respiratory tract problemswithin the first months of life to essentially asymptomaticexistence for 10 to 20 years381 and protracted survival. A fewpatients with CF do live into the sixth and seventh decadesof life.261 More than 7500 (36%) of the patients in the U.S.Cystic Fibrosis Registry are 18 years of age or older.382 Thechanging age distribution is demonstrated in Figure 38.8.

At most care centers, patients with CF are monitored bygeneral clinical assessment, which often involves the use ofa scoring system,383,384 periodic monitoring of respiratorytract pathogens, periodic chest roentgenograms, serial pul-monary function testing, and ongoing nutritional assess-ment. Initial intensive treatment is usually followed byimprovement in pulmonary function tests as well as sub-stantial improvement of weight-to-height ratios and accel-erated linear growth in children. After initial improvementor stabilization, there is often an extended period of stablelung function, which may last 5, 10, or even 15 years. Pro-gressive dysfunction inevitably supervenes. Longitudinalpatterns of pulmonary function in older individuals with CFare highly variable.385,386

The most recent statistics from the Cystic Fibrosis Foun-dation indicate that 50% of patients can now be expected


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to survive beyond age 30 years. These data were generatedfrom all patients under care in Cystic Fibrosis Foundation-sponsored centers in 1997 (Fig. 38.9). Analyses of survivalcurves over the years have suggested that longevity hasincreased steadily to the present time. Some of the improve-ment in survival may have resulted from the diagnosis ofmilder forms of the disease. However, there is considerableopinion that improved symptomatic therapy has also con-tributed to better survival.

Multiple factors determine the prognosis for individualswith CF.387 Data from all U.S. CF centers suggest that sur-vival is better for patients living in northern climates thanfor those in the South. On average, male patients live 3 yearslonger than do female patients. Blacks who survive the firstseveral years of life may have a better prognosis than whites.Age at diagnosis has not emerged as a clear determinant ofsurvival. However, a study of sibling pairs suggests that theyounger sibling who is diagnosed before 1 year of age,before the onset of symptoms, usually has better pulmonaryfunction at 7 years of age than does the older sibling diag-nosed at an older age because of symptoms.388 Outcomeanalyses of patients who have been identified at birth byscreening procedures and those who have been diagnosedafter onset of symptoms should provide more definitive evi-dence for the efficacy of early diagnosis and treatment.

Several studies suggest that the clinical features presentwhen the patient is first seen make a difference. Patients whoinitially have only steatorrhea and failure to thrive generallyimprove remarkably after institution of therapy and do wellfor extended periods of time. On the other hand, patientswho have respiratory tract symptoms when first seen usuallycontinue to have respiratory tract problems and have a lessfavorable prognosis.389 When the entire CF population isconsidered, those patients who retain pancreatic exocrinefunction display a slower progression of pulmonarydisease.32,390 Meconium ileus does not influence longevity ifthe patient survives the first months of life. Initial claimsthat CF patients with allergies have improved survivalcannot be substantiated. There are numerous indicators ofpoor prognosis once airway disease has been established,

Per

cent

50

40

30

20

10

01969 1978 1992 1997 2002

8.0

18.0

32.8

36.1

40.2

Year Year

n = 624 2350 5244 6432 9288

Figure 38.8 Percent of cystic fibrosis patientsaged 18 or older for 1969 to 2002. Data are fromthe Patient Registry, Cystic Fibrosis Foundation,Bethesda, MD.

100

80

60

40

20

0

100

80

60

40

20

0

10 20 30 40

Median survival

30.6 Years

Per

cent

sur

viva

l

Age (y)

A

B 10 20 30 40

Age (y)

Per

cent

sur

viva

l

Median survival28.2 Years

Figure 38.9 Survival curve for male (A) and female (B) cysticfibrosis patients followed in all U.S. centers in 1991. This curvedemonstrates that the median survival age, or age to which50% of the patient population may be expected to survive,exceeds 30 years for males and 28 years for females. Aggregatemedian survival is 29.4 years. Data are from the PatientRegistry, Cystic Fibrosis Foundation, Bethesda, MD. (Courtesy ofDr. S. Fitzsimmons.)

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including colonization with P. aeruginosa or B. cepacia andoccurrence of such pulmonary complications as pneumoth-orax and massive hemoptysis.391 The onset of insulin-dependent hyperglycemia has been considered a riskfactor,372 but some evidence suggests that survival rates ofthese patients parallel those of patients who have no overtproblem of glucose metabolism.392

Little is known about the influence of medical care onlongevity. Several studies suggest that patients followed atestablished care centers have a greater median survival thanthose who receive care in nonspecialized settings.393 In addi-tion, evidence suggests that center to center variation in sur-vival of patients is directly related to the intensity of carerendered in each center, including frequency of monitoring,antibiotic use, and hospitalization for treatment of pul-monary exacerbations.307

Finally, psychosocial factors undoubtedly play a promi-nent role in outcome, although this is difficult to docu-ment.394–396 The role of a supportive family is crucial. Suicideis uncommon, but it is widely recognized that a substantialnumber of adolescent and adult patients do not comply fully with therapy regimens because of denial, unresolveddependence/independence issues, and depression. Clearly,attitude and the ability to cope with a fatal illness duringmaturation and early adulthood do influence outcome.

Even though faced with a life-threatening illness and bur-dened with staggering demands on time, energy, and finan-cial resources to comply with therapy, most adolescents andyoung adults cope admirably and are able to achieve a sat-isfactory quality of life. Successful relationships,397 advancededucation, and a full-time occupation are frequentlyachieved (Table 38.8), indicating that independent lifestylesand full participation in life events are attainable goals formany patients.

SUMMARY

Cystic fibrosis is a prevalent autosomal-recessive syndromethat causes life-threatening chronic lung disease of child-hood and adulthood. It is caused by one or two of more

than 1000 identified mutations occurring in a gene on chro-mosome 7 that codes for an integral membrane protein ofepithelial cells (CFTR). This protein is a chloride channeland also regulates other ion channels in epithelial cells. Dis-turbed function results in alterations of electrolyte content,intraluminal volume, and diminished clearance of exocrinesecretions. Lung pathophysiology reflects airway obstruc-tion by accumulated mucus and secondary bacterial infection.

Diagnosis requires the identification of typical pulmonaryor pancreatic manifestations or a family history of CF com-bined with documentation of elevated chloride concentra-tions in sweat. Genotype analyses confirm the diagnosis andhave predictive implications for the clinical course.

Treatment currently focuses on control of mucus reten-tion and chronic infection in the lungs, replacement of pan-creatic enzymes, and nutritional therapy. Close monitoring,vigorous attempts to reverse deterioration of lung functionand nutritional deficits, and psychosocial support offer additional benefits.

The outcome is highly variable, but longevity hasincreased steadily and median survival now exceeds 31years. Quality of life for patients with CF has also improved.New approaches to therapy, including lung transplantation,pharmacologic interventions targeted to epithelial cellpathophysiology, and gene transfer to airway epitheliumoffer hope for further substantial therapeutic advances.

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Table 38.8 Educational and Employment Records of Adultswith Cystic Fibrosis

Parameter %

Highest Educational Degree (n = 686)Associate 10Bachelor’s 14Master’s 5Doctorate 2Other 4No advanced degree or no response 65

Employment (n = 679)Full time 37Part time 21Unemployed, seeking work 12Unemployed, not seeking work 30

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