CONSTRICTIVE AND BRONCHIOLITIS OBLITERANS WITH ORGANIZING

Juliette Wait, MD January 4, 1996

"HOOP, HOOP di HOOP" 1

I. INTRODUCTION: There is confusion about the different classifications of diseases of the bronchioles (1). This situation is similar to the different 'types' of interstitial lung diseases that were divided by the histopathologic types in the 70's. In fact, Bronchiolitis Obliterans with Organizing Pneumonia, or BOOP, was at one time described by Carrington and Liebow as bronchiolitis interstitial pneumonia (BIP) (2). All ofthese entities are defined histopathologic reactions of the lung to varying insults. The link to clinical disease depends on the presenting findings, potential etiologies and radiographic presentations. Thus, one must consider all these factors when classifying diseases of the bronchioles. Although not presently known, some cases may represent different windows into the spectrum of the same disease process. The term bronchiolitis obliterans was first used in a German paper in 1901. Since then, different terminology has been used to describe similar histopathology depending on the clinical picture. Usually, the description was of an unresolving or airway response to an inhaled toxin. In 1977 the association with Rheumatoid Arthritis was made, as well as the possible link to penicillamine therapy (3). In 1985 BOOP was described in the idiopathic form (4), although it had been described in 1983 as cryptogenic organizing pneumonitis (5). Since then, numerous papers have described it in its idiopathic form as well as in association with other etiologies. The importance is that lung biopsies may have areas demonstrating features of both BOOP or constrictive bronchiolitis. The term is usually given to the predominant feature. The distinction may be important, however, since response to therapy is often remarkable in BOOP. Also, was reported in 1983 as another separate clinical and histopathologic entity that occurs primarily in Japanese individuals, although it had been described in the Japanese literature since 1969 (6). 2

TERMINOLOGY:

Bronchiolitis obliterans in the medical literature has been used sometimes for constrictive bronchiolitis and for bronchiolitis obliterans with organizing pneumonia, which are two distinct hisotlogic entities and clinical pictures. Here the term refers to a proliferative bronchiolitis that is often associated with organizing pneumonia. Organizing pneumonia = cryptogenic organizing pneumonia = organizing diffuse alveolar damage or bronchiolitis associated interstitial pneumonia (BIP)

Constrictive bronchiolitis = obliterative bronchiolitis

D. HISTOPATHOLOGY:

A. Anatomy:

The bronchi of the lung branch several times before they become the terminal bronchioles {TB). Counting distally from the , the bronchi branch 8 to 25 times to reach airways less than 1 mm in diameter, which are the respiratory bronchioles (RB). The number of generations of branches from the terminal bronchiole to the alveolar sacs is also around 8 to 12. The terminal bronchioles are estimated to be around 2 to 4 mm in diameter. Of note, near many of the terminal bronchioles are patches of lymphocyte clusters, called lymphoid aggregates (LA). They are similar to the -associated lymphoid tissue but less well organized. They contain groups ofB lymphocytes surrounded by T cell lymphocytes beneath the basal laminae. However, they may be significantly involved in the inflammatory process that leads to bronchiolitis. 3

Acinar unit

B. Histology:

1. Acute bronchiolitis Acute bronchiolitis is primarily found in children, but also occurs in some adults. It is usually associated with an acute viral infection. Histology reveals inflammation of the terminal bronchioles, but no polyps or destruction. It is identified by acute inflammatory cells (mainly neutrophils) in bronchioles, and in adults may be found in smokers or post viral syndromes. Cellular debris accumulates in the bronchioles from necrosis of the epithelial cells and migration of inflammatory cells (7).

2. Constrictive bronchiolitis This process affects the walls of respiratory bronchioles with a few changes in alveolar ducts and alveolar walls. It ranges from mild bronchiolar inflammation and scarring to progressive concentric submucosal fibrosis and occasionally complete occlusion of the small airways. In the earliest stages, there is intraluminal, mucosal, submucosal and peribronchiolar inflammation centered on membranous and respiratory bronchioles. Epithelial necrosis is also present. There are variable numbers of polymorphonuclear neutrophils, lymphocytes, and plasma cells. Within the lumen there is a 4 predominance of neutrophils, whereas in the interstitium there is a predominance of mononuclear cells. Also found may be smooth muscle hyperplasia, bronchioloectasia with mucus stasis and plugging, and fibrosis of the small airway walls. In later stages the peribronchiolar fibrosis encroaches on the bronchiole lumen in a concentric fashion. The lesion tends to surround the lumen rather than create polypoid plugs (8,9). The lesions are patchy and may require many sections to identify. Bronochiolar metaplasia may extend onto the peribronchiolar alveolar septa. Most commonly it is post infectious, associated with dust or toxic fume inhalations, or RA, particularly those who have received penicillamine treatment (9-13). It may be implicated in some cases following smoke inhalation (14). It is not a common form ofbronchiolitis, although its incidence may be higher if those associated with smoking are included (9, 15). Some cases are sensitive to immunosuppressive therapy (16). Nevertheless, the insult to the lungs likely begins with diffuse airway epithelial injury and inflammation of the bronchioles.

MAJOR HISTOLOGIC FEATURES OF CONSTRICTIVE BRONCHIOLITIS Intraluminal, submucosal and peribronchiolar inflammation ofbronchioles Neutrophils predominate within the lumen Mucus plugs in affected bronchioles Early on, peribronchiolar mononuclear inflammation Peribronchiolar fibrosis with concentric encroachment

3. Bronchiolitis obliterans organizing pneumonia (BOOP) BOOP is characterized by acute and chronic inflammation of the bronchioles with intraluminal polyps and obstruction of the lumen, alveolar duct walls are thickened with a mild inflammatory infiltrate. The intraluminal polyps frequently have a central collection of inflammatory cells, including histiocytes, lymphocytes, and plasma cells. In cross-sections the polyps may appear almost granulomatous; but giant cells are lacking. The intraluminal 5 polyps may arise as focal areas of fibrinous exudate (9). Organizing pneumonia is a description of a reparative reaction following infectious and non-infectious ( 17) together with bronchiolitis obliterans they appear to be part of the same reparative reaction pattern of the lung. The presence of bronchiolitis obliterans organizing pneumonia by itself is non specific ( 17). Idiopathic BOOP is a clinicopathologic syndrome that requires the identification of the histologic pattern of bronchiolitis obliterans and organizing pneumonia in the clinical setting of an idiopathic interstitial pneumonia. In the description by Epler, many cases were dismissed when a cause or association could be identified ( 4). MAJOR HISTOLOGIC FEATURES OF BOOP

Patchy bronchiolitis obliteratans with organizing pneumonia Interstitial mononuclear cell infiltrate, variable in density Alveolar space foam cells Absence of extensive interstitial fibrosis Intraluminal polypoid masses of chronic inflammation and fibrosis

HISTOLOGIC FEATURES AGAINST THE DIAGNOSIS OF BOOP (2)

Hyaline membranes (fibrinous exudate may be seen focally in BOOP) Marked fibrinous alveolar exudates Necrosis Acute infammation Microabscess formation Vasculitis Prominent eosinophils Granulomas Marked alveolar lining cell and bronchiolar metaplasia Prominent interstitial fibrosis 6

4. Diffuse Panbronchiolitis (DPB) Bronchiolocentric inflammation is found ofthe terminal and respiratory bronchioles, infiltrate in bronchiolar walls is largely mononuclear with lymphocytes, plasma cells, and macrophages, while neutrophils and mucus are prominent in other areas of the biopsy. Inspissated mucus is found in the lumen. Foam cells are a key diagnostic feature, mild interstitial inflammatory infiltrate, but no fibrosis, no eosinophils, no granulomas, and vessels are always spared (6, 18, 19). The clinical course and other pathological features such as BAL cells suggest that this may be a separate disease, or a subacute form ofCB (19). Notably, the histologic description of this disease and the intraluminal infiltrates and lung lavage findings are most like those of CB. However, the smooth muscle is not hypertrophied, and foamy marcrophages within the lumen are prominent. The response to treatment of this disease also is suggestive that it is caused by a different etiologic agent than the other bronchiolitis categories (20,21). One case of recurrence in the transplanted lung has been described (22).

C. Pathogenesis Since the lung can only respond in limited ways to various insults, similar patterns of disease emerge from differing affronts to the lung. Whether these are different processes altogether or windows into a continuum of an inflammatory process involving the small airways is controversial. With acute infectious bronchiolitis, direct epithelial injury with necrosis ofthe epithelial cell and denudation ofbasallaminae appears to be the initiation of the insult (23). With continued insults, further intra-alveolar organization begins as fibrinoid inflammatory cells and their secetory factors collect locally then migrate through the gaps in the basal laminae. The cluster of cells forms buds of inflammatory cells and fibroblasts. As the fibroblastic reaction increases, the buds become more fibrotic with deposition of type III collagen and fibronectin. However, this pattern of intra­ alveolar inflammation is associated with preservation of the alveolar architecture, and little is seen on the chest radiograph. It is likely that each form ofbronchiolits begins like acute 7 infectious bronchiolits, but due to the severity or duration of the insult, or host response, different histological and clinical patterns emerge. Nevertheless, each type of inflammatory cell has a specific impact and contribution to the process, and the predominance of certain types of inflammatory cells likely contribute to the diagnosis and final outcome.

1. Neutrophils In all forms of bronchiolitis the neutrophil is believed to be the effector of the pathologic insult. The neutrophil contains many oxidative and proteolytic . mediators that can damage lung tissue (24). Several neutrophil proteases have been implicated. Myeloperoxidase and collagenase have been recovered from the airways of these patients as well as a high number ofneutrophils (16,25) Leukotriene B4 (LTB4) is also associated with neutophil chemotaxis and is elevated in BAL fluid from patients with Diffuse Panbronchiolitis found in Japan which has neutrophil predominance in the BAL fluid similar to CB (26). Similarly leukotriene C4 (LTC4) and eosinophilic cationic protein have been recovered from respiratory secretions in acute bronchiolitis and some forms of BOOP (27-30). Although not proven, the presence of increased numbers ofneutrophils and amounts of their digestive enzymes such as neutrophil collagenase suggests a role of these enzymes in the pathologic process. This has also been implicated in the pathology of other inflammatory mediated lung diseases, such as IPF and even chronic (31). A causal role for the neutrophil has also been implicated in the acute bronchiolitis caused by respiratory syncytial virus (RSV) in infants (30). The inflammation and bronchospasm is promoted by mediators ( histamine, prostaglandin F2a, and L TC4) released from neutrophils and mast cells (30). Bronchoalveolar lavage (BAL) samples of infants with RSV bronchiolitis (ages 5 to 34 weeks) yielded a predominance of neutrophils (71-85%), while lymphocytes were so sparse that flow cytometry was not possible (32). Chemotaxis and neutrophil adherence are impaired in premature infants and in the first month of life which may decrease the symptoms ofRSV in these infants. Although not well understood, additional evidence exists for involvement of eosinophils, IgE and eosinophil cationic protein in the pathophysiology of bronchiolitis and the syndrome of wheezing that may persist for months to years (30,33,34). Increased levels of 8

IgE are inversely related to the levels ofT-suppresser cells found in the airways, and may reflect abnormal regulation of the inflammatory response (30).

2. Lymphocytes Lymphocytic involvement varies considerably between the different forms of bronchiolitis. The lymphocytes involved have been primarily activated T cells. However, monoclonal antibodies were needed in acute bronchiolitis in infants to classify the lymphocytes because they were so sparse. There were a greater number of CD 4 (helper) lymphocytes than CDS (suppressor), with a ratio of22.5:1 (range 9-27:1) (32). Significant lymphocytic T cell infiltration with CD4 & CDS cells has been demonstrated in bronchoalveolar lavage in BOOP (35,36). Furthermore, the percent of lymphocytic cells bearing the CD3 (all T cells) activation markers was found to be higher in the lung lavage lymphocytes from patients with BOOP and chronic (CEP) than normals (36). Although CEP (37), and hypersensitivity pneumonitis (HS) are not forms of bronchiolitis per se, they are interstitial diseases that may clinically mimic bronchiolitis and are characterized by lymphocytosis in bronchoalveolar lavage. Interleukin-S has been identified in lung lavages from patients with bronchiolitis (38), and is also chemotaxic forT lymphocytes, but in vitro studies do not reveal that either CD4 or CDS cells have an increased response to this cytokine (39). Nevertheless, it is not elevated in lung lavages from sarcoidosis patients with lymphocytic predominance ( 40). These patients have high CD4/CDS ratios, which is the opposite of that in BOOP, and suggests a different pathophysiologic mechanism (40).

3. Alveolar macrophages when stimulated are a major producer ofll-S and other cytokines that summon additional inflammatory cells. The macrophage may respond to a variety of stimuli, including antibody-antigen reactions, viruses, or the expression of different antigens on epithelial cells (24). RSV has been shown to stimulate alveolar macrophages to produce interleukin (II-S) which is a potent attractant for neutrophils and may be a major contributor in the pathophysiology (30). The induction ofli-S messenger RNA produced from macrophages can last up to 24-36 hours whereas that for other chemotactic agents such as leukotriene B4 (L TB4) and C5a are shorter acting ( 41 ). 9 '

Macrophage production ofLTB4, however, is also considered one of the major sources of neutrophil chemotaxis. Also, macrophages produce Il-l and TNF which stimulate Il-8 production by non-immune cells, fibroblasts and type II epithelial cells of the lung (24,41). When produced in increased amounts, TNF and Il-l have other systemic effects that may be responsible for some of the systemic symptoms associated with bronchiolitis such as fever and weight loss (24). Other cytokines produced by activated macrophages, LBT4,

PAF, and thromboxane A2, may contribute to the inflammatory manifestations of increased vascular permeability which also has been described in bronchiolitis (24,42). Finally, alveolar macrophages from infants with recurrent episodes of bronchiolitis accumulate less cyclic adenosine monophosphate in response to stimulation with PGE2, salbutamol and foskolin, a response identical to adults with (27).

4. Collagen Macrophages have been shown to induce fibroblast growth and collagen synthesis due to production of fibronectin which precedes the deposition of collagen in BOOP (38). D-penicillamine in RA has been associated with specific histopathologic features of constrictive bronchiolitis, whereas it does not produce bronchiolitis in other diseases such as Wilson's disease. It blocks cross-linkage of newly synthesized collagen and elastin, and it may interfere with the healing process in inflammatory diseases. ill. CLINICAL ENTITIES THAT MAY CAUSE BRONCHIOLITIS:

The histologic responses to different insults are more limited than the number of potential etiologies. However, there are known clinical entities that may cause bronchiolitis, and these associations should raise the index of suspicion that bronchiolitis is responsible for the symptoms and signs. Since different histologic forms of bronchiolitis may be found with the same disease (e.g. rheumatoid arthritis), this section will focus on the causes rather than the histology. However, the differences in histopathology are important since responses to treatment tends to parallel those of the idiopathic forms. 10

CLINICAL SYNDROMES ASSOCIATED WITH CONSTRICTIVE BRONCHIOLITIS(43,44) Post-infectious Viral (RSV, adenovirus, , parainfluenza) Mycoplasma Allograft recipients Bone marrow recipients Lung transplant recipients Collagen vascular diseases Rheumatoid arthritis Eosinophilic fasciitis Systemic lupus erythematosus Inhaled toxins Nitrogen dioxide Ammonia Chlorine Phosgene Cigarette smoke Drugs Penicillamine Lomustine Ulcerative colitis Idio athic

CLINICAL SYNDROMES ASSOCIATED WITH HISTOLOGIC BOOP Collagen vascular diseases Rheumatoid arthritis Systemic lupus erythematosis Dermatomyositis Mixed connective tissue disease Toxins Inhalants Systemic (drugs-bleomycin, amiodarone) Chronic (organizing) infection Chronic aspiration Bacteria (Legionnela, Nocardia, pseudomonas, Klebsiella sp.) Chronic pneumonia distal to an obstruction Viruses (influenza, cytomegalovirus) Mycoplasma Pneumocystis carinii Other Vasculitis (e.g. Wegener's granulomatosis) Reaction to other insults ( eg, abscess, infarct, tumors, etc.) Idio athic 11

A. Idiopathic Forms of Bronchiolitis

1. BOOP Idiopathic BOOP must be a diagnosis of exclusion, since the histopathology can be associated with many different causes. In 1985, Epler described a group of patients with bronchiolitis ( 4). There were equal numbers of male and females, smokers and non smokers. The history revealed a course ranging from a few weeks to a few months. Their symptoms were of cough, dyspnea, fever and weight loss. The cough was usually non­ productive, but crackles were heard on pysical exam in nearly 70%. Wheezes were rarely present. PFTs revealed primarily restriction, a decreased DLCO, and impaired gas exchange. The sedimentation rate was often quite high, greater than 100, and the CXR showed areas of consolidation or patchy, ground glass densities (4,43). In addition to these presentations, an acute, fulminant syndrome has been described that rapidly progressed to (38,45). Unfortunately, this syndrome does not respond as well to therapy. In such cases, autopsy revealed extensive alveolar fibrosis (38).

2. Constrictive Bronchiolitis The incidence of constrictive bronchiolitis may be as low as 0.04% of patients with any obstruction on PFTs (15). The first cases of obliterative bronchiolitis were described in association with collagen vascular disease in 1977 (3). Since that time there have been other cases described, since some did not have known associative causes they were presumed idiopathic. Four cases were reported in 1985, and one was felt to be clearly secondary to adenovirus infection (25). The same group added another 12 cases in 1989 (16). Kraft, et al. in 1993 described another four cases of idiopathic constrictive bronchiolitis (8). These patients were mostly smokers, and had a 1-5 year history of coryza, cough (often mildly productive) and dyspnea. They had normal CXR.s with increased bronchial wall thickening, and similar changes on high resolution CT scans. Pulmonary function tests revealed obstruction or mild restriction, and evidence of air trapping. Mild to moderate hypoxemia was often present, and DLCO was frequently 12 mildly reduced but there were too few cases to generalize. Although most of these cases had no fever or weight loss, some cases dated the onset to an acute febrile event with cough. Physical exam included crackles on auscultation. For these cases, the overall response to steroids was disappointing, lung function improved slightly to not at all . These patients had normal alveoli, gradual obliteration of bronchioles by transmural fibrosis, clear or hyperlucent lungs on chest X-ray, an obstructive defect on lung function testing. This is also the pathology and clinical picture found in bronchiolits following lung transplantation or graft-vs.-host disease in bone marrow transplantation. Clinical course transpires over several weeks to months (43).

CLINICAL FEATURES OF CB AND BOOP Concentric Bronchiolitis BOOP

Onset of Symptoms months, years weeks, months Dyspnea common common Cough common common Sputum minimal frequent Fever rare frequent Rales rare common Rhonchi occasionally rare CXR hyperinflation ± infiltrates alveolar infiltrates Pulmonary function tests primarily obstruction restriction

3. Panbronchiolitis This is now accepted as a distinct clinical entity, although it is found almost exclusively in Japan or in Japanese individuals. The etiology remains obscure at this time although there appears to be a predominance in individuals with HLA B54 ( 46). Clinically, these individuals present with chronic cough, sputum production and dyspnea on exertion. They have both rales and rhonchi on physical examination (6). The chest x­ ray shows diffusely disseminated fine nodular shadows, mainly in the lower lungs with associated hyperinflation. The PFTs reveal obstruction with air-trapping and hypoxemia. 13 ' Recently, chronic (in >75%) has been described in association with the lung manifestations (19). The main differential diagnosis to exclude is chronic bronchitis or . However, early histologic material reveals a distinction. Later, the clinical picture is similar to bronchiectasis. Finally, there appears to be a unique response to treatment of this entity (see below).

B. Infectious bronchiolitis [histolotically acute, CB, and BOOP]

AGENTS ASSOCIATED WITH ACUTE BRONCHIOLITIS Common Uncommon Respiratory syncytial virus (infants) Coronavirus Parainfluenza virus Rubeola Mycoplasma pneumoniae Mumps Adenovirus Varicella zoster Influenza A and B Rhinoviruses Parvovirus B Enteroviruses

In children less than 2 years of age bronchiolitis is almost always infectious, with viruses leading: RSV, parainfluenza virus types 1-3, adenoviruses, influenza A .and B and mycoplasma pneumoniae are the most common organisms (47). The incidence in the first year oflife is 11.4% (7,48), with the highest incidence being in the winter and early spring months when spread of virus among persons is highest. One recent prospective study found bronchiolitis in 7% of previously healthy infants within the first two years of life, but the majority of those infants had reduced baseline pulmonary function before they developed illness ( 49). By age of 3, essentially 100% of children have been exposed to RSV (30). One review of children with bronchiolitis (28), revealed 34% were infected with RSV, 20% parainfluenza virus type 3, 11% each for M. pneumoniae and parainfl. type 1. Adenovirus and rhinovirus each 7% cases. Potential late complications are development of asthma and chronic lung disease. In another study from eastern Europe, 94% of children with persistent asthma following acute bronchiolitis were found to have persistence of adenoviral infection by bronchoalveolar lavage ( 48). Peripheral blood 14 eosinophil counts, eosinophil cationic protein, and IgE levels tend to be increased in infants with bronchiolitis and correlates with the symptoms of wheezing (29,50). The incidence of persistent wheezing for more than 2 years in children following acute bronchiolitis is around 25% (51,52), but may reflect a tendency toward asthma in these individuals that existed before infection ( 49). However, this disease in children does not progress to bronchiolitis obliterans. The respiratory syncytial virus, originally the chimpanzee coryza virus, is related to the paramyxoviruses but belongs to the pneumovirus family. It is highly infectious with probable transmission from hand-to-nose and an incubation period of 4 to 8 days. It replicates in the nasopharynx before spreading to the lower respiratory tree. Viral replication is in the cytoplasm of respiratory epithelial cells. Early on, the bronchioles experience an influx of acute inflammatory cells followed by an inflammatory infiltrate of lymphocytes and macrophages that accumulate in the epithelium and submucosa with necrotic debris and fibrin accumulating in the bronchiolar lumen. Clinical findings include tachypnea, tachycardia, prolonged expiration, wheezing and crackles. Infection is usually a self limited upper respiratory illness, but in infants under the age of one, almost half will develop lower respiratory symptoms, some severe (30). Overall mortality is less than 1%, unless the child has congenital heart disease where the mortality is 37% (7). RSV cultures confirm diagnosis, antibodies may be detected by ELISA, but a four-fold increase in convalescent sera is needed. It also can cause acute upper infections in older children and adults (53). Parainfluenza viruses,

Types 1,2,and 3, and other virus~s (see Table) are capable of causing human disease, including bronchiolitis. Transmission is from human to human with viral replication in the nasopharynx. The clinical symptoms and clinical course are similar to RSV. It is unknown if it causes bronchiolitis in adults. In addition to pneumonia, Mycoplasma pneumoniae can cause bronchiolitis in both adults and children. Mycoplasma organisms have no cell wall, which separates them from bacteria, but they are filamentous and motile. Pathogenesis is believed to be related to production of hydrogen peroxide and superoxide anions damaging cells. In adults this infection may progress to bronchiolitis obliterans or hyperlucent lung syndrome (Swyer- 15

James syndrome or McLouds syndrome). Cold agglutinins are present in 50-60% of patients (28). In adults, acute bronchiolitis has been associated with HIV, CMV, and varicella zoster (28,54,55). However, other infectious causes in adults have been reported: Nocardia asteroides (56,57), Aspergillus (58), Crytococcus neoformans, Legionella (59), measles, pertussis, H. influenzae, Klebsiella. spp., Haemophilus influenzae, recurrent aspiration (60), pertussis and pneumocystis carinii (28,61). Some of these cases are acute and limited or may go on to constrictive bronchiolitis or BOOP (see below).

C. Post-transplant [primarily Constrictive bronchiolitis ] 1. Bone marrow transplant (BMT) Chronic graft vs host disease (GVHD) occurs in 10% of allogenic BMT, but can occur in autologous transplants. Obstruction of the airways in BMT was first described in 1982 as a manifestation ofGVHD, then subsequent cases were described (62). GVHD was also manifested by skin involvement ( 63) and hepatic involvement. The patients with bronchiolitis had cough, wheeze or dyspnea within 6 wks to 10 months after BMT. Although PFTs demonstrated airflow obstruction, the chest radiographs were normal or consistent with hyperinflation, occasionally infiltrates were present. The clinical course was associated with a high fatality rate. The incidence of bronchiolitis in patients with chronic GVHD is estimated to be in the order of 10% (63). Risk factors for this are older age, chronic GVHD, use ofMethotrexate and decreased IgG levels. The three year mortality rate was 65% compared to 44% overall for BMTs. A decline in FEVI% was associated with a worse prognosis, as those individuals tended to die of respiratory failure. Pathogenesis: Host bronchiolar cells apparently serve as targets for donor cytotoxic T­ lymphocytes. This is similar to the responses in the skin , GI tract and liver. In support of this hypothesis is the fact that bronchiolar epithelial cells express major histocompatibility antigens on their surfaces. Class I and Class II histocompatibility antigens on the epithelium may be up regulated by other factors, such as CMV or acute rejection. In fact, expression of the Class II antigens can be induced by interferon-y, as well as from injury from agents such as bleomycin. Rather than an immunological pulmonary form of chronic 16 rejection, one theory is that the inflammation in the airways of these patients includes recurrent aspiration of oral material due to esophagitis or unrecognized viral infection. It may tum out to be a response to multiple simultaneous events. The incidence in long-term survivors has been reported to be as high as 50 to 54% (63). The predominant histologic type is obliterative bronchiolitis, although fibrosis of the wall without distortion is noted frequently, and lymphocytic bronchiolitis has been found less frequently (64). 2. Lung transplant (65-67) Bronchiolitis obliterans occurs 3 months or more after transplant, with a mortality rate of 50%, and it is the most common cause oflate morbidity and mortality (68). Its prevalence ranges from 25 to 50%. This incidence range is likely related to the clinical criteria used to make the diagnosis, and the duration the patients are followed before the report. It rarely occurs before 60 days following transplantation when acute surgical and acute rejection episodes are likely to be found. The symptoms are often insidious with cough and dyspnea, and the course is rapid with deterioration over several months (69). Histologically, the submucosa ofthe bronchi and bronchioles is infiltrated by lymphocytes and histiocytes with eosinophils, then the lesions develop intraluminal plugs similar to BOOP (69,70). Later, this inflammation progresses to obliterative bronchiolitis that includes dense eosinophilic collagen deposition. This collagen may form plaques that are eccentric, concentric or obliterate the lumen. While this picture is associated with chronic rejection, increased numbers of lymphocytes seen histologically may be due to infection with bacteria or Aspergillus. However, other infectious agents such as CMV or adenovirus have also been implicated (69,70). The immunologic etiology may not be that different in from that ofBMT. In lung transplantation the reaction is believed to be primarily an immunologically mediated process related to the transplant and directed toward the epithelial cells. Increased numbers of dentritic cells (which have been identified in the walls of the trachea and bronchi of transplant recipients with bronchiolitis obliterans) (71) as well as epithelial cells and endothelial cells act as immunologic accessory cells to activate lymphocytes and attract neutrophils. The epithelial cells express increased HLA class II antigens which stimulates the lymphocytes. Another proposed mechanism is that of ischemic injury to the 17 epithelial cells occurring at the time of surgery which leads to a later development of bronchiolitis. Again ischemia may cause the epithelial cells to express more class II HLA antigens which become the initial target or promoter for the immunologic reaction. Furthennore, since endothelial cells are targeted in rejection of other organs that are transplanted, such as liver, kidney and heart, it is also possible that the bronchiolar endothelial cells are involved in the immunological reaction. Also, the endothelial cells, epithelial cells and fibroblasts may be involved by producing various cytokines as well ( 41 ). Recently described, CD4/CD8 ratios of peripheral blood lymphocytes were decreased, and other lymphocyte phenotypes were significantly different between transplant patients with obliterative bronchiolitis than those without perhaps reflecting the chronic inflammation (72). Nevertheless, the exact etiology is not known, but researchers in this area tend to favor multiple factors (69).

D. Connective Tissue Diseases [BOOP & constrictive bronchiolitis] Although interstitial lung disease in association with various collagen vascular diseases, such as rheumatoid arthritis (RA), sclerodenna and mixed connective tissue disease is well described, isolated involvement of the tenninal bronchioles is not widely known. Perhaps because it is more common and therefore studied, this association is best described in patients with RA, but can be found in association with any of the collagen vascular diseases listed below. Most of the associations published are anecdotal. Histologically, they tend to fall into either constrictive bronchiolitis or BOOP patterns with some variations. These histologic distinctions may be important in that response to treatment may predicted.

1. Rheumatoid Arthritis In one series, obstructive patterns in PFTs were found in 30% of patients with RA (73), although the predominant abnonnality was restriction. HLA types B40 and DR1 were found to have an increased association with CB in RA but not in patients with bronchiolitis without RA. Interestingly HLA types A3 and BS were not found in either group of patients with bronchiolitis (74). The association ofbronchiolitis in RA patients 18 who also received penicillamine was described almost 20 years ago although bronchiolitis and penicillamine without RA is not common and has not been described in patients receiving it for Wilsons disease, for example (3, 75, 76). Furthermore, even though penicillamine is used for treatment of scleroderma, CB has not been described in association with this entity. Gold therapy has also been described in association with CB in RA. BOOP associated with RA is more commonly described in the literature (77) and is associated with a better prognosis than constrictive bronchiolitis. Thus, histologic diagnosis is important. 2. Sjogren's Syndrome Bronchiolitis has been occasionally described in association with Sjogren's syndrome (78), although Sjogren's was often found in association with RA. The bronchiolitis may be BOOP (79), but more commonly the primary pulmonary defect in Sjogren's syndrome is that of a lymphocytic pneumonitis with or without lymphocytic infiltration around the bronchioles (11,80,81). 3. Polymyositis and dermatomyositis Polymyositis and dermatomyositis patients were found to have BOOP, usual interstitial pneumonitis (VIP), and diffuse alveolar damage (82). Patients with BOOP had a more favorable prognosis than the other patients with VIP. Constrictive bronchiolitis, however, has not been described in association with these entities. 4. Systemic lupus erythematosis (SLE) Bronchiolitis (CB) and BOOP have been reported in association with SLE (83), but are not prominent features and are considered rare (84). 5. Essential mixed cryoglobulinemia and vasculitis These diagnoses are sometimes described in association with BOOP . An infectious etiology should be sought and treated if found, since a chronic organizing pneumonia is common. Similarly, biopsies of patients with Wegener's granulomatosis may have regions that histologically are identical to BOOP. 19

6. Others Inflammatory bowel disease, usually ulcerative colitis, has been described in association with bronchiolitis (85), and has been described in individuals not taking sulfasalazine (86). E. Toxic Fumes and Dusts [BOOP & constrictive bronchiolitis found] Numerous inhaled agents have been reported to produce bronchiolitis: Nitrogen dioxide, sulphur dioxide, ammonia, chlorine, phosgene, chloropicrin, trichloroethylene, hydrogen sulphide, fluoride, cadmium, talcum powder, zinc chloride and stearate, phosphorus pentachloride, nickel and iron carbonyl, ozone, thionyl chloride, free base cocaine and thermal injury (10, 14,44,87,88). Most injuries are produced from a strong acid, a strong base or an oxidant which forms in the distal airways. Direct epithelial injury results. Two or more noxious gases often combine to yield injury. Both histological forms may occur after exposure, but BOOP > constrictive bronchiolitis. Often an acute massive exposure results in diffuse alveolar injury and an ARDS picture, such as in Silo filler's disease which has a mortality of 20%. Recovery or exposure to a lower dose, results in a more chronic pattern with the evolution of cough and dyspnea weeks to months after exposure. Smoke inhalation can produce the same clinical picture although the mechanisms of injury are probably different. Inhalation of hot, dry air may cause upper airway damage whereas inhaltion of steam injures the distal airway mucosa. However, in a fire, many toxins ~ay be released, depending on what is being burned. Wood releases carbon monoxide, nitrogen oxides, acetaldehyde and formaldehyde; plastic release HCL and phosgene; silk, nylon and wool release ammonia and hydrogen cyanide. The less soluble fumes reach more distal airways and produce epithelial injury when they interact with water to produce acids, alkali or oxidants. Although the mechanism is unclear, perhaps through formation of free radicals, mineral dust exposure also produces damage to the small airways and a bronchiolitis. In addition, there is evidence that cigarette smoking may cause a bronchiolitis in young adults, respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) (89), which may explain, in part, some of the reversibility of the airway obstruction with cessation of smoking. These lesions are believed to be related to oxidant exposure similar 20 to that of air pollution with the production of ozone (8,44). These patients have cough and dyspnea and PFTs show a mixed picture of obstruction and some restriction. The diffusing capacity (DLCO) may be normal or reduced. The histopathologic picture is that of constrictive bronchiolitis involving the respiratory and membranous bronchioles. Although most of the interstitium is normal, some of the adjacent alveoli may show inflaiTli11ation and fibrosis. Since smoking is believed to be causal, smoking cessation is considered critical in the treatment, although some response can be obtained with steroids (8,10,89). F. Drugs (90) [BOOP & constrictive bronchiolitis] 1. Immunosuppressive drugs All immunosuppresive drugs can produce reactions identical to BOOP or CB: bleomycin, penicillamine, sulfasalazine, methotrexate, cyclophosphamide, mitomycin C, and gold are the most predominant agents (90). 2. Others Many other drugs have also been described as causing bronchiolitis: amiodarone, acebutolol, paraquat poisoning, cocaine smoking, radiation and cephalosporins. These are often in individual case reports where the only likely agent was the drug used. Some have been described frequently. Some ofthe more prominent agents are listed in the table:

Agents Associated with BOOP (90)

Gold Penicillamine Sulfasalazine Bleomycin Radiation Amiodarone Methotrexate Mitomycin-C Cyclophosphamide Cocaine a. Interferon 21

G. Hypersensitivity Pneumonitis- Sarcoidosis [Granulomatous] This is included here because it is often considered in the differential diagnosis, and may present in a similar fashion. Rarely a bronchiolitis is also found with these diagnoses. The primary clinical, pathological and radiological manifestations ofHP and Sarcoidosis are those of an interstitial lung disease. However, in Sarcoidosis airway symptoms and findings of airways obstruction occur in at least 10% to as many as 100% of patients. Obstructive changes on PFTs occur in increasing proportions of patients as the radiographic stage increases (91). Histopathologic findings include granulomatous involvement of small airways as well as an active alveolitis, although bronchiolitis per se, has not been identified (92). Airway obstruction has been reported in some cases with farmer's lung and bird breeder's lung, and some argue that a form of bronchiolitis can be present in some patients with hypersensitivity pneumonitis as well as some patients with sarcoidosis (93). However, these tend to be less typical rather than more typical manifestations of inflammatory interstitial disease.

IV. DIAGNOSIS AND TREATMENT

A. Pulmonary Function Tests (PFTs) 1. Restrictive ventilatory defects This pattern is observed more in those with BOOP not only because of the associated pneumonitis, but also because of the complete obstruction that occurs in the involved bronchioles. Thus, airflow does not reach certain areas of the lung. The patchy involvement is not reflected in the measurements of spirometry. Nevertheless, associated bronchitis, bronchiectasis and other obstructive airways diseases such as asthma may produce a combined defect of both obstructive and restrictive defects on PFTs. The diffusing capacity may be reduced or may be normal in BOOP, since the nearby alveolar structures and interstitium may be involved. Unfortunately, this does not help in the differential diagnosis. However, a severe reduction may indicate the greater presence of interstitial disease. Lung biopsy is usually needed to exclude this possibility. Generally, constrictive bronchiolitis is not associated with restrictive defects on PFTs. Both types of 22 bronchiolitis may be found in association with other diseases, such as collagen vascular diseases or asthma which may contribute to the associated findings of concomitant restriction or obstruction. For example, some collagen vascular diseases may also have a component of interstitial lung disease, and some types of bronchiolitis may be found in smokers who also have other causes for airway obstruction. The clinical setting is important in making the diagnosis. 2. Obstruction of the small airways: The hallmark of pure constrictive bronchiolitis is obstruction of the small airways with preservation of the diffusing capacity and increased lung volumes from air trapping. Restrictive ventilatory defects are usually associated with a reduction of airflow measurements that are proportional to the reduction in lung volume and are not indicative of airflow obstruction, per se. Furthermore, simple spirometry is effort dependent, and a less than maximal effort will preclude accurate interpretation. With a good, maximal effort, simple parameters such as the mean flow in the middle of expiration, between 25% and 75% ofthe expired vital capacity and maximal expiratory flow at 50% of the vital capacity may be useful to determine obstruction of the smaller airways. There is a rather wide range of normal for these tests, however, which limits their use for early detection of disease (94). The reduction in these values is due to the increased resistance in the airway segment upstream to the equal pressure point during forced exhalation. Other specialized tests for obstruction of the small airways have been developed but are not clinically useful since they are difficult to perform and also have a wide range of reproducibility. For simple spirometry, the acceptable range ofvariability in the FEV1 from week to week in normals is 11%, for forced vital capacity, FVC, it is 12%, and for FEF25-75 it is 21%. Thus, in order for changing values to be considered significantly different (i.e. to occur in fewer than 5% of normal subjects), the differences would have to be greater than these values. This becomes more important in following patients with lung or heart-lung transplants who may have PFTs performed weekly as surveillance for early signs of rejection. 23

Obstructive Pattern Restrictive Pattern

... · . \

.· ...... · · 1\tOJ.IvE I

Dashed line indicates normal predicted curve. Solid lines indicate pattern of restriction or small airways obstruction. These patterns may be found in different lung diseases, as well.

Recent studies indicate that the contour of the flow-volume loop was sensitive for early detection of obliterative bronchiolitis in single lung transplantation recipients, but was not specific due to the development of airway stenosis in many subjects (95,96).

B. Chest radiographs, CT scans

1. Constrictive Bronchiolitis A remarkable feature of CB is the presence of significant clinical symptoms and abdormalities on the PFTs in the presence of a normal CXR. On the other hand the chest x-ray may reveal subtle peripheral attenuation or hyperinflation. In patients with presumed CB (after emphysema was excluded) CT scanning revealed areas of attenuation which were described as "irregular patches of radiolucency with ill-defomed edges" (97,98). Some patients were noted to have patchy areas of increased density, but no infiltrates, and this heterogeneity is exaggerated on expiration (99, 100). Notably, emphysema has a different characteristic, with bullae noted, but panlobular emphysema as seen in a 1- 24 antitrypsin deficiency may mimic CB. CB or obliterative bronchiolitis following toxic fume exposure such as following nitrogen dioxide exposure may reveal milliary nodules 2 to 3 weeks following exposure. Other toxins such as anhydrous ammonia may produce a more pronounced inflammatory reaction revealing bronchiectasis on the chest radiographs (97). Swyer-James syndrome is regarded as a type of post-viral or other infectious bronchiolitis obliterans (CB) with primarily unilateral lung damage leaving a hyperlucent lung with a normal or reduced lung volume. CT scan, particularly HRCT, reveals bronchiectasis is almost always present in the affected lung. In addition, the ipsilateral central and peripheral pulmonary arteries are also decreased in size, and heterogeneity of lung density may be found in the other lung as well. Ventilation/perfusion scanning shows matched defects in the involved areas. 2. BOOP Peripheral, pleural-based infiltrates with alveolar opacities are characteristically found on chest x-rays ofpatients with BOOP (43,97,100,101). This may differ from the peripheral alveolar infiltrates of patients with CEP in that the infiltrates with BOOP are greatest in the bases. Small pleural effusions may be found. Airspace filling is the predominant feature, although interstitial opacities, or micro-nodules are frequently found in as many as 20-30% ofthe cases (97,102). Sometimes the opacities on plain films cannot readily be distinguished from the patterns seen in IPF, including the presence of irregular linear opacities (103,104). Furthermore, the presence of interstitial patterns may herald a worse prognosis, while nodular opacities signal a rapid response to steroids. In BOOP, the airspace abnormality on CT was described as a ground-glass density [such that the vessels are not obscured] or consolidation, and most commonly both patterns are seen (43,97,99). A pure honeycomb pattern suggesting fibrosis is not found in BOOP, although moderate mediastinal adenopathy may occur. Nevertheless, even with HRCT, distinction between IPF, BOOP and other airspace diseases cannot be made. The differential diagnosis includes lipid aspiration, sarcoidosis, Wegener's granulomatosis, lymphoma, other vasculitides, amyloidosis and CEP must be excluded. Also, due to the patchy nature of infiltrates in BOOP, CT may help determine which areas of the lung to biopsy to improve the diagnostic yield. 25

3. Panbronchiolitis Although not seen much in the Western hemisphere, the HRCT features do correlate well with pathologic findings (97,99). Diffuse small nodular opacities associated with hyperinflation are seen. As the disease progresses, the nodules increase in size and are centrilobular. Pathologically these are secretion-filled bronchioles. Later there is cystic dilatation then finally dilated proximal bronchiectasis ( 46,97).

C. Biopsy, BAL 1. Open lung Due to the patchy nature of bronchiolitis is is often advisable to use the chest x­ ray or CT to pick site (2). Frequently, lung biopsy is often not performed for CB. The reasons are two fold : first, the syndrome is rare and presentation is often associated with severe obstructive symptoms such that biopsy may be too dangerous and secondly, the diagnosis may be made on clinical grounds by a known etiologic exposure (such as toxic fumes, RA, etc) with characteristic pulmonary function studies. Histologic descriptions are based on those patients who did come to open lung biopsy or autopsy. Furthermore, the patchy nature of the process and lack of focal findings on imaging procedures increases the possibility of missing the lesion altogether, even with open lung biopsy. Open lung biopsy can help make the diagnosis ofbronchiolitis obliterans associated with transplantation, although this is also considered too invasive and the diagnosis is usually based on less risky procedures. In BOOP, on the other hand, the diagnosis is best made with open lung biopsy. Radiograhic imaging procedures may help pick the site for optimal results. Less invasive procedures for getting large samples of tissue may then be performed such as Videoassisted transthoracic surgery (105). 2. Transbronchiallung biopsy (TBB) The best data for the reliability of TBB is from the lung transplantation literature. Sampling the lung with TBB is difficult at best, with one study determining that less than half the specimens actually turned out to have evaluable fragments on microscopy (64). 26

Better tissue is obtained with more samples (64,106). For making the diagnosis of bronchiolitis in lung transplantation, the positive predictive value is low, however, because bronchiolitis obliterans is a patchy process and may be the result of insults other than lung rejection. In patients who later proved to have rejection , the sensitivity of a TBB procedure for detecting bronchiolitis obliterans was 17%, but the specificity with a TBB procedure is 94.5%, whereas the positive predictive value and negative predictive values for this procedure are both 65%, respectively (64). In lung transplantation, the isolated finding ofbronchiolitis obliterans on a TBB does not confirm rejection, particularly without the clinical syndrome suggestive of rejection, but false positive diagnoses are rare (106). Furthermore, histologic heterogeneity of bronchiolitis makes it difficult to be certain ofthe diagnosis with limited material. In spite of the limitations of the procedure, it is not possible to repeatedly obtain open lung biopsies on patients in order to determine histologic presence of rejection, and the Lung Rejection Study Group recommends that at least five specimens of lung parenchyma should be obtained for examination. It is used to make histologic confirmation of chronic rejection in approximately 80% of the cases in some institutions (70). 3. Bronchoalveolar Lavage (BAL) In addition to performing BAL for differential cell count, analysis of the components of the lymphocytes may be useful in the differential diagnosis between BOOP, CEP, and hypersensitivity pneumonitis (2,25,35). Findings in CB and diffuse panbronchiolitis may be difficult to differentiate without clinical criteria. The ratio of CD4 to CD 8 cells is decreased in BOOP, 0.38 ± 0.18 (35,36,107), compared to 2.8 ±_1.7 in non-smoking normal individuals (107), and 0.95 ± 0.6 in smokers. However, this ratio is approximately 2 in those with interstitial fibrosis, and 1.6 in patients with chronic eosinophilic pneumonia (36). This ratio is also elevated in hypersensitivity pneumonitis and Sarcoidosis. CEP, however, is associated with a significant eosinophilia on BAL. Hence, although biopsy is often needed to make the diagnosis, in some cases, BAL can obviate the need or can be used to follow response to treatment once the diagnosis is established. Commonly, BAL remains a research tool. 27

Bronchoalveolar lavage cellular findings Neutrophils Lymphocytes Eosinophils Normal 1-2% 5-10% 0-1% Constrictive bronchiolitis 50-90% 0-2% 2-12% BOOP 1-30% 25-70% 5-10% IPF 12-15% 15-20% 5-7% Hypersensitivity 1-17% 40-70% 0-2% pneumonitis

Chronic Eosinophilic 8-10% 10-20% 20-40% Pneumonia

D. Treatment and clinical course 1. Acute infectious bronchiolitis: Since the majority of cases are selflimited, the most common treatment is supportive care and observation in children with acute infectious bronchiolitis. Those cases that are more severe, hospitalization may be required for administration of oxygen, fluids, and often J3 adrenergic bronchodilators (7,47,108,109). Persistent wheezing is treated symptomatically with additional bronchodilators, and some cases are believed to evolve clinically into childhood asthma. Specific anti-viral therapy for RSV is somewhat controversial since treatment with aerosolized Ribavirin, which inhibits RNA viral replication, may shorten the course, but is only moderately successful, thus it is reserved for those infants at greatest risk for severe disease (11 0). Ribavirin is expensive, costing almost $1000/day, and poses some risk to hospital care givers (7, 111). Specific antiviral therapy is not available for most other viruses. M. pneumoniae is associated with both acute bronchiolitis and constrictive bronchiolitis in adults and children. Therapy with erythromycin is recommended for acute pneumonia, but its role in the treatment of bronchiolitis is not established. Nevertheless, if Mycoplasma is present, it seems logical to initiate therapy. In adults, acute infective bronchiolitis may progress to constrictive bronchiolitis or bronchiolitis with organizing pnuemonia. Steroid therapy in such cases is often rewarding, if other possible complicating infections have been excluded or treated. 28

Thus, superinfection with a bacterial agent should be treated with specific therapy before steroids are initiated.

Candidates for Ribavirin Therapy for Bronchiolitis (112) Infants at increased risk for severe disease Congenital heart disease Immunodefiency states Bronchopulmonary dysplasia Other chronic lung conditions Some premature infants Infants who have severe disease Arterial P02 < 65 mm Hg Rising arterial PC02 Other infants with RSV plus another risk factor Age< 6 weeks Multiple congenital abnormalities Neurolo ic or metabolic diseases

2. Constrictive bronchiolitis Treatment of constrictive bronchiolitis begins with identifying the initiating event. The first approach is to remove the irritating source if possible, such as exposure to inhaled toxins (cigarette smoke, ozone, etc.) or drug interactions (penicillamine). Underlying diseases such as GVHD or rejection of a transplanted lung are treated first with specific therapy for rejection. In the case of allograph transplants, a careful search for a possible opportunistic infection such as CMV should be made, and specific therapy directed to the agent when found. Finally, treatment with steroids may be initiated, although characteristically these cases have a disappointing response. In some cases, additional therapy with other immunosuppressive therapy may be attempted. Cases of idiopathic bronchiolitis obliterans, while relatively rare, characteristically have a slowly progressive downhill course despite therapy with steroids (8). However, many forms of constrictive bronchiolits, particularly associated with RA, have a high mortality, and the course is much shorter (5-18 months), in spite of therapy with . 29

3. BOOP Many inciting agents can produce a clinical syndrome and histological picture consistent with BOOP, and any cause that can be readily identified should be treated. Infections are particularly important since adding steroid therapy to an already infected patient may be counterproductive. Unusual agents should also be sought, even in an otherwise 'nonnal' host. Recurrent aspiration is particularly bothersome, since the patient may require more than medical management. Histopathologic examination of the lung biopsy may reveal fragments of food particles, but may not be found in all cases. A careful clinical history is important and additional studies may be necessary. As stated above, bronchiolitis associated with bone marrow or lung transplantation may be secondary to infection, to rejection, or to some other factors. Ifthe patient is a bone marrow transplant patient with low serum IgG levels, replacement with intravenous IgG may be recommended in addition to other specific therapies. Specific antibiotic therapy to agents identified in the sputum or bronchoalveolar lavage should be initiated in patients with the diagnosis ofBOOP. Idiopathic BOOP, as stated before, is a diagnosis of exclusion. These cases respond quite well to steroids (2), sometimes dramatically. However, one study showed the BAL of many patients was still abnonnal at 12 months. Also, there are reports of a rapidly progressive acute fonn of idiopathic BOOP as well as in those with an associated immunologic disorder (38,45). These patients had shortened prodromes and rapidly progressed to acute respiratory failure. The mortality was high despite therapy with steroids. These cases are felt to be rather rare, and it took these investigators 13 years to accumulate 10 such patients from three tertiary hospitals. In BOOP cases that do not respond quickly to steroids, other immunosuppressive therapy is tried. These are treated with cytoxan or immuran with varying degrees of success. Several authors advocate starting with a high dose of intravenous solu-medrol for one to three days, then switching to oral prednisone 1 mglkg/day for several additional weeks. The dose is then tapered slowly over a total of three months. The patients are monitored carefully, and at signs of relapse, the dose of steroid may be increased. The total duration of steroid therapy usually 30 ranged from three to six months, with some cases needing steroid therapy for as long as one year. 4. Panbronchiolitis Although the mechanism remains unknown, empiric therapy with oral erythromycin has been demonstrated to be an effective treatment for diffuse panbronchiolitis (20,26, 112). Furthermore, its effectiveness is not believed to be related to antimicrobial effects (112). Response has been demonstrated with low doses, 200-600 mg/day, which is below most antimicrobial therapeutic levels. Erythromycin has been shown to be an immunomodulator by reducing neutrophil counts and neutrophil-derived elastolytic-like activity (20, 113) and levels ofleukotriene B4 in BAL fluid (26) of patients with DPB. Experimentally, it attenuates neutrophil chemotactic response to Il-8 both in vivo and in vitro (21,114), and may decrease mucus production (115). Although the response rate is not 100%, the current approach in Japan is to start the patient with an oral dose of200 to 600 mg/day of erythromycin, then monitor PFTs and CXR.s for two months ( 46, 112). Therapy is continued as needed for up to 1 year. Patients not responding to erythromycin may have a progressive downhill course over several years, eventually resulting in death ( 6, 19). These patients develop symptoms typical of bronchiectasis as late manifestations. References

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