Lung Injury Due to Acute Infection

In the traditional model of lung injury due to acute infection, patients are deemed to have normal airways and lungs until they experience a specific lower respiratory tract infection resulting in irreversible damage to their airways. In the modern era in industrialized nations, most episodes of lower respiratory tract infection—adequately treated—resolve without residual damage. However, among the older generations who were not protected by readily available antibiotics and vaccines, there are individuals who offer a convincing story of recurring, localized infections following a discrete episode of “pneumonia” in their childhood or early adult years that presumably produced irreversible damage leading to bronchiectasis.

Specific traditional pathogens to which bronchiectasis has been ascribed include Bordetella pertussis, mucoid strains of S. pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, adenoviruses, rubeola (measles), and influenza. Chronic granulomatous pathogens commonly related to bronchiectasis include Mycobacterium tuberculosis, Histoplasma capsulatum, and NTM such as Mycobacterium avium complex (MAC). In addition, mixed infection, including anaerobic mouth flora related to aspiration, may result in extensive damage to the parenchyma (“lung abscesses”) with subsequent bronchiectasis.

Cystic Fibrosis

CF and CF variants are arguably the most common causes of bronchiectasis in the United States and other industrialized nations of the Western Hemisphere today. Being the most common autosomal recessive disorder among whites (1 in 2000 to 2500 live births), CF is increasingly prevalent as improved therapies allow those who are afflicted to live longer. At present, there are approximately 30,000 CF patients in the United States with approximately 45% of them estimated to be over 18 years old, or roughly 12,000 to 14,000 adults with CF. In the next decade it is predicted that about 50% of all CF patients will be adults. The specific manifestations, severity, and rapidity of progression of CF vary highly according to the genotype and other modifying factors. However, the majority of those with childhood-onset CF who survive into their adolescence or early adult years have bronchiectasis ( eFig. 48-1 ). (See Chapter 47 for details.)

In addition to these “typical” cases in which CF is recognized early in life, variants may be present in the population that predispose to bronchiectasis in adults. Among a large series of adult patients seen at National Jewish Health (NJH) in Denver with bronchiectasis associated with NTM, 117 of 865 (13.5%) were found to have one or more abnormal alleles of the cystic fibrosis transmembrane regulator gene, CFTR, well in excess of the anticipated carrier rate of 6% in the general population. In 19 of these patients (2.2% overall), there were two abnormal alleles and, in the remaining 98 (11.3%), there was only one mutation. Of note, the mean age of these patients was 61 years. The clinical importance of these heterozygous mutations may be disputed; however, patients in this cohort had a high frequency of chronic airflow obstruction, sinusitis, difficulties with conception, and coinfection with pathogens typical of CF, including mucoid strains of P. aeruginosa —all features compatible with clinical CF. Among another series of patients with bronchiectasis and/or NTM lung disease, 24 of 50 (48%) had one or more CFTR mutations. Similarly, among a cohort of 63 patients with NTM lung disease studied at the National Institutes of Health, 36% had mutations in the CFTR gene. Consistent with the assertion that these heterozygous mutations are clinically relevant is a series of 30 patients with clinical features of CF who were reported to have normal CFTR alleles on comprehensive gene sequencing. The authors concluded that factors other than mutations in CFTR could result in a clinical condition consistent with CF. It is our contention that heterozygous anomalies in the CF gene act as a predisposing factor for bronchiectasis.

Based on contemporary understanding of the complex and diverse features of CF, there appear to be two groups in whom bronchiectasis develops. The first and obvious group includes those with classic infancy/childhood-onset disease in whom clinical and laboratory data readily confirm the diagnosis of CF. The other group involves those with less severe disease that manifests later in life and for whom diagnostic testing is ambiguous. Sweat chloride test results may or may not be abnormal, and genotyping may demonstrate heterozygous or even normal CFTR alleles. We might include under this rubric males with congenital bilateral absence of the vas deferens, who have not been consistently regarded as having variant CF. In addition, there are a wide variety of genetic factors other than CFTR that influence the clinical phenotypes of the patients. (See Chapter 47 for additional discussion.)

Bronchiectasis has been described in a condition identified in the 1970s called Young syndrome. Although Young syndrome is not CF, it has a number of similar clinical features such as bronchiectasis, sinusitis, and infertility. However, unlike CF, the genetic basis for Young syndrome is not known, and, because the definition includes azoospermia, it is seen only in males. Furthermore, whereas the azoospermia related to CF is due to congenital absence of the vas deferens, in Young syndrome it is due to obstruction in the distal epididymis (i.e., obstructive azoospermia). In a comprehensive study of 15 patients with a clinical diagnosis of Young syndrome, the mean nasal mucociliary clearance, as measured by the saccharin test, was prolonged nearly threefold compared to nonsmoking controls, but the ciliary beat frequency and ultrastructural anatomy of the cilia were considered to be within normal limits. Interestingly, in one subject in whom a sample of epididymis was available, microtubular disarrangement—mostly missing or “displaced” microtubules—was seen in approximately 13% of the cilia examined. Because the incidence of Young syndrome appears to be decreasing dramatically since it was originally reported in the 1970s, it has been hypothesized that Young syndrome may be due to poisoning from mercurous chloride (calomel), a compound contained in teething powder and antihelmintics that has since been banned. Furthermore, we posit that, with more comprehensive testing for the CFTR mutation, it is quite plausible that some cases diagnosed as Young syndrome were in fact CF.

Disorders of Immunity

Immunologic deficiencies are also associated with the development of bronchiectasis. Primary diseases that result in immunodeficiency may devolve from mutations that impair B or T lymphocytes and cause abnormal humoral immunity, cellular immunity, or both. Less frequent anomalies may involve natural killer (NK) lymphocytes, neutrophils, or complement proteins. Some specific immune disorders are noted later.

Common variable immunodeficiency, or acquired hypogammaglobulinemia, is the most frequent syndrome recognized in this group of diseases. Clinically, it is seen equally among males and females, distinguishing it from X-linked agammaglobulinemia (Bruton disease), which exclusively involves young males. It may be seen throughout all age-groups, although it is most commonly recognized in early childhood. Although there are normal numbers of circulating B lymphocytes, they fail to differentiate into antibody-producing cells. This results in particular vulnerability to infections with encapsulated bacteria such as S. pneumoniae, H. influenzae, S. aureus, and P. aeruginosa. Recurring infections of the airways with these and other organisms frequently result in bronchiectasis ( eFig. 48-2 ). The diagnosis is established by demonstrating low levels of IgG, absent or markedly reduced IgA levels, and normal or reduced levels of IgM, and the failure to produce appropriate antibody responses following vaccination (normal response is a fourfold or greater increase in specific IgG level 4 weeks after immunization or at least the presence of protective titers if less than threefold increase from baseline). A variant of the hypogammaglobulinemic disorders is selective deficiency of subclasses of IgG, notably IgG2 and IgG4. Because repletion with gamma globulin is so useful in controlling the recurrent infections, pursuit of the diagnosis of deficient antibody production (common variable immunodeficiency or Bruton disease) is strongly indicated. By contrast, selective deficiency of secretory IgA, another cause of recurrent respiratory infections, cannot be controlled by repletion.

Other, less common primary immune disorders that may result in recurrent or refractory respiratory infections leading to bronchiectasis include hyper-IgM or hyper-IgE (Job syndrome) and thymic hypoplasia resulting in abnormal cellular immunity (DiGeorge syndrome). There are two forms of the hyper-IgE syndrome: an autosomal dominant form caused by mutations in the signal transducer and activator of transcription 3 (STAT3) gene, resulting in STAT3 deficiency, and an autosomal recessive form for which the precise genetic cause is not known. The susceptibility of individuals with dominant hyper-IgE syndrome to pyogenic bacteria and NTM organisms may be due to impaired production of cytokines secreted by type 1 helper T cells such as interferon-γ (IFN-γ) and TNF-α, cytokines known to be important in controlling such infections. Genetic anomalies that may result in combined humoral and cellular impairment include severe combined immunodeficiency syndrome, “bare lymphocyte” syndrome, Wiskott-Aldrich syndrome (an X-linked recessive illness associated with small platelets and eczema), cartilage-hair hypoplasia (associated with short-limbed dwarfism), ataxia-telangiectasia syndrome, and a variety of other rare disorders.

Alpha ₁ -Antitrypsin Anomalies

Deficiency or anomalies in alpha ₁ -antitrypsin (AAT) may predispose to bronchiectasis. Various phenotypic abnormalities of AAT were described prominently in a recent series of patients seen at the NJH with bronchiectasis associated with NTM. Previously there had been reports of the relationship between AAT deficiency and bronchiectasis. However, in the great majority of cases in the NJH series, the patients were not deficient in AAT but had heterozygous phenotypes, mainly MS, to a lesser extent MZ, with normal AAT levels. The prevalence of AAT anomalies in the overall cohort of NJH patients with various NTM infections was 17% ; even more striking was the 27% prevalence of AAT anomalies in the patients with NTM lung disease due to rapidly growing mycobacteria. Based on various surveys, AAT anomalies would be anticipated in roughly 8% to 9% of the U.S. population. However, the role of heterozygous anomalies of the AAT system in the pathogenesis of lung disease is controversial. The majority of the NJH patients did not have clinically significant chronic obstructive pulmonary disease (COPD) or grossly visible emphysema on CT scanning. Hence we postulate that the AAT anomalies render the patients more vulnerable to respiratory tract infections. Inferential evidence in support of this hypothesis includes an informal survey done among emphysema patients being repleted with alpha ₁ -proteinase inhibitor (Prolastin) ; 74 of the 89 responding patients described a perceptible benefit, and 56 of the 74 identified a reduction in the frequency of infectious exacerbations of their COPD. Possibly relevant to the development of bronchiectasis is the observation that AAT is produced in airway epithelium (as well as the liver) and “Z” AAT may polymerize in the lung and act as a chemoattractant for neutrophils. Evidence in support of the effect of a direct effect of AAT on infection includes the finding that aerosolized AAT suppresses P. aeruginosa lung infection in an animal model and the observation by Shapiro and colleagues that AAT inhibits replication of the human immunodeficiency virus (HIV) in whole blood. Further support for a direct role of AAT in resistance to infection is the observation in an African population that two polymorphic variants of the AAT haplotype were associated with significantly greater risks for HIV infection when compared with the other nine haplotypes common in sub-Saharan African populations. Chan and coworkers showed that AAT inhibits phagocytosis of Mycobacterium abscessus by human macrophages, partially denying the mycobacteria their preferred intracellular milieu. It should be noted that a group from France studied AAT alleles in a large cohort of bronchiectasis patients and reached a different conclusion. They found the following phenotypes in their patients: MS, 11.9%; MZ, 3.5%; SS, 1.5%; SZ, 0.5%; and ZZ, 0.5%. In this study the distribution of these phenotypes was not significantly different in their controls, and they inferred that AAT anomalies did not contribute to the risk for bronchiectasis. In a study of 74 patients with severe AAT deficiency (PiZ phenotype), however, remarkably 70 (95%) had bronchiectatic changes on CT scan ( eFig. 48-3 ) and 20 (27%) had clinically significant bronchiectasis, defined as bronchiectasis in four or more bronchopulmonary segments and chronic sputum production. Thus it appears that if one examines a group of unselected bronchiectasis patients, the prevalence of AAT anomalies is low; however, if one starts with a group with known AAT deficiency, bronchiectasis is commonly found. This observation may be related to the notion that COPD itself may be associated with bronchiectasis as discussed in the next section.

COPD

Over the past decade, likely due to increasing use of HRCT scans, a relatively high prevalence of bronchiectasis has been reported in patients with moderate-to-severe COPD. Given the 30% to 60% prevalence of bronchiectasis found in COPD patients in these studies, it would be important to evaluate AAT phenotypes to determine whether the bronchiectasis is associated more closely with severe COPD per se or with associated AAT anomalies. In one study, COPD patients with bronchiectasis had higher levels of the neutrophil chemoattractant IL-8 in the sputa and increased bacterial colonization of the lower airways, and they experienced more severe exacerbations than those without bronchiectasis. Whether bronchiectasis is a coincident sequela in COPD patients with frequent exacerbations, identifies a subgroup of COPD patients with different pathogenic mechanism, or both, remains to be determined. Martínez-García and associates found that, although COPD patients with bronchiectasis had lower FEV ₁ and FEV ₁ /FVC ratio, the presence of bronchiectasis was independently and significantly associated with increased all-cause mortality in multivariate analysis.

Ciliated Epithelium Abnormalities

Congenital structural and functional disturbances of the ciliated epithelial cells are seen in association with bronchiectasis, as well as with frequent and severe upper respiratory tract problems. These disorders appear to be an autosomal recessive process, with an estimated frequency between 1 in 12,500 to 1 in 40,000. PCD embraces a heterogeneous group of ultrastructural deficits involving the axoneme or central functional element of the cilia. The normal axoneme is composed of nine paired or doublet microtubules arrayed peripherally around two central, single microtubules; attached to the peripheral doublet microtubules are outer and inner dynein arms as well as radial spokes ( Fig. 48-5 ). The direction in which the cilia beat is determined by the orientation of the two central microtubules. In a local sheet of bronchial ciliated epithelium, the axes of the central microtubules are arrayed within a fairly narrow range, typically deviating 25 degrees or less from each other along the long axis of the airway. A variety of abnormalities have been described, including the complete or partial absence of outer or inner dynein arms, a lack of radial spokes, disordered microtubule arrangements, ciliary disorientation, and other rare disturbances. Functionally these disturbances result in reduced or disorganized beating of the ciliated epithelial cells or, in some cases, gross immotility. There may also be inversion of the normal anatomic locations for the organs of the thorax and abdomen, situs inversus universalis or partialis. PCD with situs inversus universalis is known as Kartagener syndrome ( Fig. 48-6 ). In the absence of normal ciliary activity, organ orientation appears random during embryogenesis, resulting in situs inversus in roughly half of the cases. Evidence in support of this theory includes discordant organ orientation in monozygotic twins with disordered ciliary motility.

Ultrastructure of the cilia.

The structure and function of cilia are elegant and complex. Each ciliated epithelial cell possesses approximately 200 cilia. The direction of ciliary beating is determined by the orientation of the central pair of microtubules. Dysfunction of the ciliary apparatus may involve a variety of structural abnormalities in the cilia or disorganization of the ciliary axes. The cilia beat in a relatively fluidic periciliary medium; above that, adherent by a thin physicochemical junction, is a gelatinous layer of mucus (not shown).

Bronchiectasis: Kartagener syndrome.

A, Frontal chest radiograph shows dextrocardia with basal predominant linear opacities, the latter consistent with bronchial wall thickening and bronchiectasis. B, Axial chest CT shows dextrocardia and severe, cystic bronchiectasis, particularly on the left ( arrow ). Note the left lung shows a morphologic configuration resembling a right middle lobe (same arrow ). Numerous small nodules are consistent with small airway impaction.

(Courtesy Michael Gotway, MD.)

The ineffectual beating of the ciliated cells results in stagnation and accumulation of mucus, which classically is associated with early-onset refractory or recurrent infections of the upper and lower respiratory tract, including otitis media, mastoiditis, sinusitis, and bronchitis. Bronchiectasis is a common sequela of PCD, typically involving the dependent zones, including the lower lobes, right middle lobe, and/or the lingular segment of the left upper lobe ( Fig. 48-7 ). Patients with PCD, sinusitis, and bronchiectasis also have a marked tendency toward colonization and infection with H. influenzae. The mechanism(s) for this predilection is unknown, but defective adaptive immunity is a plausible candidate. The ciliary defect also involves the flagella of the spermatozoa, resulting usually, although not universally, in male infertility. Patients may have a history of neonatal respiratory distress, a characteristic early-life complication of PCD.

Dependent-zone bronchiectasis in primary ciliary dyskinesia (PCD).

This 35-year-old white woman has classic PCD. She has atelectasis and saccular bronchiectasis involving the right middle lobe, the medial basilar segment of the right lower lobe, and the anteromedial aspects of her left lower lobe. She has previously been treated for Mycobacterium avium complex and now has refractory infections with P. aeruginosa.

Diagnosing PCD is often problematic. Consideration of this diagnosis should be given in the setting of early-onset upper and lower respiratory infections (see earlier). Male infertility, although suggestive, may be due to Young syndrome in a North American population. A suggestive feature on HRCT is predominant bronchiectasis in the lower lobes, with or without right middle lobe or lingular involvement and sparing of the upper lobes (unpublished data). Diffuse, poorly defined flocculent centrilobular opacities in the lower lobes is typical of PCD, reflecting chronic bronchiolitis. Either electron microscopic analysis of the ultrastructure of the cilia or clearly documented ciliary dysfunction via high-speed video microscopy is the gold standard for diagnosis. However, such testing is complicated by the following factors: (1) chronic infection may denude the airways of ciliated epithelium, and (2) chronic infection may damage cilia, resulting in nondiagnostic findings. In one report, computer-assisted analysis was shown to increase the diagnostic yield significantly over conventional transmission electron microscopy for inner dynein arm disturbances. Direct measurements of ciliary beat frequency or coordination is available only in selected research centers. Using a ciliary beat frequency of less than 11 beats/sec to determine who should have ultrastructural analysis may result in an unacceptable number of missed cases. Instead, measurement of the ciliary dyskinesia score—a reflection of the ciliary beat pattern—is a significantly more sensitive and specific screening test for PCD using ultrastructural analysis as the gold standard. Among males, dysmotile or immotile spermatozoa may be demonstrated, and ultrastructural analysis of the sperm flagella may confirm the diagnosis. The saccharin test has also been employed as an inferential test of ciliary dysfunction. In this minimally invasive test, a particle of sodium saccharin (≈1 mm in diameter) is placed on the inferior turbinate, roughly 1 cm from the anterior end of the turbinate to avoid the area covered with squamous epithelium. The patient remains in the sitting position with the head slightly tipped forward and breathing normally. The time for the subject to taste sweetness—an indication of nasal mucociliary clearance and thus of ciliary function in other parts of the body—is then recorded. In negative (normal) test results, the elapsed time is less than 30 minutes. The primary utility of the saccharin test is to exclude PCD. Abnormal saccharin test results are consistent with, but not diagnostic of, PCD, because individuals with other disorders that result in chronic rhinosinusitis may have denuded their ciliated epithelium or have inflammatory factors that impair ciliary beating. Thus the test should not be done within a month of an upper respiratory infection.

A relatively accurate test for PCD is measurement of nasal nitric oxide (NO) levels. In a large cohort with proven PCD, nasal NO levels were significantly lower than in normal persons or subjects with CF. Of interest, parents of PCD patients had lower-than-normal nasal NO levels, intermediate between controls and patients, despite the absence of clinical disease. Several mutations are known to be associated with PCD in genes, including DNAI1, DNAH5, and DNAH11, that encode axonemal motor proteins, structural and regulatory elements, and cytoplasmic proteins involved in assembly of cilia. While genetic testing for PCD is not widely available, it is likely to be the diagnostic test of choice in the not too distant future.

Bronchial Cartilage or Elastic Fiber Defects

Cartilaginous “C-rings” are present throughout the entire trachea as well as in the large and medium-sized airways, typically down to the fourth through sixth generations of the ramifying bronchi. The primary functional role of these structures is to maintain airway patency during expiration, including during cough.

Mounier-Kuhn syndrome, or congenital tracheobronchomegaly, is a rare disorder associated with gross enlargement or dilation of the trachea and segmental bronchi ( Fig. 48-8 and eFig. 48-4 ). The underlying defect is atrophy and even absence of elastic fibers and smooth muscle tissues of the large airways. In addition, primary or secondary atrophy of the connective tissue between the rings may result in outpouchings or diverticula, potentially serving as reservoirs for recurrent infections. Distal to the involved airways, bronchial structures generally appear normal. Clinically, Mounier-Kuhn patients may present in their early years or as late as the fourth decade with recurring lower respiratory infections. In advanced stages, airway collapsibility may result in severe airflow obstruction. The diagnosis is readily made by finding extraordinary dilation of the trachea and central bronchi on CT scans (see eFig. 48-4B-D ), with airway dimensions 3 standard deviations greater than normal; for men, transverse and sagittal tracheal diameter greater than 25 mm and greater than 27 mm, respectively, is considered abnormally enlarged, whereas in women, the respective values are greater than 21 mm and greater than 23 mm. Special considerations in management include positive end-expiratory pressure support and silicone or metallic stenting. Lung transplantation is an option, although unique issues associated with Mounier-Kuhn syndrome include recurrent infections when tracheal diverticula are present and difficulty with bronchial anastomosis due to discrepancy in the airway diameters between the donor and the recipient lungs.

Congenital tracheobronchomegaly (Mounier-Kuhn syndrome) with bronchiectasis.

This 73-year-old woman has had recurring respiratory infections throughout her adult life, most recently associated with Mycobacterium avium complex. A, On the posteroanterior view, a massively dilated trachea ( arrow ) is seen. B, The dilated trachea with prominent cartilaginous rings is confirmed on a CT scan ( between arrows ). C, Not only is the trachea enlarged, but the main-stem bronchi are dilated ( between arrows ).

(Courtesy Michael Gotway, MD.)

Williams-Campbell syndrome, or congenital bronchial cartilage deficiency syndrome, is another rare disorder that tends to present early in life with recurring infection and bronchiectasis. Familial cases have been reported in this condition, although the precise genetic defect is not known. The absence of cartilage from the segmental to the first few generations of the subsegmental airways is the typical finding in Williams-Campbell syndrome, although more proximal bronchi (lobar and main stem) may be rarely affected as well. There is no evidence that cartilage is deficient in tissues other than the lungs. Characteristic findings on CT scan include more extensive peripheral bronchiectasis than would be anticipated by the clinical history and a more proximal extension of bronchiectasis than usual ( Fig. 48-9 and eFig. 48-5 ). Inspiratory ballooning and expiratory collapse of the airways on chest CT scan is characteristic of Williams-Campbell syndrome. The degree of peripheral airway distortion suggests that this disorder entails more than simply the absence of proximal cartilage. Patients with Williams-Campbell syndrome are particularly predisposed to proximal bronchomalacia after transplantation due to the combined effects of cartilage deficiency in the main-stem bronchi plus decreased blood supply to the proximal airways due to loss of collateral circulation of the transplanted lung.

Williams-Campbell syndrome.

This 50-year-old man had a lifelong history of recurring respiratory infections and productive cough. The airways are massively dilated with collections of respiratory secretions pooling in some of the cystic spaces. Notable are the normal dimensions of the main-stem bronchi ( between arrows).

Connective Tissue Abnormalities

Among the various formally described heritable disorders of the connective tissues, Marfan syndrome has been reported to be associated with bronchiectasis. Other lung disorders associated with Marfan syndrome include distal acinar emphysema, cystic degeneration, spontaneous pneumothorax, bullae, apical fibrosis, and a congenital pulmonary malformation known as middle lobe hypoplasia. In addition to the airway and parenchymal abnormalities, persons with Marfan syndrome may have various other anomalies, including pectus excavatum, pectus carinatum, scoliosis, straight back syndrome, mitral valve prolapse, and aortic insufficiency with dilation of the aortic root. Two of these conditions, scoliosis and pectus excavatum, are also found often in patients with other heritable connective tissue disorders, including Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, Ehlers-Danlos syndrome, and cutis laxa.

This constellation of findings is reminiscent of the prototypic female patients we and others see with bronchiectasis, most commonly in association with chronic NTM lung disease. Based on analogy to these heritable disorders, we believe that there may be subtle anomalies or polymorphic variants of connective tissue that predispose to bronchiectasis and/or to NTM infection eventually leading to formation of bronchiectasis. Phenotypic findings that are common among these patients include various combinations of scoliosis, straight back syndrome, pectus excavatum or unusually narrowed anteroposterior chest diameter, pectus carinatum, and/or mitral valve prolapse. In 67 consecutive pulmonary NTM patients seen at the NJH between 1985 and 1987, of whom 43 (64%) were women, pectus excavatum and scoliosis were found to be significantly more prevalent in NTM patients compared to contemporary pulmonary tuberculosis patients (27% versus 9% for pectus excavatum and 52% versus 13% for scoliosis). Among a series of 63 patients reported from the National Institutes of Health with NTM lung disease, predominantly manifested by bronchiectasis, careful morphometric studies were performed. Compared with the women in the National Health and Nutrition Examination Survey database, patients with NTM lung disease were found to be significantly taller and more slender. In addition, pectus excavatum, scoliosis, and mitral valve prolapse were found in excess of expected rates. However, the patients did not have dolichostenomelia (a long, narrow frame), hyperdistensible joints, arachnodactyly, or overt aortic root involvement to suggest classic Marfan syndrome. Neither do they have the cutaneous or joint abnormalities typical of Ehlers-Danlos syndrome.

A large, prospective study of 103 pulmonary NTM patients (all of whom had bronchiectasis) and 101 uninfected controls well matched for age, sex, and race found that NTM patients were significantly taller, had significantly lower mean body mass index and percent body fat, and had significantly higher prevalence of scoliosis and pectus excavatum than controls. In addition, following stimulation of whole blood with various agonists, including live M. intracellulare, pulmonary NTM patients had significantly lower mean IFN-γ level than controls but similar levels of other proinflammatory cytokines and chemokines, including TNF-α, IL-1β, IL-6, IL-8, IL-12, IL-18, and regulated on activation, normal T-cell expressed and secreted (RANTES). In a follow-up study, unstimulated and M. intracellulare –stimulated blood from 20 pulmonary NTM patients and 20 controls were randomly selected from the same two original cohorts and measured for transforming growth factor-β (TGF-β). In contrast to that seen with IFN-γ, the mean M. intracellulare –stimulated TGF-β level was significantly greater in pulmonary NTM patients than controls. Whether this reduced production of the host-protective cytokine IFN-γ and/or increased production of the immunosuppressive cytokine TGF-β plays a role in causing NTM lung disease remains to be determined.

Because the thoracic abnormalities such as pectus excavatum, scoliosis, straight back syndrome, and mitral valve prolapse that have been described in a substantial number of patients with NTM lung disease are some of the classic features of Marfan syndrome, we reasoned that perhaps some NTM patients, although not meeting clinical criteria for classic Marfan syndrome, possess a subclinical variant of Marfan syndrome. Marfan syndrome is caused by mutations of the fibrillin 1 (FBN1) gene, with more than 600 different mutations of FBN1 identified. Because some mutations may result in a milder Marfan syndrome phenotype, we posit that some who possess a lesser variant of FBN1 gene mutation do not have overt Marfan syndrome but remain at increased risk for NTM lung disease.

Our hypothesis does not identify the “prime factor” in the pathogenesis of the bronchiectasis: do the airways dilate because of an intrinsic structural defect, is there an immune defect that increases the risks for infections that set in motion the coughing and inflammation that lead to bronchiectasis, or are both factors present? The first supposition is that there is a propensity for bronchiectasis due to “weakness” of the connective tissue of the bronchial tree. The observation that fibrillin-1 is part of the extracellular matrix and that bronchiectasis and cystic changes seen in Marfan syndrome may develop without overt NTM lung infection suggests the plausibility of intrinsic vulnerability of the bronchial wall to bronchiectasis. Furthermore, it is also of great interest that Marfan syndrome has been linked to middle lobe hypoplasia because the right middle lobe is arguably the most commonly affected lobe in NTM-associated bronchiectasis. The second supposition is supported by the fact that the morphologic anomalies seen with Marfan syndrome have been traced to increased localized production of TGF-β, a cytokine that increases susceptibility to mycobacteria. Interestingly, some of the other heritable conditions with overlapping physical features to Marfan syndrome, despite having mutations in entirely different genes— FBN1 in Marfan syndrome, TGFBR1 and TGFBR2 genes in Loeys-Dietz syndrome, and SKI gene in Shprintzen-Goldberg syndrome—all have in common an increase in TGF-β signaling.

Could slenderness itself—independent of malnutrition or any underlying illness—predispose individuals to mycobacterial infections? One intriguing hypothesis for the increased susceptibility to mycobacterial infections in thin individuals is that the susceptibility is due to a relative deficiency of leptin, which is normally produced by fat cells. A study of over 100 pulmonary NTM patients and a similar number of uninfected controls demonstrated that the normal direct relationship between body fat and leptin—and the expected inverse relationship between body fat and adiponectin—were preserved in the control subjects, but both relationships were lost in pulmonary NTM patients. Experimental corroboration for the leptin hypothesis comes from studies showing that leptin-deficient (Ob/Ob) mice are more susceptible to Mycobacterium tuberculosis and M. abscessus lung infections.

In view of the preponderance of females in recent series with bronchiectasis associated with MAC, two theories have been proposed. “Lady Windermere’s syndrome,” named after a character in a novel by Oscar Wilde, posits that women—in the effort to be demure or elegant—voluntarily suppress their cough, leading to accumulation of secretions and chronic infections. However, it has been our observation that these patients cough frequently. Rather than voluntary suppression, it seems more plausible that their coughing may be ineffectual due to airway collapsibility, which interrupts movement of secretions out of the bronchial tree.

An alternative proposition came from Japan, where they, too, have noted a particular female vulnerability to bronchiectasis with MAC, largely among elderly, postmenopausal women. Tsuyuguchi and associates demonstrated that among female mice, oophorectomy led to higher mycobacterial loads in the lungs and spleen following intravenous challenge with MAC. Furthermore, estrogen repletion normalized the bacillary burden, and ex vivo macrophages supplemented by estrogens were more competent at limiting mycobacterial growth.

However, neither the putative relationship to connective tissue disorders nor the alleged role of estrogen deficiency can explain the high prevalence of females in recent reports of MAC-related bronchiectasis. In these series, 80% to 95% of patients described have been women. Certainly, this might reflect referral or reporting bias. Furthermore, we cannot exclude the possibility of sex-associated effects on connective tissue strength/integrity or cellular immunity.

An additional remarkable element of the reported cases of MAC-associated bronchiectasis is the strong preponderance of whites. White females constitute 80% to 95% in recent series, including those compiled in communities/areas with large African American, Hispanic, or other minority populations. Again, given the potential for referral, reporting, or ascertainment biases, we cannot be sure of the validity of these observations. However, among the specialists with whom we correspond, this is a strongly held perception. The relatively higher prevalences of CF and AAT anomalies in European-derived populations may partially, but not wholly, explain this apparent imbalance in the white population but would not explain the preponderance of white women in some series.

Fowler and coworkers compared ciliary beat frequency in epithelial cells obtained from the nasal turbinates of patients with pulmonary NTM disease, PCD, CF, and in healthy normal subjects. Interestingly, they found reduced basal ciliary beat frequency (≈2 beats/sec less than normal subjects) and less-than-expected increases in ciliary beat frequency upon stimulation of the epithelial cells with various Toll-like receptor agonists. In contrast, a normal increase in ciliary beat frequency was seen with Toll-like receptor 4 agonist (lipopolysaccharide) stimulation, suggesting that the ciliary defect may be more functional than anatomic. Nasal NO level was also decreased in the pulmonary NTM patients compared to normal subjects; significantly, addition of either a chemical NO donor or a cyclic 3′,5′-guanosine monophosphate–specific phosphodiesterase type 5 inhibitor (sildenafil) to the respiratory epithelial cell of pulmonary NTM patients restored their ciliary beat frequency.

Congenital and Developmental Anomalies

Conditions such as sequestration, agenesis, hypoplasia, and atresia may primarily cause bronchiectasis or may predispose to infections that secondarily cause bronchiectasis. Sequestrations presumably develop because of accessory primordial lung buds, which may be invested within normal lung tissue (intralobar) or external to the normal lungs (extralobar). Sequestrations may or may not connect with the bronchial tree and often derive their blood supply directly from the aorta. Clinically, they most commonly present with recurrent and/or chronic lower respiratory tract infections beginning in the second or third decade of life. Radiographically, they usually appear as irregular, peculiar densities abutting the diaphragm in the posterior basal regions. Unilateral hyperlucent lung (Swyer-James-MacLeod syndrome) is characterized by unilateral bronchiolitis leading to hyperinflation. In some cases, bronchiectasis is present. The etiology and pathogenesis of this rare disorder are uncertain but may involve developmental or acquired disturbances of the bronchial tree.

Idiopathic Inflammatory Disorders

There are a wide array of conditions associated with bronchiectasis that might be included under the rubric of idiopathic inflammatory disorders. They are all systemic illnesses that variably involve the lungs and, in such cases, may or may not result in bronchiectasis.

Sarcoidosis is by far the most common of these disorders. (See Chapter 66 for a comprehensive review.) Broadly, sarcoidosis may involve the airways by several fundamental mechanisms: diffuse parenchymal scarring resulting in traction ( eFig. 48-6 ) and airway distortion, endobronchial granulomatous inflammation including stricture with poststenotic infection, or compression secondary to hypertrophic peribronchial lymphadenopathy.

Rheumatoid arthritis (RA) may entail a variety of pulmonary manifestations. In two early series, bronchiectasis was seen in 3.2% and 5.2% of referral populations of RA patients. More recently, bronchiectasis has been described in considerably higher percentages of RA patients undergoing HRCT scanning: 20% to 35% ; surely these studies were skewed by selecting patients with respiratory problems to undergo CT scanning. However, bronchiectasis was seen in 8% of RA patients without respiratory symptoms. Notably, the majority of the patients in the previously discussed series did not have RA-associated interstitial fibrosis as a presumed cause of the bronchiectasis. Potential causal mechanisms include increased propensity for infections, either intrinsic to RA or secondary to steroid or cytotoxic therapy. Sjögren syndrome in association with RA has also been proposed as a risk factor, but the evidence is inconsistent. Clinically, it should be noted that the presence of bronchiectasis in RA patients was associated with an unfavorable prognosis in one series.

Ankylosing spondylitis has been classically associated with upper lung zone fibrocystic degeneration (see Fig. 98-16 ) and ankylotic fusion of the junctions of the ribs and vertebrae, resulting in restricted ventilation. However, in a large series from the Mayo Clinic, pulmonary involvement was described in only 1.2% of the patients ( eFig. 48-7 ). Bronchiectasis independent of apical fibrocystic disease has been seen in a small series from the United Kingdom. Ankylosing spondylitis was reported in association with MAC in an early series from the NJH.

Systemic lupus erythematosus may involve an assortment of pulmonary complications, including those intrinsic to systemic lupus erythematosus and others related iatrogenically (see Chapter 65 ). Bronchiectasis, as such, was described in 21% of systemic lupus erythematosus patients studied with HRCT in one series ; factors related to bronchiectasis were not well studied. As with RA, the presence of Sjögren syndrome may be a comorbid element.

Sjögren syndrome, keratoconjunctivitis sicca, and xerostomia (dry eyes and mouth), may exist in the primary form or in association with other collagen vascular diseases such as RA or systemic lupus erythematosus. Pulmonary complications of Sjögren’s syndrome include lymphocytic interstitial pneumonia, lymphoma or pseudolymphoma, and/or pulmonary hypertension (see Chapter 65 ). Bronchiectasis has also been noted. It is reasoned that lymphocytic inflammation results in impaired function of mucous glands, in turn resulting in decreased volumes and increased viscosity of mucus. This leads to airway obstruction, poor clearance, and chronic infection. There have not been large surveys employing the CT lung scan in Sjögren syndrome patients to quantify the risk for bronchiectasis. However, we have recently seen several elderly female patients with primary Sjögren syndrome in whom bronchiectasis was prominent.

Inflammatory bowel disease has been related directly to bronchiectasis. Inflammatory bowel disease–associated bronchiectasis appears to be more common with ulcerative colitis than Crohn disease. In the majority of cases, the inflammatory bowel disease antedates the lung manifestations, but in some cases the pulmonary symptoms may herald the inflammatory bowel disease. One unique observation of ulcerative colitis–associated bronchiectasis is that it may develop after therapeutic colectomy. Proposed pathogenic relationships include a cryptogenic infection that incites both airway and intestinal inflammation, common epithelial targets of autoimmunity, or sensitizing agents that are inhaled and/or ingested.

Relapsing polychondritis is identified essentially as progressive inflammation, weakness, and deformity of cartilaginous structures, including the ears, nose, larynx, and tracheobronchial tree, typically associated with nonerosive polyarthritis. In addition, there may be inflammatory and/or functional disturbances of the eyes, auditory/vestibular components of the ears, and aorta (vasculitis with aneurysm). Respiratory involvement is a common clinical element of relapsing polychondritis (tracheal and bronchial cartilage inflammation, resulting airway collapse and airflow limitation) ( eFig. 48-8 ) and a major cause of mortality. Bronchiectasis in such patients may be due to primary bronchial damage and/or recurrent infection.

Aspiration/Inhalation Accidents

Spillage of foreign matter into the airways may result in bronchiectasis. There are two fairly distinct scenarios in which such matter might be aspirated into the lungs and cause sufficient damage to result in chronic deformity of the airways. One is the direct spillage of secretions from the oropharynx, infamous for containing a plethora of microorganisms, including microaerophilic and anaerobic bacteria, which can produce necrotizing pneumonia. The other is introduction of materials refluxed from the esophagus and/or stomach, which, in addition to the microorganisms noted earlier, contain food particles, hydrochloric acid, biliary or pancreatic secretions, and microbes indigenous to the gut, including Helicobacter pylori .

Laryngeal protective functions are imperfect, and “microaspiration” is common. Thus we might presume that aspiration leading to lower respiratory tract infections involves greater-than-usual volumes and/or more noxious contents. Also, it is reasonable to posit that once the airways have been damaged, a lesser inoculum can have more substantial clinical effects, a variant of the “vicious circle” theory.

Many factors influence the likelihood/frequency of aspiration. They include (1) depressed sensorium (trauma, alcohol or drug abuse, postictal confusion state, general anesthesia); (2) altered brain-stem function (following cerebrovascular accident, after polio, primary neurologic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, or syringomyelia); (3) altered laryngeal structure/function (after surgery following irradiation); (4) esophageal disorders (dysmotility, obstruction by tumors or strictures, muscular dystrophy, achalasia, tracheoesophageal fistulas, or lower esophageal sphincter incompetence); and (5) gastric dysfunction (dysmotility or outlet obstruction).

Although all of these elements may contribute to the risk for infection (and bronchiectasis), it seems likely that gastroesophageal reflux is the most common factor. Among a cohort of bronchiectasis patients noted previously from the NJH, approximately three fourths of them had demonstrated abnormalities of esophageal morphologic features (dilation and thickening), function (dysmotility), anatomy (hiatal herniation), or competence (overt reflux). Indeed, the frequency of esophageal disturbances was so high that one might question whether the esophageal findings were the cause of recurring infections/bronchiectasis or, in some cases, an effect. In the latter regard, it is important to note that among series of patients with chronic asthma and idiopathic pulmonary fibrosis, the incidence of demonstrated esophageal dysfunction ranged from 80% to 95%. It is plausible that labored breathing with wide disparities between intra-abdominal and intrathoracic pressure and/or chronic coughing, which stresses and dilates the diaphragmatic ring, might disrupt the lower esophageal sphincter and subject the esophagus to distending forces. An additional factor that could contribute to gastroesophageal reflux disease is the medications employed for these pulmonary disorders, including anticholinergics, β ₂ -agonists, theophylline, and corticosteroids, all of which impair lower esophageal sphincter function, and broad-spectrum antibiotics, which alter gastroesophageal flora.

In any case, clinicians should be alert to the potential of gastroesophageal reflux disease/aspiration as having a primary or contributing role in the development of bronchiectasis. For those suspected of disordered deglutition, tailored hypopharyngography employing contrast materials of varying consistency may identify unsuspected aspiration. It is important to note that some patients spill contrast material into their trachea without any awareness or coughing. Such studies may be performed with a speech therapist, who can also aid patients with safer techniques for eating, drinking, and swallowing.

Impaired esophageal motility may be suggested on CT scans of the lungs in which the esophagus is grossly dilated, there is excessive air present along the course of the esophagus, or the walls of the esophagus are thickened. Impaired motility may often be demonstrated on a simple barium swallow. The extent of impaired contractility may be measured by esophageal manometry; this is critical if reconstitution of the lower esophageal sphincter is contemplated. Demonstrating actual reflux may be problematic. If gross reflux is demonstrated on a routine study, it is sufficient for a presumptive diagnosis. However, if symptoms or other clinical features suggest gastroesophageal reflux disease and the upper gastrointestinal series has negative results, an 18- to 24-hour pH probe with or without measurement of impedance may both identify and quantify reflux episodes. Nonacid reflux may result in chronic cough and even lung injury. Among the implications of these findings is that acid-inhibition measures may not be sufficient to protect the airways. For individuals with evidence of recurrent aspiration, elevation of the head of the bed should be done routinely.

Toxic inhalation or thermal injury may also be associated with bronchiectasis. Acute and chronic inflammation of the tracheobronchial tree, bronchiolitis, bronchiolitis obliterans, and diffuse alveolar damage may be a consequence of exposure to toxic metal fumes (e.g., aluminum, cadmium, chromium, nickel) or toxic gases (e.g., ammonia, chlorine, phosgene, sulfur dioxide) (see Chapter 75 ). In severe cases, bronchiectasis may ensue because of either infectious complications of the exposure, denuding of the ciliated epithelium, or progressive fibrosis. Similarly, chronic airway damage and bronchiectasis may evolve following thermal or smoke injury.

Postobstructive Disorders

Foreign bodies may be aspirated into the airways in association with infants and children putting foreign objects in their mouths, choking events while eating, trauma, or loss of consciousness, including seizures. In some cases the obstructing object may be radiopaque (teeth, bone, or metal objects), but in most instances the obstructing material (e.g., peanuts, vegetables) is not discernible by radiographic study. Tumors, benign or malignant, may also result in airway obstruction, poor drainage, recurrent/chronic infection, and bronchiectasis. The more common tumor types include bronchogenic carcinomas (particularly the squamous cell variety), carcinoid tumors ( eFig. 48-9 ), and papillomas. Extrinsic airway compression due most often to hypertrophic lymphadenitis from granulomatous diseases such as sarcoidosis or infections, including tuberculosis or histoplasmosis, may severely narrow or even occlude large airways. In patients with “focal” bronchiectasis (particularly those with disease limited to only one region, one segment, one lobe [see eFig. 48-9 ], or even one lung), bronchoscopic examination to exclude an obstructing lesion should be performed early if other causes are not evident.

Allergic Bronchopulmonary Aspergillosis

In acute or subacute allergic bronchopulmonary aspergillosis (or other mycoses) (ABPA/M), patients develop mucoid plugs in the medium-sized bronchi. The inflammation and distention typically results in thin-walled bronchiectasis of the central airways ( Fig. 48-10 ; see Fig. 48-3 ). Central bronchiectasis, often with mucoid impaction, is characteristic of ABPA, and occasionally the mucoid impaction may show high attenuation, reflecting the organism’s ability to fix calcium salts, iron, and manganese ( Fig. 48-11 ). Although ABPA/M typically is seen in the setting of recurrent/refractory (steroid-dependent) asthma, clinicians should be aware that these episodes may also include fever, malaise, pleuritic chest pain, and cough productive of purulent secretions. Such episodes may be confused with pneumonia, acute bronchitis, and/or exacerbations of simple bronchiectasis, especially if the asthmatic component is absent or minimal. The picture may be particularly obscure if the ABPA/M is present in individuals with CF, a disorder in which ABPA/M is relatively more common. Features mindful of ABPA/M include characteristic findings on CT scanning, eosinophilia, elevated IgE levels, and dramatic responses to corticosteroids.

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