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Current perspectives on endobronchial tuberculosis
Cuneyt Tetikkurt
SUMMARY. Endobronchial tuberculosis (EBTB) is the tuberculous infection of the tracheobronchial tree, with microbial and histopathological evidence. EBTB is present in 10-40% of patients with active tuberculosis. It can easily be confused with other diseases since the clinical findings are non specific. A clear chest X-ray does not exclude the diagnosis because the X-ray appearances may be normal in 20% of patients. A “tree-in-bud” appearance is a characteristic high resolution computed tomography (HRCT) appearance in EBTB. Bronchoscopic examination is the key to diagnosis, and CT and bronchoscopy are the methods used for the assessment of treatment options. Early diagnosis with prompt treatment is important to prevent the serious complications of EBTB, such as bronchostenosis and bronchiectasis. Antituberculous chemotherapy is effective in controlling the infection but may not preclude residual bronchostenosis. Corticosteroid therapy for the prevention of bronchial stenosis remains controversial. This article presents a clinical, radiological and pathological overview of EBTB, with the current treatment options. Pneumon 2008; 21(3):–

Introduction

Endobronchial tuberculosis (EBTB) is defined as a specific inflammation of the tracheobronchial tree caused by the tubercle bacillus. The definitive diagnosis depends on culture of mycobacterium from bronchoscopic material. The disease develops as a common complication of active tuberculosis, but the exact pathogenesis is not yet completely understood. EBTB is present in 10-40 % of patients with active tuberculosis and causes some degree of bronchial stenosis in more than 90 % of the patients1. It is a highly infectious disease that poses a diagnostic challenge because the disease presents with non specific clinical findings and the lesion may not be evident on the chest X-ray. Bronchoscopic examination with microbiological and histopathological evidence is needed for diagnosis. Frequently, the diagnosis is delayed since its decreased incidence and the non specific clinical findings diminish the suspicion of tuberculosis. EBTB may also present a therapeutic challenge due to its sequelae of bronchial stenosis. Early diagnosis and prompt treatment may prevent the development of complications. Bronchostenosis may occur as a result of specific inflammation despite effective treatment. Steroid treatment for bronchostenosis remains controversial. Interventional bronchoscopy or surgery should be considered for the management of stenosis that occurs despite medical treatment. In this review, the pathogenesis, morphological changes and radiologic and bronchoscopic findings of EBTB are discussed, along with the current treatment options.

Epidemiology

EBTB was relatively common before the advent of effective treatment. The incidence of EBTB among post-mortem specimens from people with tuberculosis was as high as 40% prior to the introduction of antituberculosis chemotherapy, but with modern treatment the incidence of EBTB has declined to 10% of cases of pulmonary tuberculosis2. Salkin presented data from 125 consecutive autopsies and 622 admissions to the Hopemont Sanatorium in West Virginia. Every patient underwent initial rigid bronchoscopy and serial bronchoscopies were performed every 3 to 6 months. Tuberculous lesions were observed in 50 (40%) of the autopsies and 97 (15.5%) of the patients undergoing bronchoscopy. Patients with positive sputum and cavity formation demonstrated endobronchial lesions more frequently than those without these characteristics3.

In a series of 1,000 autopsies, Auerbach demonstrated endobronchial tuberculosis in 42% of the cases. Most of the lesions were located on the posterior wall of the tracheobronchial tree. Cavities were always present in patients with grossly evident ulcers4. The incidence of EBTB varies from 10% to 37% in patients investigated by bronchoscopy5-7. Most recently, the incidence has been reported to be about 20%8-10. EBTB occurs more commonly in young women, but Van den Brade et al. described a significant geriatric population affected9-11. Modern treatment may be effective in the decline of EBTB. Currently, its incidence may be underestimated since diagnostic bronchoscopy is not performed on every patient with tuberculosis.

Pathogenesis

The pathogenesis of EBTB is not clearly understood. Currently, five possible mechanisms are considered in the development of EBTB: a) direct extension form an adjacent parenchymal focus, b) implantation of organisms from infected sputum, c) haematogenous dissemination, d) lymph node erosion into a bronchus, and e) spread of infection via the lymphatics6. Meissner demonstrated mucosal and submucosal involvement in all patients with EBTB. He postulated that EBTB developed as a result of direct implantation of tubercle bacilli in the tracheobronchial tree from a distal parenchymal focus12. Chang et al. have demonstrated endobronchial involvement in patients with intrathoracic tuberculous lymphadenopathy. They suggested bronchial perforation as a possible mechanism in some patients13. More recently, Baran found endobronchial abnormalities in patients with intrathoracic tuberculous lymphadenopathy without parenchymal lesions14. Direct perforation of tuberculous lymph nodes into the bronchi is uncommon in adults. Lymphatic and haematogenous spread are less commonly observed mechanisms. Parenchymal infiltrations, cavitary lesions, hilar and mediastinal lymph node enlargement have all been observed in patients in the author's department15. Recently, Kim et al. showed that elevated TGF-gamma and TGF-beta levels in bronchial lavage fluids of patients with EBTB may be related to its pathogenesis. Lowered initial serum TGF-beta levels and changes in the levels of TGF-beta observed in the serum after treatment have been implicated in the development of bronchial stenosis during the course of the disease16. It is believed that more than one mechanism is usually responsible for the development of EBTB in adults.

Clinical features

The clinical presentation of EBTB is variable. The clinical features depend on the site and the extent of involvement. The disease may occur in the absence of recognized symptoms. It may have an insidious onset, simulating lung carcinoma, or an acute onset mimicking asthma, foreign body aspiration or pneumonia10,17,18. The duration of symptoms at consultation varies from 0 to 26 weeks. Systemic symptoms may not be prominent in EBTB. Fever is observed in 50-87%, night sweats in 55% and weight loss in 71% of patients9-15. Fever may be low grade at the onset but may become marked as the disease progresses. It is typically subfebrile and develops in the afternoon7,8. The respiratory symptoms in EBTB are usually nonspecific. A barking cough is the most common symptom. The cough slowly progresses over weeks or months and may become more frequent. Sputum production is rare but bronchorrhoea has been reported. Haemoptysis occurs occasionally but is rarely massive. With lymph node rupture, chest pain may occur in the sternal or parasternal region, which is sharp or dull and is encountered in about 15% per cent of patients. Dyspnoea is often associated with atelectasis. Constitutional symptoms including anorexia, weight loss and night sweats may occur8-10.

Physical examination may reveal no abnormalities in one third of the patients. Examination of the respiratory system may detect râles, decreased breath sounds, a localized monophasic wheeze, rhonchi and bronchial breathing. Persistent unilateral wheeze is indicative of EBTB. Stridor may occur with ulceration and cicatrization of the larynx or trachea. Routine laboratory examination is rarely helpful in establishing a diagnosis. Various haematologic manifestations have been reported in EBTB, but laboratory abnormalities associated with EBTB are non specific. Patients may have elevated ESR rates and CRP levels. The most common haematologic abnormalities are an increase the leucocyte count, but mild leukopenia, lymphopenia, absolute or relative monocytosis and decrease in the CD4 count may occur. Anaemia and low serum iron and total iron binding capacity are observed. The anaemia is probably due to decreased marrow iron stores and suppression of erythropoiesis by inflammatory mechanisms and occurs in 10% of the patients. Macrocytic anaemia is rare19-21.

A clear chest radiograph does not exclude the diagnosis of EBTB as the chest X-ray may be normal in 10% of the patients. Endobronchial spread of tuberculosis can be reasonably presumed to have occurred when multiple nodules measuring 2 to 10 mm in diameter are seen at a distance from a cavity or an area of consolidation. The radiological manifestations of bronchogenic spread include multiple nodular opacities and consolidation. Bronchial wall thickening, bronchial stenosis, poststenotic dilatation, lobar hyperinflation, mucoid impaction and atelectasis are other radiologic features of bronchogenic disease. The associated pulmonary parenchymal lesions may be obscured by atelectasis. Classical radiological features of tuberculosis such as cavitation, pleural effusion, hilar and mediastinal lymphadenopathy may also be observed. Bronchial stenosis, bronchiectasis and broncholiths may occur as late complications of endobronchial disease22-24.

High resolution computed tomography (HRCT) is more sensitive than conventional chest X-ray in demonstrating early endobronchial spread. Studies using HRCT have shown a much higher prevalence of the disease. HRCT findings consistent with endobronchial spread were seen in 98% of 41 patients in one study and 97% of 31 patients in another study. Radiographic findings consistent with endobronchial spread of tuberculosis have been reported in 10-20% of patients with active postprimary disease23. The most common findings on HRCT are the 2-4 mm centrilobular nodules and branching linear structures known as the "tree-in-bud" appearance, which represents caseation necrosis within and around the bronchioles. Miliary tuberculosis and endobronchial involvement may coexist (Figure 1). Other abnormalities in decreasing order of frequency are 4-8 mm diameter nodules with poorly defined margins, lobular areas of consolidation and thickening of the interlobular septa25,26.

A low yield is reported of positive sputum smear examination in the diagnosis of endobronchial tuberculosis8,9. Chung and Lee found a 53% yield27. This low yield on sputum AFB smears is due to mucus entrapment by proximal bronchial granulation tissue. Therefore, a negative sputum smear does not preclude the diagnosis of EBTB. Bronchoscopy with bronchoscopic sampling has been the key to diagnosis, producing a yield of greater than 90% on both smear and culture.

Image 1

Figure 1. Miliary tuberculosis with left lower lobe narrowing due to endobronchial involvement.

The experience of the bronchoscopist is of great importance for eliciting the bronchoscopic findings that contribute to diagnosis. A bronchoscopic biopsy is the most reliable method for the diagnosis of EBTB. Needle aspiration may provide only a cytological diagnosis. Bronchial biopsy is positive 30-84 % of patients27-29. The cytomorphologic alterations of tuberculosis are suitable for diagnosing bronchial tuberculosis on fiberoptic bronchoscopic brushings, the sensitivity of which is no lower than that of bronchial biopsy or bacteriologic examination for defining bronchial tuberculosis30.

The clinical course of EBTB is variable because of its several possible different pathogenetic mechanisms, interaction between mycobacteria, host immunity and treatment effects. Chung and Lee have classified EBTB into seven subtypes according to the bronchoscopic findings: actively caseating, oedematous-hyperaemic, fibrostenotic, tumorous, granular, ulcerative and the nonspecific bronchitic type. This new classification is valuable for predicting the outcome because it is closely related to the extent of disease progression and is widely accepted for defining EBTB by bronchoscopy2,27.

Image 2

Figure 2. Bronchoscopic view of tumorous endobronchial tuberculosis (With kind permission of Springer Science+Business Media,18).

 

Early bronchoscopic findings consist of erythema, mucosal granularity including discrete submucosal tubercles and shallow mucosal ulcers. White, gelatinous granulation tissue may also be present. In more advanced cases, deep ulcers, tumour-like granulation tissue, hyperplastic inflammatory polyps and finally bronchostenosis occur. These lesions may simulate lung cancer (Figure 2) on gross appearance2,10,17,27. The earliest lesions are lymphocytic infiltrations of the mucosa with or without congestion. Mucosal granularity develops from submucosal tubercles and superficial or deep ulcerations. Ulcers may evolve into granulation tissue or polypoid masses. Eventually fibrostenosis develops. A rapid evolution of EBTB occurs with treatment. The effectiveness of treatment in preventing endobronchial stenosis is debatable as 60-95% of adequately treated patients have developed bronchial stenosis10,31. Mild to moderate narrowing or pinhole stenosis of the trachea, and the main or lobar bronchus may develop. The healing process and the natural course of EBTB are shown in Figure 327. Stenosis may occur as late as three years after treatment. Patients with tracheal involvement may have serious sequelae such as respiratory failure, collapse of the lung, and postobstructive pneumonitis. Bronchiectasis is another common complication of EBTB that develops secondary to pulmonary destruction and fibrosis. Bronchial stenosis contributes to the development of bronchiectasis. HRCT may be useful for the diagnosis of bronchiectasis. Bronchocentric granulomatosis consisting of granulomas around small bronchi and bronchioles may also develop. This is a histologic pattern and not a disease. In the late stages of the disease bronchiolitis obliterans may result8,32-34.

Treatment

The treatment of EBTB is the same as that for pulmonary tuberculosis. Five standard first line drugs are used for the treatment of EBTB: isoniazid (INH), rifampin (RIF), EMB, pyrazinamide (PZA) and streptomycin (STR). It is necessary to know the dosages and adverse reactions caused by these drugs. Full assessment for drug susceptibility or resistance is essential. Patients should be evaluated at least monthly for adverse reactions to these drugs. It is helpful to have a baseline measurement of hepatic enzymes, bilirubin, complete blood count, serum creatinine and uric acid prior to initiating treatment. If EMB is included in the regimen, visual acuity and red-green colour perception should be evaluated. Hearing tests should be performed prior to initiation of STR35. A 6 month treatment consisting of INH, RIF and PZA for the first two months, followed by INH and RIF for the next 4 months is the treatment for patients with fully susceptible organisms. In drug resistant tuberculosis, treatment must be based on susceptibility results2.

Image 3

Figure 3. The healing process and the natural course of endobronchial tuberculosis (EBTB) lesions27.

Since bronchial stenosis is relatively common and may occur despite adequate antituberculous and steroid therapy, interventional bronchoscopic or surgical management may be indicated. The role of corticosteroids in reversing bronchostenosis is controversial9,10. Corticosteroids are more likely to be useful in the earlier stages of EBTB when hypersensitivity is the predominant mechanism. They are not likely to be helpful in advanced cases when extensive fibrosis is present. Before corticosteroids are given adequate antituberculosis chemotherapy should have been started. The usual dose of corticosteroids is 40-60 mg daily for 4-6 weeks, tapered gradually over the next few weeks2-37. The steroids may acutely reduce bronchial narrowing and reduce the extent of poststenotic lung damage. They may also reduce the long term evolution of high-grade bronchial stenosis38. Verhaege et all demonstrated resolution of EBTB with submucosal methylprednisolone injection39. Rikimaru showed that healing time of ulcerous lesions was shorter and bronchial stenosis was less severe in patients treated with aeresol streptomycin and dexamethasone40.

A major issue in the treatment of EBTB is evaluation of bronchoscopic findings during treatment. The therapeutic outcome of each type of EBTB can be predicted by follow-up bronchoscopy during the initial three months, with the exception of the tumorous type. The tumorous type may show diverse progress and unexpected changes. The evolution of the lesions is complicated and stenosis may develop at a later time. CT may also be very useful in the evaluation of bronchial stenosis or obstruction15,33. In tumorous type bronchial stenosis, the prognosis is grave if the condition is not treated aggressively. Laser resection or electrosurgery may be performed to prevent further stenosis27,41. If the fibrostenosis is long an endobronchial stent can be placed after balloon dilatation, which is only a temporary mesasure. In the caseating, oedematous and tumorous forms of EBTB the therapeutic results of stent placement are poor because of severe inflammation. Dumon stents are appropriate since removal or placement is always possible. Ultraflex stents should not be used because their removal is difficult42. Restenosis due to granulation tissue is treated by laser or electrocoagulation. Stents may be removed one year after placement. In granular, ulcerative or nonspecific EBTB significant bronchostenosis does not develop. Laser resection and surgery are the gold standard for the treatment of bronchial stenosis and long term appropriate antituberculosis treatment should be administered for nine to twelve months to prevent restenosis2,36.

Conclusions

The diagnosis of EBTB depends on the presence of specific endobronchial inflammatory lesions and culture of mycobacterium from bronchoscopic samples. The treatment strategy should be individualized according to the presumptive natural course of the subtype of EBTB detected on the initial bronchoscopic examination. The desired therapeutic outcome of EBTB is healing without significant sequelae. At the other extreme, the other possible end point is stenosis and bronchial obstruction. All subtypes fall between these two end points and may transform or progress into other subtypes during treatment. The extent of disease progression and formation of granulation tissue determine the critical point between these two end points. Bronchial stenosis occurs if the disease progresses beyond this critical point, and therefore early diagnosis and prompt treatment of EBTB is important to minimize or prevent bronchial stenosis. Bronchial stenosis may occur despite effective antituberculous treatment. The role of steroids in the prevention of bronchostenosis is controversial.

The therapeutic outcome of each subtype can be predicted by bronchoscopy in the initial three months. The evolution of the tumorous subtype is usually complicated and severe bronchostenosis may develop. In such patients, aggressive treatment should be performed before the stenosis becomes irreversible and long term follow-up is advisable. Bronchoscopy is mandatory not only for the initial diagnosis but also for follow-up and to prevent bronchostenosis. Spiral CT may also be very useful in evaluating bronchial lesions such as stenosis or obstruction and detecting bronchiectasis. For the treatment of bronchostenosis that has already developed interventional therapeutic modalities such as electrocautery, laser therapy or stent insertion should be considered. Drug treatment should be given for active inflammation before interventional procedures and should be continued for a minimum of three months to prevent recurrence. Laser photoresection and electrosurgery are other effective treatment modalities for tuberculous bronchial stenosis. Surgical resection may be indicated in subjects unresponsive to interventional bronchoscopic treatment. Bronchoplastic surgery is performed for tracheal or major bronchial strictures in order to preserve lung function. Appropriate antituberculous treatment should be given for at least nine months to prevent recurrence or restenosis in such patients.

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