Swyer syndrome

(CHEST 1999; 116:1063-1074)

Key words: bronchiectasis; inflammatory bowel disease; rheumatologic diseases

Abbreviations: AS = ankylosing spondylitis; CD = Crohn's disease; HLA = human leukocyte antigen; HRCT high-resolution CT; IBD = inflammatory bowel disease; LIP = lymphocytic interstitial pneumonitis; NIP = nonspecific chronic interstitial pneumonitis; RA = rheumatoid arthritis; RP = relapsing polychondritis; SLE = systemic lupus erythematosus; TB = tuberculosis; UC = ulcerative colitis; YNS = yellow nail syndrome

Bronchiectasis is defined as an abnormal, irreversible dilatation of the bronchi. It is not a disease per se, but it represents the end stage of a variety of pathologic processes.[1] Laennec first described the clinical entity of bronchiectasis in 1819, but the clinical pattern of bronchiectasis has changed in the last century due to the early treatment of necrotizing pneumonias, better control of tuberculosis (TB), and the prevention of predisposing pulmonary infections by routine immunization. Advances in medical treatment have also lead to an increased survival to adulthood of patients with cystic fibrosis, hypogammaglobulinemia, and immotile cilia syndrome, all of which predispose to bronchiectasis.

Recently, bronchiectasis has been described as "an orphan disease," with a prevalence estimated to be low and decreasing,[2] but no reliable statistical estimates are available. The true prevalence of bronchiectasis most likely is underestimated, as less severe forms of bronchiectasis have been documented with the increased use of high-resolution CT (HRCT).[3-11] It should also be recognized that an underlying cause for bronchiectasis is found in [is less than] 40% of patients,[12] and that HRCT features alone do not allow a confident distinction between idiopathic bronchiectasis and known causes of bronchiectasis.[13,14]

The most commonly cited classification of bronchiectasis was based on bronchographic and autopsy findings and included three patterns of bronchiectasis: cylindrical, varicose, and saccular or cystic.[15]

However, the clinical usefulness of designating bronchiectasis to one of these patterns is questionable, and no study to date has shown a clinical, epidemiologic, or pathophysiologic difference between these patterns.[16]

This review will discuss the major systemic diseases associated with bronchiectasis and will describe specific diagnostic and therapeutic modalities apart from the traditional interventions for any type of bronchiectatic process. We will exclude diseases that are associated with abnormal host defenses (hypogammaglobulinemias, ciliary dyskinesis); genetic disorders (cystic fibrosis, [[Alpha].sub.1]-antitrypsin deficiency); and postinfectious processes, including allergic bronchopulmonary aspergillosis, since these processes predominantly affect the lung (Table 1).

Table 1--Conditions Associated With Bronchiectasis

RHEUMATOLOGIC DISEASES

Rheumatoid Arthritis

Pleuropulmonary involvement is one of the extra-articular manifestations of rheumatoid arthritis (RA), with a prevalence estimated at [is less than] 5%.[17,18] Pleuropulmonary manifestations of RA include the following: interstitial pulmonary fibrosis; pleural disease (pleuritis with or without effusion, sterile or septic empycma, necrobiotic nodules with bronchopulmonary fistula, or pyopneumothorax); rheumatoid necrobiotic nodules; respiratory tract infection, especially typical and atypical TB; bronchiolitis obliterans with or without organizing pneumonia; pulmonary vascular lesions and pulmonary hypertension; apical fibrobullous disease; thoracic cage immobility; and upper airway dysfunction due to cricoarytenoid arthritis.[19] Bronchiectasis is typically not mentioned as an extra-articular manifestation of RA; however, an association between the two disorders is well recognized.

Bronchiectasis in patients with RA received considerable interest earlier in this century. Their association was discounted on the argument that pulmonary TB was more common in patients with rheumatoid disease and that the bronchiectasis was related to TB.[20] The latter has been disproven by recent studies where no historical or radiographic evidence of previous TB was found in patients with RA and bronchiectasis.[11,19,21,22]

To further strengthen the association between RA and bronchiectasis, Walker[21] found the incidence of bronchiectasis to be 3.1% in RA, compared to 0.3% in patients with osteoarthritis. He also noted that the incidence among newly referred patients with RA was 3.2%, demonstrating that the association was not spuriously related to a more careful follow-up of patients with these two diseases. When the incidence of bronehiectasis was compared to pulmonary fibrosis in patients with RA, Walker found an incidence of pulmonary fibrosis to be 1.6% in the same population. In the series by Solanki and Neville,[22] the association of bronehiectasis 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 manifestation of RA.

The association of bronchiectasis and RA has been reassessed, with the identification of bronchiectasis in 20 to 35% of patients with RA who have undergone HRCT.[5-8,11] These findings suggest a higher frequency of bronchial abnormalities in RA than has previously been reported in postmortem studies, in which the prevalence of bronchiectasis ranged from 0 to 10%.[2,23] Although bronchiectasis was detected with a higher frequency in patients with respiratory symptoms, HRCT findings of bronchiectasis were identified in 8% of asymptomatic patients.[6] To exclude the effects of smoking, several studies have shown that bronchiectasis has been identified in RA patients who were never smokers.[6-8] The incidence of concomitant interstitial pulmonary fibrosis was low in most studies ([is less than or equal to] 10%),[6-8,11] suggesting that "traction bronchiectasis" is not responsible for the presence of bronchiectasis.

The temporal relationship between bronchiectasis and RA is still debated, but several explanations have been proposed to account for this association. As with most pleuropulmonary manifestations of RA, bronchiectasis can precede or develop after the onset of RA.[15,24,25] In the former group, prior evidence of bronchial infection and/or chronic bronchial suppuration has led to the hypothesis that chronic bacterial infection plays a causative role in triggering an immune reaction leading to articular involvement.[21-23,25] This hypothesis is supported by the finding that RA starts at a younger age in patients with bronchiectasis.[26] The interval between bronchiectasis and the onset of RA symptoms ranged from 1 to 34 years (mean, 19 years) in the series of Solanki and Neville,[22] and a mean of 36.5 years in men and 28.5 years in women in Walker's series.[21] However, there is no evidence that patients with preexisting bronchiectasis have more severe RA than those without bronchiectasis,[11,25] suggesting that it is unlikely that chronic suppuration per se drives the rheumatoid disease. If lung infection is causally related to the onset of RA, it probably occurs by allowing exposure to a range of bacterial antigenic stimuli that triggers the disease in genetically predisposed individuals.[25]

In contrast, it has been suggested that several factors related to RA itself or to its treatment may increase the incidence of respiratory infections and account for the delayed presentation of bronchiectasis in patients with established RA. Despite in vitro studies showing decreased neutrophil chemotaxis[27] or defects in monocyte bactericidal activity[28] in RA patients, two recent studies[29,30] have shown no increased incidence of infections when RA patients are compared to control patients with osteoarthritis or other soft tissue rheumatic diseases. Because of the possible influence of antirheumatic drugs on the lung, it has been reported that corticosteroids alone may contribute to the development of bronchiectasis by increasing the risk for infection and/or inhibiting healing of the bronchial wall following infection.[19,30] Of the disease-modifying drugs, only methotrexate has been shown to be associated with an increased incidence of opportunistic infections involving the lung; however, most of these patients were also receiving corticosteroids. Thus, an additive immunosuppressive effect may have been contributory.[19,30,31]

Early studies had suggested that secondary Sjogren's syndrome seen in RA could predispose patients to recurrent respiratory infections and bronchiectasis.[25,32,33] In disagreement to these studies, two recent reports[11,34] failed to observe any relationship between the frequency of secondary Sjogren's' syndrome and the presence of bronchiectasis.

Another possibility is that RA and bronchiectasis may share a common genetic predisposition. Hillarby and colleagues[35] showed an association of human leukocyte antigen (HLA)-DR4 in patients with RA and bronchiectasis and a slight increase in HLA-DR1, which was not statistically different when compared to either bronchiectasis alone or control subjects. In this same study, subjects with RA and bronchiectasis also showed an association with DQA1*0501 (p = 0.039), DQB1*0201 (p = 0.0017) and DQB1*0601 (p = 0.0001), which were statistically increased when compared to RA alone. DQB1*0601 was not statistically increased in frequency in subjects with bronchiectasis alone when compared to control subjects. Despite these findings, there is no evidence that the association of pulmonary complications with particular DQB variants represents a direct effect of genes at the DQB locus on susceptibility to these respiratory features. It appears likely that the final expression of rheumatoid disease represents an interaction between alleles at several loci within the major histocompatiblility gene complex.[35]

As stated previously, there is no evidence that patients with preexisting bronchiectasis have more severe RA than those without bronchiectasis[11,23,25]; however, there is a decreased survival in patients with the coexistence of these two conditions. Swinson and colleagues[36] demonstrated that patients with RA and bronchiectasis are 7.3 times more likely to die during a 5-year follow-up period than the general population, 5.0 times more likely to die than those with RA alone, and 2.4 times more likely to die than those with bronchiectasis alone. These differences were not attributed to age, sex, or RA disease duration or severity. These data emphasize the importance of bronchiectasis in the prognosis and management of RA patients.

Sjogren's Syndrome

Sjogren's syndrome is a chronic, inflammatory, autoimmune disorder characterized by the triad of keratoconjunctivitis sicca, xerostomia, and, in over half of cases, a connective tissue disorder. The natural history and frequency of respiratory involvement in primary Sjogren's syndrome remain a subject of considerable controversy due to the differences in studied populations (primary, secondary, or mixed Sjogren's patients) and the methods used to study the respiratory system, which vary from predominantly clinical to mainly functional. It is not surprising, therefore, that the prevalence of pulmonary abnormalities in Sjogren's syndrome range from 9 to 75%.[37-41] Thus, it is problematic to assess the incidence of bronchiectasis in primary Sjogren's syndrome.

Several pulmonary complications have been reported 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 in Sjogren's syndrome, but it has been difficult to determine which of the manifestations is the result of Sjogren's syndrome and not of the underlying associated connective tissue disease.[46]

It is believed that the invasion of mucous glands in the tracheobronchial tree by lymphocytes results in atrophy and hyposecretion of these glands. This leads to plugging of the respiratory tract by inspissated secretions followed by atelectasis, infection, and bronchial wall destruction, with the consequent development of bronchiectasis.[37,47] However, a lack of documentation of bronchiectasis in recent studies of patients with primary Sjogren's syndrome[39-41,44,48,49] questions this association. In defense of the hypothesis, most of these studies did not include HRCT in the evaluation of their patients and, therefore, lack the sensitivity to make the diagnosis of bronchiectasis.

In conclusion, pulmonary manifestations in primary Sjogren's syndrome are common, but the precise pathophysiology and incidence is unknown. Bronchiectasis may complicate the course of disease in these patients and should be sought for in the appropriate clinical setting with chest radiographs and HRCT scans.

Ankylosing Spondylitis

Pleuropulmonary involvement in ankylosing spondylitis (AS) is an uncommon, yet well-recognized, extra-articular manifestation of this disease. Rosenow and associates,[50] in a retrospective study of 2,080 patients with AS, reported the incidence of pleuropulmonary involvement to be 1.2%. In smaller and less detailed studies, the incidence varied from 0 to 30%. These studies were based almost entirely on standard chest radiographs, with occasional pathologic confirmation.[51-53]

The most common thoracic finding is ankylosis of the costovertebral junctions, severely limiting expansion of the chest. In the report by Rosenow and associates,[50] apical fibrobullous disease and superinfection of these cavities with fungal (usually Aspergillus) and mycobacterial (usually nontuberculous) organisms were the most common findings. Isolated cases of pleural disease (pleural effusion, pleural fibrosis, pneumothorax)[50]; localized pulmonary amyloidosis[54]; and cor pulmonale and bronchiolitis obliterans with organizing pneumonia[55] have been reported. With the advent of HRCT, nonapical interstitial lung disease, bronchiectasis, and mediastinal lymphadenopathy have been detected.[10] Casserly and colleagues[10] found airway disease manifested as bronchial wall thickening or bronchiectasis in 6 of 26 patients (23%). Two of the six patients had traction bronchiectasis in association with severe apical fibrosis. Primary bronchiectasis was seen in four patients, three of whom were current smokers; in one patient, bronchiectasis was identified on plain radiography.[10]

Relapsing Polychondritis

Relapsing polychondritis (RP) is a rare inflammatory disease of unknown cause, primarily affecting cartilage-containing tissues, with subsequent degeneration and fibrosis. Respiratory involvement has been noted in 56% of patients and, in general, indicates a poor prognosis, accounting for approximately 50% of deaths in those cases of RP where the cause of death was determined.[56]

Respiratory tract involvement may occur early in the course of RP, involving primarily the glottic, laryngeal, and subglottic soft tissues with inflammation and edema, and frequently requiring tracheostomy.[56-58] Later, there may be cartilaginous dissolution of any or all of the tracheal and bronchial cartilages, leading to a peculiar type of obstructive pulmonary disease. This is due to increased collapsibility of the airways and/or fixed narrowing from granulation tissue and fibrosis.[57,58] The tracheobronchial tree narrowing is usually continuous throughout its length; however, the extent to which more peripheral bronchi are involved is uncertain.[57]

Bronchiectasis involving large and medium-size bronchi was described at autopsy[59] and in a case report utilizing HRCT.[3] Whether or not bronchiectasis is directly attributable to chondritis is unclear. Bronchiectasis has been shown in regions of recurrent pneumonias, as well as in pneumonia-free regions. It is thought that proximal obstruction of the trachea and main bronchi may impair drainage of secretions, predisposing patients to recurrent infection. Therefore, bronchial walls that have already been injured by chondritis may be additionally weakened.[3]

With the frequency and potential for sudden decompensation of patients with RP, the importance of surveillance and appropriate treatment of respiratory tract infections and consequent bronchiectasis cannot be overemphasized.

Systemic Lupus Erythematosus

Thoracic involvement in systemic lupus erythematosus (SLE) can be categorized as primary or secondary. Primary involvement includes pleuritis with or without effusion, alveolitis, interstitial fibrosis, lupus pneumonitis, bronchiolitis obliterans with organizing pneumonia, obliterative bronchiolitis, pulmonary vasculitis and hemorrhage, pulmonary arterial hypertension, and pulmonary thromboembolic disease. Secondary effects include basal atelectasis from diaphragmatic dysfunction, opportunistic infections, drug toxicity, and the pleuropulmonary consequences of cardiac and renal failure.[60] The many reviews and case reports of pleuropulmonary involvement in SLE reflect a great diversity in prevalence and nature of abnormalities, with a quoted incidence ranging from 7 to 100%, and a clinical spectrum varying from acute fulminant lung injury to indolent and chronic forms of interstitial pulmonary disease.

Airways disease defined as bronchiectasis or bronchial wall thickening had not been reported until Fenlon and coworkers[9] described the HRCT findings in patients with SLE. In this series, airways disease was observed in 34% (12/34) of the cases, with bronchiectasis reported in 21%. Chest radiographs and pulmonary function tests were poor predictors for airway involvement. There was no regional predilection, with abnormalities equally distributed in the upper, mid, and lower zones. Nine of the 12 patients (75%) with airways disease were never smokers, suggesting that neither smoking nor an increased susceptibility to its effects are the main cause of its development. Of the 34 patients, 28 patients (82%) denied respiratory symptoms, and only 5 patients (15%) had abnormal findings on chest examination.

The incidence of bronchial abnormalities in the series of Fenlon and coworkers[9] was similar to that reported in the RA population, but was significantly higher than suggested by reports in SLE patients using chest radiographs and pulmonary function testing alone.[61]

The cause of the bronchial abnormalities is unknown, but it may be due to an increased susceptibility to infection as seen in the RA population. More studies are needed to evaluate the clinical incidence and significance of bronchiectasis detected in asymptomatic SLE patients. It is recommended that HRCT be offered to patients with SLE whose clinical, pulmonary function, and chest radiography findings are equivocal or suggest the development of early or possibly reversible airways disease.

Marfan's Syndrome

Marfan's syndrome is a connective tissue disorder that is inherited as an autosomal dominant pattern with variable expression. In its classical form, it comprises abnormalities in the musculoskeletal, cardiovascular, and ocular systems. Pulmonary manifestations are estimated to occur in 10% of patients,[62,63] the most common being spontaneous pneumothorax[62,64] and emphysema.[65] Other presentations include interstitial parenchymal disease with honeycombing,[66] congenital malformations of the bronchus, cystic pulmonary disease,[63,67] and increased susceptibility to respiratory infections due to bronchiectasis.[63,68-70]

The etiology of pulmonary manifestations is unknown, but it logically could be explained by the underlying connective tissue disorder. Currently, the pathogenesis is believed to be related to abnormal collagen cross-linking due to a biochemical defect in the [Beta]-2 chain of type I collagen.[71,72] The resultant precocious weakness of the abnormal collagen in tissues undergoing mechanical stress is termed abiotrophy.[73] This weakness in pulmonary connective tissue is unrelated to inflammatory disease of the lung and could be expected to be progressive.[74] The progressive connective tissue weakness could explain the various pulmonary manifestations previously cited.

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 involvement in UC was thought to be rare, having been reported in only 3 of 1,400 patients (0.21%) with inflammatory bowel disease (IBD).[76] It was not until the publication by Kraft and coworkers[77] that respiratory involvement was included in the list of established complications of IBD.[78]

Since then, five major clinicopathologic categories of respiratory involvement have been described[79,80]: (1) airway disease, including subglottic stenosis, chronic bronchitis, chronic bronchial suppuration, bronchiectasis, and chronic bronchiolitis; (2) interstitial lung disease, including bronchiolitis obliterans with organizing pneumonia, unspecified interstitial lung disease, and pulmonary infiltrates and eosinophilia; (3) necrobiotic parenchymal nodules; (4) serositis with pleural or pericardial effusions; and (5) pulmonary vascular disease, including vasculitis and pulmonary embolism. The majority of patients reported in the literature disease (43 to 63%) have had airway disease,[79-83] with chronic bronchitis and bronchiectasis being the most common, 21% and 25%, respectively.[80]

The typical patient with airway involvement has no history of childhood respiratory illnesses, is a nonsmoker, and unexpectedly develops chronic cough productive of variable amounts of sputum. Camus and colleagues[80] reported that respiratory symptoms were diagnosed after IBD in 85% of cases. In 79% of these cases (37/47), IBD was inactive, either because of prior medical treatment or coloproctectomy. Respiratory involvement predated IBD in 14%, whereas IBD and respiratory involvement were concomitant in 5%.

The pathogenesis of UC causing bronchiectasis is unknown, but both morphologic and developmental similarities exist between colonic and bronchial epithelium. Both are derived from primitive gut and have columnar epithelia with goblet cells and submucosal mucous glands. The nonspecific inflammatory changes beneath the bronchial epithelium are histologically similar to those seen beneath colonic epithelium in UC.[84,85] It was initially thought that a systemic immunologically mediated phenomenon (ie, circulating immune complexes) was responsible for the bronchial and colonic changes and would tend to remit after colectomy. However, the rapid appearance and progression of chronic bronchial suppuration after colectomy suggested that circulating inflammatory mediators or reactive oxygen radicals known to be released by the inflamed colonic mucosa are not the primary cause for bronchopulmonary inflammation.[80,86] An autoimmune process is supported by Butland and associates,[82] in which a majority of their patients had a positive family history of autoimmune phenomenon and positive antinuclear antibody and anti-smooth muscle antibodies. An alternative hypothesis has suggested that common irritants (antigens) that are inhaled and ingested sensitize the lung and gut-associated lymphoid tissue, and future mucosal breaks could lead to an allergic inflammatory response in both sites.[81,87]

While the immunopathogenesis of bronchopulmonary-associated complications in UC remains unknown, therapy has been guided by case reports and not by controlled studies. In contrast to the treatment recommendations for some of the other extraintestinal manifestations of IBD, colonic surgery should not be proposed in an attempt to control the airway disease,[80] Instead, a long-lasting and striking response has been seen following inhaled or systemic corticosteroids, an uncommon finding in chronic bronchitis or bronchiectasis.[80-83,88] Inhaled corticosteroids were more effective in treating chronic bronchitis than in treating bronchiectasis.[80] However, the apparent ineffectiveness of inhaled corticosteroids may not relate to the failure of these drugs, but rather to their impaired disposition in airways filled with inspissated secretions. In two of these cases, Camus and coworkers[80] performed multiple BALs with methylprednisolone with a dramatic response. In summary, inhaled corticosteroids should be used early as a first-line treatment in patients with IBD and bronchial involvement. For nonresponders, topical corticosteroids via BAL or systemic corticosteroids should be attempted prior to colonic surgical intervention.

Crohn's Disease

The involvement of respiratory manifestations in patients with Crohn's disease (CD) is even more unusual than in those with UC.[80] A review of the literature only finds a few cases of pulmonary parenchymal involvement in CD patients, including the following cases: eight cases of interstitial lung disease,[89-91] one case of bronchiolitis obliterans organizing pneumonia,[80] one case of lung infiltrates with peripheral eosinophilia,[80] and three cases of chronic bronchitis.[77,80] No cases of bronchiectasis have been reported in any of the large IBD studies,[75,76,80] but in none of these studies has HRCT scan been used to evaluate the presence of bronchiectasis. A case report of bronchiectasis following colectomy for CD was recently reported.[92] This patient presented with a purulent productive cough 3 months postcolectomy and bronchiectasis on HRCT that was absent on a HRCT 2 months after colectomy. Although the association of bronchiectasis and CD in this case raises the possibility of a chance association, strong circumstantial support for a real association includes a clear temporal relationship to colectomy and, unlike idiopathic bronchiectasis, a repeated failure to identify bacterial pathogens and an impressive response to oral corticosteroids.[92]

SARCOIDOSIS

Sarcoidosis is a disease of unknown cause characterized by an excess of helper T lymphocytes at sites of involvement.[93] In the lung, the noncaseating granulomas occur mainly in the peribronchial, perivascular, and subpleural areas, and in the bronchial mucosa. Endobronchial manifestations of sarcoidosis are common, as confirmed by blind biopsies of apparently normal bronchial mucosa that yield granulomas in up to 37% of patients.[94] Although common, it is rarely of sufficient magnitude to cause bronchial narrowing and atelectasis that result in symptoms and disability.[95,96]

Endobronchial sarcoid may produce reversible narrowing of the tracheobronchial tree by inflammatory edema or an endobronchial mass, or it may produce permanent narrowing due to cicatricial stenosis.[97-100] The majority of the reports suggest that bronchial narrowing, either inflammatory or cicatricial, occurs only in the late stages of the disease, when there is extensive pulmonary fibrosis. However, there are reports of bronchial stenosis in patients with normal chest radiographs[99] or stage II disease.[96,1001]

Therefore, the pathogenesis of bronchiectasis in sarcoidosis can be largely attributed to "traction bronchiectasis" secondary to anatomic distortion from pulmonary and peribronchial fibrosis. However, the development of localized bronchiectasis in patients without extensive fibrosis can be explained either by endobronchial granulomas with bronchial mucosal scarring or a disease akin to the right-middle-lobe syndrome.

Endobronchial sarcoidosis has received little attention as a cause of bronchiectasis; however, bronchographic studies in 11 patients with bronchostenosis revealed bronchiectasis in 5 patients.[96] In four patients, there was mild bronchial dilatation and loss of the normal distal tapering, and one patient had saccular bronchiectasis. The development of bronchiectasis in these cases may be due to destruction or weakening of the bronchial wall by granulomatous inflammation. In no other condition, except TB, has the combination of widespread bronchostenosis and bronchiectasis been described to occur together. This combination should be highlighted as an important consequence of bronchial lesions in sarcoidosis.

Although rare, the development of bronchiectasis as a result from right-middle-lobe syndrome has been described.[102,103] In these two cases, minimal adenopathy or bronchostenosis was seen; however, chronic lymphadenitis was evident, explaining the interference with lymphatic drainage rather than mechanical obstruction from adenopathy. A vicious cycle of inadequate drainage, nonspecific inflammation, and secondary lymphadenopathy in the drainage pathway could account for the bronchial wall destruction and development of bronchiectasis.

YELLOW NAIL SYNDROME

Yellow nail syndrome (YNS) is a rare entity, and its diagnosis is based on clinical criteria since there are no pathognomonic laboratory tests. Samman and White[104] first described the association of yellow nails with primary lymphedema in 1964 and termed it the "yellow nail syndrome." Two years later, Emerson[105] described the full triad of slow-growing yellow nails, lymphedema, and pleural effusions; in 1972, Hiller and colleagues[106] reported that the presence of two of the three symptoms was sufficient to establish the diagnosis. Recently, the frequent association of rhinosinusitis[107] and the more uncommon association of bronchiectasis[106,108-114] with YNS may warrant its recognition as part of the syndrome.

Over 100 cases of YNS have been reported since its original description, with a male to female ratio of 1:1.6.[113] The median age of onset is 40 years, but it has been recognized as early as birth[105,115,116] and as late as the seventh decade.[106,117]

Impaired lymph drainage is thought to be the underlying defect that is responsible for the varied clinical findings in patients with YNS. This theory is supported by lymphangiographic findings that in most patients showed a paucity of hypoplastic or dilated lymphatics.[104,105,113,118,119] Electron microscopy has[120] shown dilated but otherwise normal lymphatics, suggesting n obstruction of lymph flow either in the major lymph vessels or at the lymph nodes. The mechanism underlying the lymphatic malformation has not been defined, but a genetic predisposition has been suggested.[116] The wide range in age and type of onset of YNS suggests that a precipitating event (such as infection, hypostasis, insect bite, or injury) increases local capillary permeability, and increasing the load on the already deficient lymphatic system may be required.[104]

Sixty-three percent of the published cases of YNS had pleuropulmonary symptoms. Respiratory tract involvement was the initial symptom in 9.9% of the cases, and pleural effusions were found in 36% of all cases.[113] The majority of patients often had a 10- to 20-year history of recurrent attacks of chronic bronchitis occasionally associated with bronchographically 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 bronchi and bronchioles are richly supplied with lymphatic vessels, with one network in the mucosa and another in submucosal tissue.[121] Therefore, it is thought that bronchiectasis in YNS may be related to hypoplasia of the bronchial lymphatics, similar to that described previously in the lower limb lymphangiographic studies.[106,110] Other possible mechanisms for the development of bronchiectasis include immunologic abnormalities that have occasionally been described in association with this condition. These include hypogammaglobulinemia,[109,122] low circulating B cells,[123] and macroglobulinemia.[124] All of these mechanisms, alone or in combination, will increase the susceptibility to recurrent infections and will impair airway defenses, with the consequent destruction of airways and development of bronchiectasis.

The clinical prognosis of YNS has been difficult to assess due to varying degrees of severity. No deaths secondary to YNS have been reported, and partial or complete recovery of the nail symptoms have occurred in 30% of patients, with occasional relapses.[113] The lymphedema, pleural effusions, and bronchiectasis appear to be persistent and should be treated symptomatically.

AIDS

Pulmonary manifestations in patients with AIDS have been extensively described and include a wide range of infections, as well as inflammatory and neoplastic processes.[125-128] However, the occurrence of bronchiectasis has rarely been noted.[4,129-132] The incidence of bronchiectasis in the HIV-infected population remains to be established, since it is frequently undiagnosed because of a low index of suspicion and because chest radiographs may be normal or nonspecific.

The etiology of bronchiectasis in AIDS patients is likely to be multifactorial, but recurrent bronchopulmonary infection is probably one of the most important contributing factors.[4,129-132] Vulnerability to infection within the tracheobronchial tree may indicate direct effects of HIV infection on the pulmonary system. In addition to T-cell dysfunction, impaired function of pulmonary monocytes and macrophages and an abnormal humoral immune system predisposes this population to infections with resultant airway and parenchymal injury.[133-155]

Moskovic and associates,[129] in an evaluation of 11 patients with AIDS and Pneumocystis carinii pneumonia by HRCT, found evidence of bronchial wall thickening in association with parenchymal consolidation in 9 patients, findings specifically suggestive of "reversible bronchiectasis."[136] Interestingly, in these cases, the degree of bronchial wall thickening did not appear related to the degree of consolidation. In two additional cases, there was evidence of bronchial dilatation, distinct from cystic or destructive parenchymal lesions. Therefore, these authors suggest that inflammation caused by P carinii pneumonia affects not only distal airspaces but larger proximal airways as well.[129]

McGuinness and coworkers[4] further documented the occurrence of bronchiectasis on CT scans in 10 HIV and/or AIDS patients in the absence of mycobacterial infection or a history of prior recurrent pyogenic infections. In these series, 6 of the 10 patients with a history of recent pneumonia demonstrated bronchiectasis on CT within 4 weeks of their only known episode of pneumonia, while 3 of the remaining 4 patients demonstrated bronchiectasis within 16 weeks of their first documented episode of pneumonia. In eight cases, bronchiectasis was noted to be multilobar despite radiographic evidence of infection limited to only one or a few lobes.

The extent of bronchiectasis in the series of McGuinness and coworkers[4] appears to exceed that which might have been anticipated given the brief time interval between the onset of infection and the development of bronchiectasis. This shortened time frame suggests that AIDS patients have an accelerated form of bronchiectasis[4] or that previous pulmonary infections were undocumented as a result of their immunocompromised status.

The possibility of nonspecific chronic interstitial pneumonitis (NIP) or LIP as an etiologic factor for bronchiectasis in this population has been suggested. Two patients have been reported to have CT-proven bronchiectasis without antecedent histories of infection and transbronchial biopsy evidence of NIP and LIP.[4] In larger studies of AIDS patients with NIP or LIP, bronchiectasis has not been mentioned, but none of these studies used CT to evaluate for bronchiectasis. 137-141

Despite the small number of reports on bronchiectasis in HIV/AIDS patients, it seems appropriate to consider its inclusion as one of the pulmonary manifestations of HIV infection. Before this is accepted, a large prospective study, including HRCT studies, needs to be undertaken clarify the incidence of bronchiectasis, as well as to evaluate its distribution across the various HIV risk groups, its natural history, and the interplay of the multiple factors that may be involved in its pathogenesis.

As the life expectancy of HIV-infected patients increases with the new antiretroviral and protease inhibitor agents and the improved prevention and treatment of opportunistic infections, the incidence and comorbidity of bronchiectasis in these individuals could become important.

MISCELLANEOUS

Bronchial endometriosis with bronchiectasis in a 60-year-old woman ,with cyclic hemoptysis for 30 years has been reported.[142] The relationship between pulmonary endometriosis and bronchiectasis remains uncertain. Recurrent bleeding in the airways and interstitium with subsequent inflammation and healing process may be a possible mechanism for the development of bronchiectasis. Infection in the area of bleeding is another possibility.[142]

Nodular pulmonary amyloidosis was thought to be the cause of bronchiectasis presumably secondary to compression of a bronchus.[143] Secondary amyloidosis has been associated with bronchiectasis in five reported cases. In four of these, amyloid deposition was associated with a previous history of TB followed by fibrosis and traction bronchiectasis.[144] The remaining case was that of a 42-year-old man with long-standing recurrent infections and the development of bronchiectasis and amyloid deposition.[145]

Bronchiectasis in association with celiac disease was reported in a 48-year-old woman with chronic fatigue and purulent productive cough and wheezing.[146] The temporal relationship of her bronchiectasis and celiac disease, and the subsequent stabilization of her symptoms and improvement in pulmonary physiology following treatment with inhaled corticosteroids suggests a relationship between the two conditions. The cause of the association of pulmonary disorders with celiac disease remains poorly defined. Absorption of an extrinsic allergen or immune complexes through an abnormal GI mucosa may lead to the pulmonary disease.[147] Alternatively, the association of celiac disease with HLA status and various autoimmune diseases[148] suggests that a common disturbance in immunity may underlie both celiac disease and pulmonary disorders.

CONCLUSION

Bronchiectasis is considered an uncommon disorder; however, with the advances in modern medicine, the recognition of this disorder is increasing due to the use of HRCT and to the prolonged life span of multiple diseases that have allowed the time for the development of bronchiectasis. This review intends to present the systemic diseases that have been associated with bronchiectasis and, therefore, to stimulate the physician to search for the development of bronchiectasis in these disorders, since morbidity and mortality in these patients should decrease if appropriate treatment is begun early. In compiling all of the available information in the English literature related to bronchiectasis in systemic diseases, it is evident that there are a lack of studies for a condition that is probably underdiagnosed and undertreated.

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(*) From the Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Medical University of South Carolina, Charleston, SC.

Manuscript received March 1, 1999; revision accepted May 13, 1999.

Correspondence to: Steven A. Sahn, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, 96 Jonathan Lucas St, Suite 812, PO Box 250623, Charleston, SC 29425; e-mail: sahnsa@musc.edu3

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