Bronchiectasis in Systemic Disease - Chest

DOI 10.1378/chest.116.4.1063 1999;116;1063-1074Chest

Mark Cohen and Steven A. Sahn

*Bronchiectasis in Systemic Diseases

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Bronchiectasis in Systemic Diseases*

Mark Cohen, MD; and Steven A. Sahn, MD, FCCP

(CHEST 1999; 116:1063–1074)

Key words: bronchiectasis; inflammatory bowel disease; rheu-matologic diseases

Abbreviations: AS 5 ankylosing spondylitis; CD 5 Crohn’s dis-ease; HLA 5 human leukocyte antigen; HRCT 5 high-resolu-tion CT; IBD 5 inflammatory bowel disease; LIP 5 lymphocyticinterstitial pneumonitis; NIP 5 nonspecific chronic interstitialpneumonitis; RA 5 rheumatoid arthritis; RP 5 relapsing poly-chondritis; SLE 5 systemic lupus erythematosus; TB 5 tuber-culosis; UC 5 ulcerative colitis; YNS 5 yellow nail syndrome

B ronchiectasis is defined as an abnormal, irrevers-ible dilatation of the bronchi. It is not a disease

per se, but it represents the end stage of a variety ofpathologic processes.1 Laennec first described theclinical entity of bronchiectasis in 1819, but theclinical pattern of bronchiectasis has changed in thelast century due to the early treatment of necrotizingpneumonias, better control of tuberculosis (TB), andthe prevention of predisposing pulmonary infectionsby routine immunization. Advances in medical treat-ment have also lead to an increased survival toadulthood of patients with cystic fibrosis, hypogam-maglobulinemia, and immotile cilia syndrome, all ofwhich predispose to bronchiectasis.

Recently, bronchiectasis has been described as “anorphan disease,” with a prevalence estimated to below and decreasing,2 but no reliable statistical esti-mates are available. The true prevalence of bronchi-ectasis most likely is underestimated, as less severeforms of bronchiectasis have been documented withthe increased use of high-resolution CT (HRCT).3–11

It should also be recognized that an underlying causefor bronchiectasis is found in , 40% of patients,12

and that HRCT features alone do not allow aconfident distinction between idiopathic bronchiec-tasis and known causes of bronchiectasis.13,14

The most commonly cited classification of bron-chiectasis was based on bronchographic and autopsyfindings and included three patterns of bronchiecta-sis: cylindrical, varicose, and saccular or cystic.15

However, the clinical usefulness of designating bron-chiectasis to one of these patterns is questionable,and no study to date has shown a clinical, epidemi-ologic, or pathophysiologic difference between thesepatterns.16

This review will discuss the major systemic dis-eases associated with bronchiectasis and will de-scribe specific diagnostic and therapeutic modalitiesapart from the traditional interventions for any typeof bronchiectatic process. We will exclude diseasesthat are associated with abnormal host defenses(hypogammaglobulinemias, ciliary dyskinesis); ge-netic disorders (cystic fibrosis, a1-antitrypsin defi-ciency); and postinfectious processes, including al-lergic bronchopulmonary aspergillosis, since theseprocesses predominantly affect the lung (Table 1).

Rheumatologic Diseases

Rheumatoid Arthritis

Pleuropulmonary involvement is one of the extra-articular manifestations of rheumatoid arthritis (RA),with a prevalence estimated at , 5%.17,18 Pleuropul-monary manifestations of RA include the following:interstitial pulmonary fibrosis; pleural disease (pleu-ritis with or without effusion, sterile or septic empy-ema, necrobiotic nodules with bronchopulmonaryfistula, or pyopneumothorax); rheumatoid necrobi-otic nodules; respiratory tract infection, especiallytypical and atypical TB; bronchiolitis obliterans withor without organizing pneumonia; pulmonary vascu-lar lesions and pulmonary hypertension; apical fibro-bullous disease; thoracic cage immobility; and upperairway dysfunction due to cricoarytenoid arthritis.19

Bronchiectasis is typically not mentioned as an extra-articular manifestation of RA; however, an associa-tion between the two disorders is well recognized.

Bronchiectasis in patients with RA received con-siderable interest earlier in this century. Their asso-ciation was discounted on the argument that pulmo-nary TB was more common in patients withrheumatoid disease and that the bronchiectasis wasrelated to TB.20 The latter has been disproven byrecent studies where no historical or radiographicevidence of previous TB was found in patients withRA and bronchiectasis.11,19,21,22

To further strengthen the association between RAand bronchiectasis, Walker21 found the incidence ofbronchiectasis to be 3.1% in RA, compared to 0.3%

*From the Division of Pulmonary and Critical Care Medicine,Allergy and Clinical Immunology, Medical University of SouthCarolina, Charleston, SC.Manuscript received March 1, 1999; revision accepted May 13,1999.Correspondence to: Steven A. Sahn, MD, FCCP, Division ofPulmonary and Critical Care Medicine, Allergy and ClinicalImmunology, 96 Jonathan Lucas St, Suite 812, PO Box 250623,Charleston, SC 29425; e-mail: [email protected]

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in patients with osteoarthritis. He also noted that theincidence among newly referred patients with RAwas 3.2%, demonstrating that the association was notspuriously related to a more careful follow-up ofpatients with these two diseases. When the incidenceof bronchiectasis was compared to pulmonary fibro-sis in patients with RA, Walker found an incidence ofpulmonary fibrosis to be 1.6% in the same popula-tion. In the series by Solanki and Neville,22 theassociation of bronchiectasis and RA was 5.2%,compared with 4.7% for pulmonary fibrosis and RA.

Therefore, the association of bronchiectasis and RA,although rare, as is pulmonary fibrosis and RA,should be considered as a real, rather than spurious,association and should be included as a manifestationof RA.

The association of bronchiectasis and RA has beenreassessed, with the identification of bronchiectasisin 20 to 35% of patients with RA who have under-gone HRCT.5–8,11 These findings suggest a higherfrequency of bronchial abnormalities in RA than haspreviously been reported in postmortem studies, inwhich the prevalence of bronchiectasis ranged from0 to 10%.2,23 Although bronchiectasis was detectedwith a higher frequency in patients with respiratorysymptoms, HRCT findings of bronchiectasis wereidentified in 8% of asymptomatic patients.6 To ex-clude the effects of smoking, several studies haveshown that bronchiectasis has been identified in RApatients who were never smokers.6–8 The incidenceof concomitant interstitial pulmonary fibrosis waslow in most studies (# 10%),6–8,11 suggesting that“traction bronchiectasis” is not responsible for thepresence of bronchiectasis.

The temporal relationship between bronchiectasisand RA is still debated, but several explanations havebeen proposed to account for this association. Aswith most pleuropulmonary manifestations of RA,bronchiectasis can precede or develop after theonset of RA.15,24,25 In the former group, prior evi-dence of bronchial infection and/or chronic bron-chial suppuration has led to the hypothesis thatchronic bacterial infection plays a causative role intriggering an immune reaction leading to articularinvolvement.21–23,25 This hypothesis is supported bythe finding that RA starts at a younger age in patientswith bronchiectasis.26 The interval between bronchi-ectasis and the onset of RA symptoms ranged from 1to 34 years (mean, 19 years) in the series of Solankiand Neville,22 and a mean of 36.5 years in men and28.5 years in women in Walker’s series.21 However,there is no evidence that patients with preexistingbronchiectasis have more severe RA than thosewithout bronchiectasis,11,25 suggesting that it is un-likely that chronic suppuration per se drives therheumatoid disease. If lung infection is causallyrelated to the onset of RA, it probably occurs byallowing exposure to a range of bacterial antigenicstimuli that triggers the disease in genetically predis-posed individuals.25

In contrast, it has been suggested that severalfactors related to RA itself or to its treatment mayincrease the incidence of respiratory infections andaccount for the delayed presentation of bronchiecta-sis in patients with established RA. Despite in vitrostudies showing decreased neutrophil chemotaxis27

or defects in monocyte bactericidal activity28 in RA

Table 1—Conditions Associated With Bronchiectasis

Predominantly affecting the lungPostinfectious bronchial damage

Bacterial: Staphylococcus aureus, Haemophilus influenza,Mycoplasma pneumoniae, anaerobes (recurrent aspiration),Mycobacterium tuberculosis, and atypical mycobacteria(Mycobacterium avium-complex)Fungus: Aspergillus (including allergic bronchopulmonaryaspergillosis), histoplasmosis and coccidioidomycosisViral: measles, pertussis, and adenovirus

Abnormal host defenseImmune deficiency:

Primary: selective or panhypogammaglobulinemia,complement deficiencySecondary: malignancy, chemotherapy, posttransplant, etc

Ciliary dyskinesia: immotile cilia, Kartagener’s syndrome,Young’s syndrome, secondary ciliary dyskinesia

CongenitalCystic fibrosis and variantsa-1 protease inhibitor deficiencyUnilateral hyperlucent lung (Swyer-James syndrome)Tracheobronchomegaly (Mounier-Kuhn syndrome)Congenital cartilage deficiency (Williams-Campbell syndrome)Pulmonary sequestration

Mechanical bronchial obstructionIntrinsic: foreign body, tumor, viscid secretionsExtrinsic: right middle lobe syndrome, adenopathy

Postinflammatory pneumonitisAspirationInhalation of toxic gases

Diffuse panbronchiolitisIdiopathic pulmonary fibrosis

Systemic diseasesCollagen vascular diseases:

RASjogren’s syndromeASRPSLEMarfan’s syndrome

Inflammatory bowel diseaseUCCD

Celiac diseaseSarcoidosisYNSAIDSEndometriosisAmyloidosis

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patients, two recent studies29,30 have shown no in-creased incidence of infections when RA patients arecompared to control patients with osteoarthritis orother soft tissue rheumatic diseases. Because of thepossible influence of antirheumatic drugs on thelung, it has been reported that corticosteroids alonemay contribute to the development of bronchiectasisby increasing the risk for infection and/or inhibitinghealing of the bronchial wall following infection.19,30

Of the disease-modifying drugs, only methotrexatehas been shown to be associated with an increasedincidence of opportunistic infections involving thelung; however, most of these patients were alsoreceiving corticosteroids. Thus, an additive immuno-suppressive effect may have been contributory.19,30,31

Early studies had suggested that secondarySjogren’s syndrome seen in RA could predisposepatients to recurrent respiratory infections and bron-chiectasis.25,32,33 In disagreement to these studies,two recent reports11,34 failed to observe any relation-ship between the frequency of secondary Sjogren’s’syndrome and the presence of bronchiectasis.

Another possibility is that RA and bronchiectasismay share a common genetic predisposition. Hill-arby and colleagues35 showed an association of hu-man leukocyte antigen (HLA)-DR4 in patients withRA and bronchiectasis and a slight increase in HLA-DR1, which was not statistically different whencompared to either bronchiectasis alone or controlsubjects. In this same study, subjects with RA andbronchiectasis also showed an association withDQA1*0501 (p 5 0.039), DQB1*0201 (p 5 0.0017)and DQB1*0601 (p 5 0.0001), which were statisti-cally increased when compared to RA alone.DQB1*0601 was not statistically increased in fre-quency in subjects with bronchiectasis alone whencompared to control subjects. Despite these find-ings, there is no evidence that the association ofpulmonary complications with particular DQB vari-ants represents a direct effect of genes at the DQBlocus on susceptibility to these respiratory features.It appears likely that the final expression of rheuma-toid disease represents an interaction between allelesat several loci within the major histocompatiblilitygene complex.35

As stated previously, there is no evidence thatpatients with preexisting bronchiectasis have moresevere RA than those without bronchiectasis11,23,25;however, there is a decreased survival in patientswith the coexistence of these two conditions. Swin-son and colleagues36 demonstrated that patients withRA and bronchiectasis are 7.3 times more likely todie during a 5-year follow-up period than the generalpopulation, 5.0 times more likely to die than thosewith RA alone, and 2.4 times more likely to die thanthose with bronchiectasis alone. These differences

were not attributed to age, sex, or RA diseaseduration or severity. These data emphasize the im-portance of bronchiectasis in the prognosis andmanagement of RA patients.

Sjogren’s Syndrome

Sjogren’s syndrome is a chronic, inflammatory,autoimmune disorder characterized by the triad ofkeratoconjunctivitis sicca, xerostomia, and, in overhalf of cases, a connective tissue disorder. Thenatural history and frequency of respiratory involve-ment in primary Sjogren’s syndrome remain a sub-ject of considerable controversy due to the differ-ences in studied populations (primary, secondary, ormixed Sjogren’s patients) and the methods used tostudy the respiratory system, which vary from pre-dominantly clinical to mainly functional. It is notsurprising, therefore, that the prevalence of pulmo-nary abnormalities in Sjogren’s syndrome range from9 to 75%.37–41 Thus, it is problematic to assess theincidence of bronchiectasis in primary Sjogren’ssyndrome.

Several pulmonary complications have been re-ported in patients with primary Sjogren’s syndrome,including lymphocytic interstitial pneumonitis (LIP),pseudolymphoma and lymphoma,42,43 atelectasis,bronchiectasis,39,44 and pulmonary hypertension.45

Other manifestations have been described inSjogren’s syndrome, but it has been difficult todetermine which of the manifestations is the result ofSjogren’s syndrome and not of the underlying asso-ciated connective tissue disease.46

It is believed that the invasion of mucous glandsin the tracheobronchial tree by lymphocytes re-sults in atrophy and hyposecretion of these glands.This leads to plugging of the respiratory tract byinspissated secretions followed by atelectasis, in-fection, and bronchial wall destruction, with theconsequent development of bronchiectasis.37,47 How-ever, a lack of documentation of bronchiectasis inrecent studies of patients with primary Sjogren’s syn-drome39–41,44,48,49 questions this association. In de-fense of the hypothesis, most of these studies did notinclude HRCT in the evaluation of their patientsand, therefore, lack the sensitivity to make the diag-nosis of bronchiectasis.

In conclusion, pulmonary manifestations in pri-mary Sjogren’s syndrome are common, but the pre-cise pathophysiology and incidence is unknown.Bronchiectasis may complicate the course of diseasein these patients and should be sought for in theappropriate clinical setting with chest radiographsand HRCT scans.

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Ankylosing Spondylitis

Pleuropulmonary involvement in ankylosing spon-dylitis (AS) is an uncommon, yet well-recognized,extra-articular manifestation of this disease. Rose-now and associates,50 in a retrospective study of2,080 patients with AS, reported the incidence ofpleuropulmonary involvement to be 1.2%. In smallerand less detailed studies, the incidence varied from 0to 30%. These studies were based almost entirely onstandard chest radiographs, with occasional patho-logic confirmation.51–53

The most common thoracic finding is ankylosis ofthe costovertebral junctions, severely limiting expan-sion of the chest. In the report by Rosenow andassociates,50 apical fibrobullous disease and superin-fection of these cavities with fungal (usually Aspergil-lus) and mycobacterial (usually nontuberculous) or-ganisms were the most common findings. Isolatedcases of pleural disease (pleural effusion, pleuralfibrosis, pneumothorax)50; localized pulmonary amy-loidosis54; and cor pulmonale and bronchiolitis oblit-erans with organizing pneumonia55 have been re-ported. With the advent of HRCT, nonapicalinterstitial lung disease, bronchiectasis, and medias-tinal lymphadenopathy have been detected.10 Cas-serly and colleagues10 found airway disease mani-fested as bronchial wall thickening or bronchiectasisin 6 of 26 patients (23%). Two of the six patients hadtraction bronchiectasis in association with severeapical fibrosis. Primary bronchiectasis was seen infour patients, three of whom were current smokers;in one patient, bronchiectasis was identified on plainradiography.10

Relapsing Polychondritis

Relapsing polychondritis (RP) is a rare inflamma-tory disease of unknown cause, primarily affectingcartilage-containing tissues, with subsequent degen-eration and fibrosis. Respiratory involvement hasbeen noted in 56% of patients and, in general,indicates a poor prognosis, accounting for approxi-mately 50% of deaths in those cases of RP where thecause of death was determined.56

Respiratory tract involvement may occur early inthe course of RP, involving primarily the glottic,laryngeal, and subglottic soft tissues with inflamma-tion and edema, and frequently requiring tracheos-tomy.56–58 Later, there may be cartilaginous dissolu-tion of any or all of the tracheal and bronchialcartilages, leading to a peculiar type of obstructivepulmonary disease. This is due to increased collaps-ibility of the airways and/or fixed narrowing fromgranulation tissue and fibrosis.57,58 The tracheobron-chial tree narrowing is usually continuous through-

out its length; however, the extent to which moreperipheral bronchi are involved is uncertain.57

Bronchiectasis involving large and medium-sizebronchi was described at autopsy59 and in a casereport utilizing HRCT.3 Whether or not bronchiec-tasis is directly attributable to chondritis is unclear.Bronchiectasis has been shown in regions of recur-rent pneumonias, as well as in pneumonia-free re-gions. It is thought that proximal obstruction of thetrachea and main bronchi may impair drainage ofsecretions, predisposing patients to recurrent infec-tion. Therefore, bronchial walls that have alreadybeen injured by chondritis may be additionally weak-ened.3

With the frequency and potential for suddendecompensation of patients with RP, the importanceof surveillance and appropriate treatment of respira-tory tract infections and consequent bronchiectasiscannot be overemphasized.

Systemic Lupus Erythematosus

Thoracic involvement in systemic lupus erythem-atosus (SLE) can be categorized as primary orsecondary. Primary involvement includes pleuritiswith or without effusion, alveolitis, interstitial fibro-sis, lupus pneumonitis, bronchiolitis obliterans withorganizing pneumonia, obliterative bronchiolitis,pulmonary vasculitis and hemorrhage, pulmonaryarterial hypertension, and pulmonary thromboem-bolic disease. Secondary effects include basal atelec-tasis from diaphragmatic dysfunction, opportunisticinfections, drug toxicity, and the pleuropulmonaryconsequences of cardiac and renal failure.60 Themany reviews and case reports of pleuropulmonaryinvolvement in SLE reflect a great diversity inprevalence and nature of abnormalities, with aquoted incidence ranging from 7 to 100%, and aclinical spectrum varying from acute fulminant lunginjury to indolent and chronic forms of interstitialpulmonary disease.

Airways disease defined as bronchiectasis or bron-chial wall thickening had not been reported untilFenlon and coworkers9 described the HRCT find-ings in patients with SLE. In this series, airwaysdisease was observed in 34% (12/34) of the cases,with bronchiectasis reported in 21%. Chest radio-graphs and pulmonary function tests were poorpredictors for airway involvement. There was noregional predilection, with abnormalities equally dis-tributed in the upper, mid, and lower zones. Nine ofthe 12 patients (75%) with airways disease werenever smokers, suggesting that neither smoking noran increased susceptibility to its effects are the maincause of its development. Of the 34 patients, 28

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patients (82%) denied respiratory symptoms, andonly 5 patients (15%) had abnormal findings on chestexamination.

The incidence of bronchial abnormalities in theseries of Fenlon and coworkers9 was similar to thatreported in the RA population, but was significantlyhigher than suggested by reports in SLE patientsusing chest radiographs and pulmonary functiontesting alone.61

The cause of the bronchial abnormalities is un-known, but it may be due to an increased suscepti-bility to infection as seen in the RA population. Morestudies are needed to evaluate the clinical incidenceand significance of bronchiectasis detected in asymp-tomatic SLE patients. It is recommended thatHRCT be offered to patients with SLE whoseclinical, pulmonary function, and chest radiographyfindings are equivocal or suggest the development ofearly or possibly reversible airways disease.

Marfan’s Syndrome

Marfan’s syndrome is a connective tissue disorderthat is inherited as an autosomal dominant patternwith variable expression. In its classical form, itcomprises abnormalities in the musculoskeletal, car-diovascular, and ocular systems. Pulmonary manifes-tations are estimated to occur in 10% of patients,62,63

the most common being spontaneous pneumotho-rax62,64 and emphysema.65 Other presentations in-clude interstitial parenchymal disease with honey-combing,66 congenital malformations of thebronchus, cystic pulmonary disease,63,67 and in-creased susceptibility to respiratory infections due tobronchiectasis.63,68–70

The etiology of pulmonary manifestations is un-known, but it logically could be explained by theunderlying connective tissue disorder. Currently, thepathogenesis is believed to be related to abnormalcollagen cross-linking due to a biochemical defect inthe b-2 chain of type I collagen.71,72 The resultantprecocious weakness of the abnormal collagen intissues undergoing mechanical stress is termed abi-otrophy.73 This weakness in pulmonary connectivetissue is unrelated to inflammatory disease of thelung and could be expected to be progressive.74 Theprogressive connective tissue weakness could explainthe various pulmonary manifestations previouslycited.

Inflammatory Bowel Disease

Ulcerative Colitis

Extraintestinal manifestations of ulcerative colitis(UC) are common, occurring in up to 45% of

patients, and include uveitis, arthritis, skin lesions,and liver disease.75 In contrast, pulmonary involve-ment in UC was thought to be rare, having beenreported in only 3 of 1,400 patients (0.21%) withinflammatory bowel disease (IBD).76 It was not untilthe publication by Kraft and coworkers77 that respi-ratory involvement was included in the list of estab-lished complications of IBD.78

Since then, five major clinicopathologic categoriesof respiratory involvement have been described79,80:(1) airway disease, including subglottic stenosis,chronic bronchitis, chronic bronchial suppuration,bronchiectasis, and chronic bronchiolitis; (2) inter-stitial lung disease, including bronchiolitis obliteranswith organizing pneumonia, unspecified interstitiallung disease, and pulmonary infiltrates and eosino-philia; (3) necrobiotic parenchymal nodules; (4) se-rositis with pleural or pericardial effusions; and (5)pulmonary vascular disease, including vasculitis andpulmonary embolism. The majority of patients re-ported in the literature disease (43 to 63%) have hadairway disease,79–83 with chronic bronchitis andbronchiectasis being the most common, 21% and25%, respectively.80

The typical patient with airway involvement has nohistory of childhood respiratory illnesses, is a non-smoker, and unexpectedly develops chronic coughproductive of variable amounts of sputum. Camusand colleagues80 reported that respiratory symptomswere diagnosed after IBD in 85% of cases. In 79% ofthese cases (37/47), IBD was inactive, either becauseof prior medical treatment or coloproctectomy. Re-spiratory involvement predated IBD in 14%,whereas IBD and respiratory involvement were con-comitant in 5%.

The pathogenesis of UC causing bronchiectasis isunknown, but both morphologic and developmentalsimilarities exist between colonic and bronchial epi-thelium. Both are derived from primitive gut andhave columnar epithelia with goblet cells and sub-mucosal mucous glands. The nonspecific inflamma-tory changes beneath the bronchial epithelium arehistologically similar to those seen beneath colonicepithelium in UC.84,85 It was initially thought that asystemic immunologically mediated phenomenon(ie, circulating immune complexes) was responsiblefor the bronchial and colonic changes and wouldtend to remit after colectomy. However, the rapidappearance and progression of chronic bronchialsuppuration after colectomy suggested that circulat-ing inflammatory mediators or reactive oxygen radi-cals known to be released by the inflamed colonicmucosa are not the primary cause for bronchopul-monary inflammation.80,86 An autoimmune process issupported by Butland and associates,82 in which amajority of their patients had a positive family history

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of autoimmune phenomenon and positive antinu-clear antibody and anti-smooth muscle antibodies.An alternative hypothesis has suggested that com-mon irritants (antigens) that are inhaled and ingestedsensitize the lung and gut-associated lymphoid tis-sue, and future mucosal breaks could lead to anallergic inflammatory response in both sites.81,87

While the immunopathogenesis of bronchopulmo-nary-associated complications in UC remains un-known, therapy has been guided by case reports andnot by controlled studies. In contrast to the treat-ment recommendations for some of the other ex-traintestinal manifestations of IBD, colonic surgeryshould not be proposed in an attempt to control theairway disease.80 Instead, a long-lasting and strikingresponse has been seen following inhaled or systemiccorticosteroids, an uncommon finding in chronicbronchitis or bronchiectasis.80–83,88 Inhaled cortico-steroids were more effective in treating chronicbronchitis than in treating bronchiectasis.80 How-ever, the apparent ineffectiveness of inhaled cortico-steroids may not relate to the failure of these drugs,but rather to their impaired disposition in airwaysfilled with inspissated secretions. In two of thesecases, Camus and coworkers80 performed multipleBALs with methylprednisolone with a dramatic re-sponse. In summary, inhaled corticosteroids shouldbe used early as a first-line treatment in patients withIBD and bronchial involvement. For nonresponders,topical corticosteroids via BAL or systemic cortico-steroids should be attempted prior to colonic surgicalintervention.

Crohn’s Disease

The involvement of respiratory manifestations inpatients with Crohn’s disease (CD) is even moreunusual than in those with UC.80 A review of theliterature only finds a few cases of pulmonary paren-chymal involvement in CD patients, including thefollowing cases: eight cases of interstitial lung dis-ease,89–91 one case of bronchiolitis obliterans orga-nizing pneumonia,80 one case of lung infiltrates withperipheral eosinophilia,80 and three cases of chronicbronchitis.77,80 No cases of bronchiectasis have beenreported in any of the large IBD studies,75,76,80 but innone of these studies has HRCT scan been used toevaluate the presence of bronchiectasis. A case re-port of bronchiectasis following colectomy for CDwas recently reported.92 This patient presented witha purulent productive cough 3 months postcolec-tomy and bronchiectasis on HRCT that was absenton a HRCT 2 months after colectomy. Although theassociation of bronchiectasis and CD in this caseraises the possibility of a chance association, strongcircumstantial support for a real association includes

a clear temporal relationship to colectomy and,unlike idiopathic bronchiectasis, a repeated failure toidentify bacterial pathogens and an impressive re-sponse to oral corticosteroids.92

Sarcoidosis

Sarcoidosis is a disease of unknown cause charac-terized by an excess of helper T lymphocytes at sitesof involvement.93 In the lung, the noncaseatinggranulomas occur mainly in the peribronchial,perivascular, and subpleural areas, and in the bron-chial mucosa. Endobronchial manifestations of sar-coidosis are common, as confirmed by blind biopsiesof apparently normal bronchial mucosa that yieldgranulomas in up to 37% of patients.94 Althoughcommon, it is rarely of sufficient magnitude to causebronchial narrowing and atelectasis that result insymptoms and disability.95,96

Endobronchial sarcoid may produce reversiblenarrowing of the tracheobronchial tree by inflamma-tory edema or an endobronchial mass, or it mayproduce permanent narrowing due to cicatricial ste-nosis.97–100 The majority of the reports suggest thatbronchial narrowing, either inflammatory or cicatri-cial, occurs only in the late stages of the disease,when there is extensive pulmonary fibrosis. How-ever, there are reports of bronchial stenosis inpatients with normal chest radiographs99 or stage IIdisease.96,101

Therefore, the pathogenesis of bronchiectasis insarcoidosis can be largely attributed to “tractionbronchiectasis” secondary to anatomic distortionfrom pulmonary and peribronchial fibrosis. How-ever, the development of localized bronchiectasis inpatients without extensive fibrosis can be explainedeither by endobronchial granulomas with bronchialmucosal scarring or a disease akin to the right-middle-lobe syndrome.

Endobronchial sarcoidosis has received little at-tention as a cause of bronchiectasis; however, bron-chographic studies in 11 patients with bronchosteno-sis revealed bronchiectasis in 5 patients.96 In fourpatients, there was mild bronchial dilatation and lossof the normal distal tapering, and one patient hadsaccular bronchiectasis. The development of bron-chiectasis in these cases may be due to destruction orweakening of the bronchial wall by granulomatousinflammation. In no other condition, except TB, hasthe combination of widespread bronchostenosis andbronchiectasis been described to occur together.This combination should be highlighted as an impor-tant consequence of bronchial lesions in sarcoidosis.

Although rare, the development of bronchiectasisas a result from right-middle-lobe syndrome has

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been described.102,103 In these two cases, minimaladenopathy or bronchostenosis was seen; however,chronic lymphadenitis was evident, explaining theinterference with lymphatic drainage rather thanmechanical obstruction from adenopathy. A viciouscycle of inadequate drainage, nonspecific inflamma-tion, and secondary lymphadenopathy in the drain-age pathway could account for the bronchial walldestruction and development of bronchiectasis.

Yellow Nail Syndrome

Yellow nail syndrome (YNS) is a rare entity, and itsdiagnosis is based on clinical criteria since there areno pathognomonic laboratory tests. Samman andWhite104 first described the association of yellownails with primary lymphedema in 1964 and termedit the “yellow nail syndrome.” Two years later,Emerson105 described the full triad of slow-growingyellow nails, lymphedema, and pleural effusions; in1972, Hiller and colleagues106 reported that thepresence of two of the three symptoms was sufficientto establish the diagnosis. Recently, the frequentassociation of rhinosinusitis107 and the more uncom-mon association of bronchiectasis106,108–114 with YNSmay warrant its recognition as part of the syndrome.

Over 100 cases of YNS have been reported sinceits original description, with a male to female ratio of1:1.6.113 The median age of onset is 40 years, but ithas been recognized as early as birth105,115,116 and aslate as the seventh decade.106,117

Impaired lymph drainage is thought to be theunderlying defect that is responsible for the variedclinical findings in patients with YNS. This theory issupported by lymphangiographic findings that inmost patients showed a paucity of hypoplastic ordilated lymphatics.104,105,113,118,119 Electron micros-copy has120 shown dilated but otherwise normallymphatics, suggesting n obstruction of lymph floweither in the major lymph vessels or at the lymphnodes. The mechanism underlying the lymphaticmalformation has not been defined, but a geneticpredisposition has been suggested.116 The widerange in age and type of onset of YNS suggests thata precipitating event (such as infection, hypostasis,insect bite, or injury) increases local capillary perme-ability, and increasing the load on the already defi-cient lymphatic system may be required.104

Sixty-three percent of the published cases of YNShad pleuropulmonary symptoms. Respiratory tractinvolvement was the initial symptom in 29% of thecases, and pleural effusions were found in 36% of allcases.113 The majority of patients often had a 10- to20-year history of recurrent attacks of chronic bron-chitis occasionally associated with bronchographi-

cally or HRCT-verified bronchiectasis,106,108–114

chronic sinusitis, pneumonia, or pleuritis.The pathogenesis of bronchiectasis in YNS is

unknown. It is recognized, however, that bronchiand bronchioles are richly supplied with lymphaticvessels, with one network in the mucosa and anotherin submucosal tissue.121 Therefore, it is thought thatbronchiectasis in YNS may be related to hypoplasiaof the bronchial lymphatics, similar to that describedpreviously in the lower limb lymphangiographicstudies.106,110 Other possible mechanisms for thedevelopment of bronchiectasis include immunologicabnormalities that have occasionally been describedin association with this condition. These includehypogammaglobulinemia,109,122 low circulating Bcells,123 and macroglobulinemia.124 All of thesemechanisms, alone or in combination, will increasethe susceptibility to recurrent infections and willimpair airway defenses, with the consequent de-struction of airways and development of bronchiec-tasis.

The clinical prognosis of YNS has been difficult toassess due to varying degrees of severity. No deathssecondary to YNS have been reported, and partial orcomplete recovery of the nail symptoms have oc-curred in 30% of patients, with occasional relaps-es.113 The lymphedema, pleural effusions, and bron-chiectasis appear to be persistent and should betreated symptomatically.

AIDS

Pulmonary manifestations in patients with AIDShave been extensively described and include a widerange of infections, as well as inflammatory andneoplastic processes.125–128 However, the occurrenceof bronchiectasis has rarely been noted.4,129–132 Theincidence of bronchiectasis in the HIV-infected pop-ulation remains to be established, since it is fre-quently undiagnosed because of a low index ofsuspicion and because chest radiographs may benormal or nonspecific.

The etiology of bronchiectasis in AIDS patients islikely to be multifactorial, but recurrent bronchopul-monary infection is probably one of the most impor-tant contributing factors.4,129–132 Vulnerability to in-fection within the tracheobronchial tree may indicatedirect effects of HIV infection on the pulmonarysystem. In addition to T-cell dysfunction, impairedfunction of pulmonary monocytes and macrophagesand an abnormal humoral immune system predis-poses this population to infections with resultantairway and parenchymal injury.133–135

Moskovic and associates,129 in an evaluation of 11patients with AIDS and Pneumocystis carinii pneu-

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monia by HRCT, found evidence of bronchial wallthickening in association with parenchymal consoli-dation in 9 patients, findings specifically suggestiveof “reversible bronchiectasis.”136 Interestingly, inthese cases, the degree of bronchial wall thickeningdid not appear related to the degree of consolidation.In two additional cases, there was evidence of bron-chial dilatation, distinct from cystic or destructiveparenchymal lesions. Therefore, these authors sug-gest that inflammation caused by P carinii pneumo-nia affects not only distal airspaces but larger proxi-mal airways as well.129

McGuinness and coworkers4 further documentedthe occurrence of bronchiectasis on CT scans in 10HIV and/or AIDS patients in the absence of myco-bacterial infection or a history of prior recurrentpyogenic infections. In these series, 6 of the 10patients with a history of recent pneumonia demon-strated bronchiectasis on CT within 4 weeks of theironly known episode of pneumonia, while 3 of theremaining 4 patients demonstrated bronchiectasiswithin 16 weeks of their first documented episode ofpneumonia. In eight cases, bronchiectasis was notedto be multilobar despite radiographic evidence ofinfection limited to only one or a few lobes.

The extent of bronchiectasis in the series ofMcGuinness and coworkers4 appears to exceed thatwhich might have been anticipated given the brieftime interval between the onset of infection and thedevelopment of bronchiectasis. This shortened timeframe suggests that AIDS patients have an acceler-ated form of bronchiectasis4 or that previous pulmo-nary infections were undocumented as a result oftheir immunocompromised status.

The possibility of nonspecific chronic interstitialpneumonitis (NIP) or LIP as an etiologic factor forbronchiectasis in this population has been suggested.Two patients have been reported to have CT-provenbronchiectasis without antecedent histories of infec-tion and transbronchial biopsy evidence of NIP andLIP.4 In larger studies of AIDS patients with NIP orLIP, bronchiectasis has not been mentioned, butnone of these studies used CT to evaluate forbronchiectasis.137–141

Despite the small number of reports on bronchi-ectasis in HIV/AIDS patients, it seems appropriateto consider its inclusion as one of the pulmonarymanifestations of HIV infection. Before this is ac-cepted, a large prospective study, including HRCTstudies, needs to be undertaken clarify the incidenceof bronchiectasis, as well as to evaluate its distribu-tion across the various HIV risk groups, its naturalhistory, and the interplay of the multiple factors thatmay be involved in its pathogenesis.

As the life expectancy of HIV-infected patientsincreases with the new antiretroviral and protease

inhibitor agents and the improved prevention andtreatment of opportunistic infections, the incidenceand comorbidity of bronchiectasis in these individu-als could become important.

Miscellaneous

Bronchial endometriosis with bronchiectasis in a60-year-old woman with cyclic hemoptysis for 30years has been reported.142 The relationship be-tween pulmonary endometriosis and bronchiectasisremains uncertain. Recurrent bleeding in the airwaysand interstitium with subsequent inflammation andhealing process may be a possible mechanism for thedevelopment of bronchiectasis. Infection in the areaof bleeding is another possibility.142

Nodular pulmonary amyloidosis was thought to bethe cause of bronchiectasis presumably secondary tocompression of a bronchus.143 Secondary amyloid-osis has been associated with bronchiectasis in fivereported cases. In four of these, amyloid depositionwas associated with a previous history of TB followedby fibrosis and traction bronchiectasis.144 The re-maining case was that of a 42-year-old man withlong-standing recurrent infections and the develop-ment of bronchiectasis and amyloid deposition.145

Bronchiectasis in association with celiac diseasewas reported in a 48-year-old woman with chronicfatigue and purulent productive cough and wheez-ing.146 The temporal relationship of her bronchiec-tasis and celiac disease, and the subsequent stabili-zation of her symptoms and improvement inpulmonary physiology following treatment with in-haled corticosteroids suggests a relationship betweenthe two conditions. The cause of the association ofpulmonary disorders with celiac disease remainspoorly defined. Absorption of an extrinsic allergen orimmune complexes through an abnormal GI mucosamay lead to the pulmonary disease.147 Alternatively,the association of celiac disease with HLA status andvarious autoimmune diseases148 suggests that a com-mon disturbance in immunity may underlie bothceliac disease and pulmonary disorders.

Conclusion

Bronchiectasis is considered an uncommon disor-der; however, with the advances in modern medi-cine, the recognition of this disorder is increasingdue to the use of HRCT and to the prolonged lifespan of multiple diseases that have allowed the timefor the development of bronchiectasis. This reviewintends to present the systemic diseases that havebeen associated with bronchiectasis and, therefore,

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to stimulate the physician to search for the develop-ment of bronchiectasis in these disorders, sincemorbidity and mortality in these patients shoulddecrease if appropriate treatment is begun early. Incompiling all of the available information in theEnglish literature related to bronchiectasis in sys-temic diseases, it is evident that there are a lack ofstudies for a condition that is probably underdiag-nosed and undertreated.

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DOI 10.1378/chest.116.4.1063 1999;116; 1063-1074Chest

Mark Cohen and Steven A. Sahn*Bronchiectasis in Systemic Diseases

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Bronchiectasis in Systemic Disease - Chest