Clinical manifestations and evaluation of pulmonary tuberculosis

Author Anton Pozniak, MD, FRCP Section Editor C Fordham von Reyn, MD Deputy Editor Elinor L Baron, MD, DTMH Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2013. | This topic last updated: ago 19, 2013. INTRODUCTION The lungs are the major site for Mycobacterium tuberculosis infection. Clinical manifestations of tuberculosis (TB) include primary TB, reactivation TB, laryngeal TB, endobronchial TB, lower lung field TB infection, and tuberculoma. Pulmonary complications of TB can include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction, malignancy, and chronic pulmonary aspergillosis. The clinical manifestations and evaluation of pulmonary TB will be reviewed here. The clinical manifestations of pulmonary TB in children and HIV-infected patients are discussed separately, as are the epidemiology, pathogenesis, laboratory diagnosis, and treatment of pulmonary TB. Extrapulmonary and miliary TB are also discussed separately. (See related topics.) CLINICAL MANIFESTATIONS Primary tuberculosis Primary tuberculosis (TB) was considered to be mainly a disease of childhood until the introduction of effective chemotherapy with isoniazid in the 1950s. Many studies since that time have shown an increased frequency in the acquisition of TB in adolescents and adults [1,2]. Symptoms and signs The natural history of primary TB was well described in a prospective study of 517 new tuberculin

converters living on the Faroe Islands off the coast of Norway from 1932 to 1946 [3]. The study included 331 adults and 186 children; all were followed for more than five years. The clinical manifestations of primary TB varied substantially in this population, and symptoms and signs referable to the lungs were present in approximately one-third of patients. Fever was the most common symptom, occurring in 70 percent of 232 patients in whom fever was not a condition for enrollment in the study. The fever onset was generally gradual and low grade but could be as high as 39C and lasted for an average of 14 to 21 days. Fever resolved in 98 percent of patients by 10 weeks. Fever was not usually accompanied by other symptoms, although approximately 25 percent of patients developed pleuritic or retrosternal pain. One-half of patients with pleuritic chest pain had evidence of a pleural effusion. Retrosternal and dull interscapular pain were ascribed to enlarged bronchial lymph nodes and sometimes worsened with swallowing. Rarer symptoms included fatigue, cough, arthralgias, and pharyngitis. (See "Tuberculous pleural effusions in HIVnegative patients" and "Tuberculous pleural effusions in HIV-infected patients".) Radiographic abnormalities In primary pulmonary TB, the chest radiograph is often normal. The most common chest radiograph abnormality in one series was hilar adenopathy, occurring in 65 percent of cases [3]. Hilar changes could be seen as early as one week after skin test conversion and within two months in all cases. These radiographic findings resolved slowly, often over a period of more than one year. Approximately one-third of the 517 converters developed pleural effusions, typically within the first three to four months after infection, but occasionally as late as one year. Pulmonary infiltrates were documented in 27 percent of patients. Perihilar and right sided infiltrates were the most common, and ipsilateral hilar enlargement was the rule. While

contralateral hilar changes sometimes were present, only 2 percent of patients had bilateral infiltrates. Lower and upper lobe infiltrates were observed in 33 and 13 percent of adults, respectively; 43 percent of adults with infiltrates also had effusions. Most infiltrates resolved over months to years. However, in 20 patients (15 percent of cases), the infiltrates progressed within the first year after skin test conversion, socalled progressive primary TB. The majority of these patients had progression of disease at the original site, and four developed cavitation. Other studies which provide insight into the clinical manifestations of TB have focused retrospectively upon patients with cultureproven TB [4-6]. In one series from Canada, 188 patients were assessed, all of whom were culture positive and had abnormal chest radiographs [5]. Thirty patients (18 percent) were classified clinically as having primary TB. The most common finding was hilar lymphadenopathy, present in 67 percent. Right middle lobe collapse may complicate the adenopathy but usually resolves with therapy. Several factors probably favor involvement of the right middle lobe: It is more densely surrounded by lymph nodes. It has a relatively longer length and smaller internal caliber. It has a sharper branching angle. In this retrospective series, pleural effusions were present in 33 percent and were the sole abnormality in 23 percent of cases [5]. Pulmonary infiltrates were present in 63 percent of patients, and 85 percent of infiltrates were in the mid- to lower lung fields. Two patients had cavitation and two others evidence of endobronchial spread. Natural history After primary infection, 90 percent of individuals with intact immunity control further replication of the bacilli, which may then enter a latent phase. The remaining 10 percent of individuals

develop a TB pneumonia with expansion of infiltrates at the site of the initial seeding or near the hilum, and may have hilar lymphadenopathy or present with disease at more distant sites, commonly with cervical lymph nodes, meningitis, pericarditis, or miliary dissemination. Progression to local disease or dissemination occurs more frequently in those with poor immune responses, such as HIV, chronic kidney failure, poorly controlled diabetes mellitus, and older adults. (See "Microbiology and pathogenesis of tuberculosis", section on 'Natural history of infection'.) Reactivation tuberculosis Multiple terms have been used to describe this stage of TB: chronic TB, postprimary disease, recrudescent TB, endogenous reinfection, and adult type progressive TB. Reactivation TB represents 90 percent of adult cases among HIV-negative individuals, and results from reactivation of a previously dormant focus seeded at the time of the primary infection. The apical posterior segments of the lung are frequently involved (image 1). The original site of spread may have been previously visible as a small scar called a Simon focus. Symptoms Reactivation TB may remain undiagnosed and potentially infectious for two to three years or longer, with development of symptoms only late in the course of the disease. The symptoms of reactivation TB have been described retrospectively, mainly in case series of hospitalized patients in single institutions [79]. In these series, symptoms typically began insidiously and were present for weeks or months before the diagnosis was made. One-half to two-thirds of patients developed cough, weight loss, and fatigue. Fever and night sweats or night sweats alone were present in approximately onehalf. Chest pain and dyspnea each were reported in approximately one-third of patients, and hemoptysis in approximately one-quarter. Many patients had vague or nonspecific symptoms; almost one-third of

patients had pulmonary TB diagnosed after an admission for unrelated complaints [7]. Fever is usually low grade at onset but becomes marked with progression of disease. It is classically diurnal, with an afebrile period early in the morning and a gradually rising temperature throughout the day, reaching a peak in the late afternoon or evening. Fever subsides during sleep but night sweats may occur. Fever and night sweats are more common among patients with advanced pulmonary TB [10]. Cough may be absent or mild initially and may be nonproductive or productive of only scant sputum. Initially, it may be present only in the morning, when accumulated secretions during sleep are expectorated. As the disease progresses, cough becomes more continuous throughout the day and productive of yellow or yellow-green and occasionally blood-streaked sputum, which is rarely foul-smelling. Symptomatic individuals are more likely to have smearpositive sputum [11]. Frank hemoptysis, due to caseous sloughing or endobronchial erosion, typically occurs later in the disease and is rarely massive. Nocturnal coughing is associated with advanced disease, often with cavitation. Dyspnea can occur in the setting of extensive parenchymal involvement, pleural effusions, or a pneumothorax. Pleuritic chest pain is not common but, when present, signifies inflammation abutting or invading the pleura, with or without an effusion. Rarely this can progress to frank empyema. In the absence of treatment, patients may present with painful ulcers of the mouth, tongue, larynx, or GI tract due to chronic expectoration and swallowing of highly infectious secretions; these findings are rare in the setting of antituberculous therapy. Anorexia, wasting (consumption), and malaise are common features of advanced disease and may be the only presenting features in some patients. Ambulatory patients with active TB may have milder and less specific symptoms

than hospitalized patients (table 1). In a study including 313 TB cases identified among ambulatory patients, cough >2 weeks was observed among 52 percent of patients with pulmonary disease; fever >2 weeks was observed among 29 percent of patients [12]. In addition, clinical symptoms were observed less frequently among patients of Asian ethnicity than other patients. Presentation in older adults In nonendemic countries, the incidence of pulmonary TB is two to three times higher among older adults, especially those in old age homes, and the risk of death is higher compared with younger patients [13,14]. Comparative studies have suggested some differences in manifestations of pulmonary TB between elderly and younger patients. A meta-analysis including 12 studies noted no significant difference between patients >60 years and patients <60 years with respect to time to diagnosis, prevalence of cough, sputum production, weight loss, or fatigue/malaise [15]. Findings observed less commonly among the elderly included fever, sweats, hemoptysis, cavitary disease, and a positive tuberculin skin test, and they were likely to present with the nonspecific symptoms of dyspnea and fatigue. Findings observed more frequently among the elderly included hypoalbuminemia, leukopenia, and underlying disorders such as cardiovascular disease, chronic obstructive pulmonary disease (COPD), diabetes, malignancy, and gastrectomy. Cavitary disease is less common and multilobar and lower lobe involvement more common. Because of other comorbidities such as COPD, the diagnosis in older adults can be delayed or missed [16,17]. Physical findings Physical findings of pulmonary TB are not specific and usually are absent in mild or moderate disease. Dullness with decreased fremitus may indicate pleural thickening or effusion. Rales may be present throughout inspiration, or may be heard only after a short cough (post-tussive rales). When

large areas of the lung are involved, signs of consolidation associated with open bronchi, such as whispered pectoriloquy or tubular breath sounds, may be heard. Distant hollow breath sounds over cavities are called amphoric, after the sound made by blowing across the mouth of jars used in antiquity (amphorae). Extrapulmonary signs include clubbing and findings localized to other sites of involvement. (See "Clinical manifestations, diagnosis, and treatment of extrapulmonary and miliary tuberculosis".) Laboratory findings Routine hematology and biochemistry laboratory studies are frequently normal in the setting of pulmonary TB. The C-reactive protein (CRP) can be elevated in up to 85 percent of patients [18]. Late in the disease, hematologic changes may include normocytic anemia, leukocytosis, or, more rarely, monocytosis. Hyponatremia may be associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [19] or rarely with adrenal insufficiency. Hypoalbuminemia and hypergammaglobulinemia also can occur as late findings. Radiographic abnormalities Most patients with reactivation TB have abnormalities on chest radiography, even in the absence of respiratory symptoms [7,20]. Reactivation TB typically involves the apical-posterior segments of the upper lobes (80 to 90 percent of patients), followed in frequency by the superior segment of the lower lobes and the anterior segment of the upper lobes (image 1 and image 2) [7,21-23]. In multiple large series of TB among adults, 70 to 87 percent had upper lobe infiltrates typical of reactivation; 19 to 40 percent also had cavities, with visible air-fluid levels in as many as 20 percent of cases [7,21-23]. Adults without upper lobe infiltrates have atypical radiographic patterns (13 to 30 percent of cases) [4,24,25]. These findings include hilar adenopathy (sometimes associated with right middle lobe collapse), infiltrates or cavities in the middle or lower lung zones, pleural effusions, and solitary

nodules. These atypical findings are more common in the setting of primary TB and probably represent increasing incidence of primary TB rather than atypical forms of reactivation TB. (See 'Primary tuberculosis' above.) Up to 5 percent of patients with active TB present with upper lobe fibrocalcific changes thought to be indicative of healed primary TB. However, such patients should be evaluated for active TB in the setting of pulmonary symptoms or absence of serial films documenting stability of the lesion. A normal chest radiograph is also possible even in active pulmonary TB. As an example, in one Canadian study of 518 patients with culture-proven pulmonary TB, 25 patients (5 percent) had normal chest xrays; 23 of these patients had pulmonary symptoms at the time of the normal radiograph [26]. In this series conducted over a 10-year period, normal chest x-rays represented less than 1 percent of the radiographs in 1988 to 1989, but increased to 10 percent from 1996 to 1997. Computed tomographic (CT) scanning is more sensitive than plain chest radiography for diagnosis, particularly for smaller lesions located in the apex of the lung [27]. CT scan may demonstrate a cavity or apicoposterior infiltrates, cavities, pleural effusions, fibrotic lesions causing distortion of lung parenchyma, elevation of fissures and hila, pleural adhesions, and formation of traction bronchiectasis. High-resolution (HR) CT is the imaging technique of choice to detect early bronchogenic spread. The most common findings consist of centrilobular 2- to 4-mm nodules or branching linear lesions representing intrabronchiolar and peribronchiolar caseation necrosis [28]. Magnetic resonance imaging (MRI) has been used to show intrathoracic lymphadenopathy, pericardial thickening, and pericardial and pleural effusions [29]. There is no role for routine use of positron emission tomography (PET) for evaluation of TB. PET uptake of F-fluoro-2-

deoxyglucose (FDG) does not differentiate infection from tumor, but the macrophages in active TB do not proliferate and do not need 11C-choline, resulting in low Ccholine uptake; this in contrast to the macrophages in malignancy. Therefore, the combination of a high FDG and low 11Ccholine uptake on PET may be useful, but not diagnostic of TB [30]. Endobronchial tuberculosis Endobronchial TB is defined as tuberculous infection of the tracheobronchial tree. It may develop via direct extension to the bronchi from an adjacent parenchymal focus (usually a cavity), via spread of organisms to the bronchi via infected sputum, or via hematogenous spread. Lesions are more likely to be observed in the main and upper bronchi; in 5 percent of patients the lower trachea is involved [31]. Prior to the availability of antituberculous therapy, endobronchial TB was relatively common in the setting of primary infection and reactivation TB [32-35]. In a 1943 study in a TB sanatorium in West Virginia, lesions in the tracheobronchial tree were observed in 15 percent of cases via rigid bronchoscopy and in 40 percent of cases at autopsy [32]. Endobronchial disease was observed more frequently among patients with extensive pulmonary TB, particularly cavitary lesions. Upper lung parenchymal or cavitary disease with bronchogenic spread to the lower lung fields was commonly observed, presumably from pooled infected secretions. Since the availability of antituberculous therapy, endobronchial TB has been described in 10 to 40 percent of patients with active pulmonary TB [36,37]. Some degree of bronchial stenosis is observed in 90 percent of cases; early diagnosis and prompt treatment prior to development of fibrosis are important to reduce the likelihood of this complication. Endobronchial disease in patients with primary infection has also been associated with impingement of enlarged lymph nodes on the bronchi [38-41]. Associated

inflammation can lead to endobronchial ulceration or perforation. Other complications of endobronchial TB include obstruction, atelectasis (with or without secondary infection), bronchiectasis, and tracheal stenosis [42]. Symptoms Symptoms may be acute in onset, and be confused with bacterial pneumonia, asthma [43], or foreign body aspiration [44]. The clinical manifestations can also be subacute or chronic, resembling bronchogenic carcinoma [44]. A barking cough has been described in approximately two-thirds of patients with endobronchial disease, often accompanied by sputum production [40-42,45,46]. Rarely patients develop so-called bronchorrhea, which is production of more than 500 mL/day of sputum [47]. In some cases, caseous material from endobronchial lesions or calcific material from extension of calcific nodes into the bronchi is expectorated, which is known as lithoptysis. Wheezing and hemoptysis may also be observed. Lymph node rupture can be associated with chest pain. The presence of dyspnea may signal obstruction or atelectasis. Physical findings Diminished breath sounds, rhonchi, or wheezing may be heard. The wheeze is low-pitched, monophonic, constant, and is auscultated consistently over the same area on the chest wall. Radiographic abnormalities A normal chest radiograph is observed in 10 to 20 percent of cases. The most common radiographic finding of endobronchial TB in adults is an upper lobe infiltrate and cavity with ipsilateral spread to the lower lobe and possibly to the superior segment of the contralateral lower lobe (image 3). Patchy, small lower lobe infiltrates may progress to confluence or even cavitation. Extensive endobronchial TB can also be associated with bronchiectasis on CT scan. When endobronchial TB occurs in patients with primary disease, segmental atelectasis may be the only finding; atelectasis is more

frequent in the right middle lobe and the anterior segment of the right upper lobe. Because endobronchial lesions can exist without extensive parenchymal abnormalities, normal chest radiographs may be observed in 10 to 20 percent of patients. In such cases, CT scanning may demonstrate endobronchial lesions or stenosis. Diagnosis The diagnosis of endobronchial TB may be established by bronchoscopy, which may demonstrate erythematous, vascular, and/or ulcerated tissues. Granulation tissue may be bulky or polypoid. Hilar node rupture may be visible as a mass protruding into the bronchial lumen; with perforation of the node into the bronchus, caseous or calcific material may be seen extruding into the lumen. Bronchial stenosis also may be visible [42,48]. The likelihood of developing stenosis is increased in the setting of a distorted airway or a mass occluding the airway. Brushings of the lesions or lavage of the distal airways can increase the frequency of positive smears; the yield for cultures of this material is >90 percent [31,36]. (See "Diagnosis of pulmonary tuberculosis in HIV-negative patients", section on 'Clinical specimens'.) Clinical approach Treatment regimens for endobronchial disease are the same as for other forms of pulmonary TB. (See "Treatment of pulmonary tuberculosis in HIV-negative patients" and "Treatment of pulmonary tuberculosis in the HIV-infected patient".) The role of steroid therapy in the treatment of endobronchial disease is not certain. Steroids may improve acute inflammatory manifestations but have not been clearly shown to prevent long-term complications such as fibrosis and stenosis [41,49,50]. Repeated dilation, stents, and laser treatment have all been used for management of stenotic complications with varying success, dependent on case selection and operator skill. Resection may also be warranted [51-53]. (See"Diagnosis

and management of central airway obstruction".) Other manifestations Laryngeal tuberculosis Prior to the availability of antituberculous therapy, laryngeal TB was considered a terminal condition as it usually occurred during progression of pulmonary disease, developing soon before death. Since the availability of antituberculous therapy, laryngeal TB has become rare (<1 percent of TB cases). It can also occur in the absence of pulmonary disease as an extrapulmonary manifestation. Symptoms include dysphonia, cough, dysphagia, odynophagia, stridor, and hemoptysis [54]. The true vocal cords, epiglottis, and false vocal cords are the most common sites involved, and areas of hyperemia, nodules, ulcerations, or exophytic masses can be seen on laryngoscopy. Lower lung field tuberculosis Lower lung field TB refers to disease involvement below the hila (including the perihilar regions) on a frontal chest x-ray [55]. The incidence in adults is 2 to 9 percent [7,55]. Consolidation in lower lung field TB tends to be more extensive and homogeneous than upper lobe TB [56-58]. Cavitation may occur, and large cavities have been described. Symptoms in lower lobe TB are generally either subacute in onset (mean of 12 weeks) or chronic (up to 6 months). Lower lobe TB is frequently misdiagnosed initially as viral or bacterial pneumonia, bronchiectasis, or carcinoma. Lower lobe involvement can be a manifestation of primary TB (with involvement of adjacent lymph nodes), reactivation TB (involving the superior segments of the lower lobes), or endobronchial TB [56,57,59]. Endobronchial TB can affect lower lung fields in both primary infection (especially when adjacent lymph nodes are involved) and reactivation (spread from upper lobe disease can secondarily infect the lower lung fields).

Older adult patients and those with HIV, diabetes, renal or hepatic disease, those receiving corticosteroids, and those with underlying silicosis appear at highest risk for lower lobe TB. However, many patients have no underlying medical illnesses. Studies in nursing homes suggest that lower lobe TB may be a manifestation of tuberculous infection in an older, tuberculinnegative population with significant underlying diseases or anergy [59]. In some cases, the patients are suspected or known to have had previous TB but develop exogenous reinfection, perhaps due to a loss of demonstrable tissue hypersensitivity. Tuberculoma Rounded mass lesions can develop during primary infection or when a focus of reactivation TB becomes encapsulated [58]. Cavitation is rare. The differential diagnosis of pulmonary coin lesions is extensive, and the diagnosis of tuberculoma can be difficult since airway cultures are often negative. Fine needle aspiration or open lung biopsy may be necessary for diagnosis. (See "Diagnostic evaluation and management of the solitary pulmonary nodule".) COMPLICATIONS OF TUBERCULOSIS Pulmonary complications of tuberculosis (TB) include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction (including pulmonary gangrene), malignancy, and chronic pulmonary aspergillosis. Hemoptysis Hemoptysis occurs most frequently in the setting of active tuberculosis, but may also occur after completion of treatment [60-62]. Many patients with hemoptysis are acid-fast bacilli (AFB) smear positive and usually have cavitary disease. Bleeding usually is of small volume, appearing as blood-streaked sputum. Massive hemoptysis is a rare complication since the advent of chemotherapy. Prior to effective chemotherapy, massive hemoptysis accounted for approximately 5 percent of deaths from TB.

Sources of massive hemoptysis due to TB include the pulmonary artery, bronchial arteries, intercostal arteries, and other vessels supplying the lung. "Rasmussen's aneurysm" refers to the formation of an aneurysm in the setting of cavitary infection which extends into the adventitia and media of bronchial arteries, resulting in inflammation and thinning of the vessel wall [63]. This aneurysm subsequently ruptures into the cavity, producing massive hemoptysis. One autopsy series of 80 patients with TB noted the presence of Rasmussen's aneurysms in only 7 percent of patients with massive hemoptysis [64]. Hemoptysis after the completion of therapy for TB only occasionally represents TB recurrence. Other causes include residual bronchiectasis, an aspergilloma or other fungus ball invading or colonizing an old healed cavity, a ruptured broncholith that erodes through a bronchial artery, a carcinoma, or another infectious or inflammatory process. In some circumstances, conservative management is sufficient even for major or massive hemoptysis [65], except in the cases of impending exsanguination, which require immediate surgical care. Initial care includes bed rest, postural management, volume replacement, cough suppression, and intravenous vasopressin [66]. (See"Massive hemoptysis: Initial management".) Patients with significant hemoptysis should undergo rapid evaluation to define the source of bleeding and facilitate immediate intervention. Older studies suggest that after an episode of massive hemoptysis or repeated episodes of severe hemoptysis, surgical intervention improves survival [6769]. When medical management fails (25 to 50 percent of patients after 24 hours), options include surgical ligation of arteries, resection of a lung lobe, endobronchial tamponade, and bronchial artery embolization. Both ligation and embolization can be complex because of the frequent presence of multiple feeder

arteries often connecting systemic with bronchial circulation [70]. Pneumothorax Prior to the availability of antituberculous therapy, spontaneous pneumothorax was a frequent and dangerous complication of pulmonary TB [71]. Since the availability of antituberculous therapy, spontaneous pneumothorax associated with TB has been reported in about 1 percent of hospitalized patients [7274]. A case series from Turkey reported pneumothorax in 1.5 percent of cases of pulmonary TB [74]. In regions where TB is endemic, it may be the most common cause of spontaneous pneumothorax [75]. Pneumothorax appears to result from the rupture of a peripheral cavity or a subpleural caseous focus with liquefaction into the pleural space [72,73]. Inflammation can lead to development of a bronchopleural fistula, which can persist or seal off spontaneously. The lung may reexpand if the bronchopleural fistula seals spontaneously, but more commonly tube drainage is required. Factors preventing successful tube drainage and expansion include extensive pulmonary parenchymal disease with large fistulas, a long interval between pneumothorax and chest tube insertion, and the development of an empyema due to TB and/or bacterial superinfection. However, successful closure of even extensive air leaks has been reported after as much as six weeks of tube drainage accompanied by appropriate antituberculous chemotherapy [76]. (See "Secondary spontaneous pneumothorax in adults".) Bronchiectasis Bronchiectasis may develop following primary or reactivation TB and can be associated with hemoptysis [7782]. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".) Following primary TB infection, extrinsic compression of a bronchus by enlarged nodes may cause bronchial dilation distal to the obstruction. There may be no evidence of parenchymal TB.

In the setting of reactivation TB, progressive destruction and fibrosis of lung parenchyma may lead to localized bronchial dilation. If endobronchial disease is present, bronchial stenosis may result in distal bronchiectasis. Bronchiectasis is more frequent in the common sites of reactivation TB (apical and posterior segments of the upper lobe), but may be found in other areas of the lung. Extensive pulmonary destruction Rarely, TB can cause progressive, extensive destruction of areas of one or both lungs [83,84]. In primary TB, occasionally lymph node obstruction of the bronchi together with distal collapse, necrosis, and bacterial superinfection can produce parenchymal destruction [84]. More commonly, destruction results from years of chronic reactivation TB, typically in the absence of effective chemotherapy. Symptoms include progressive dyspnea, hemoptysis, and weight loss. In one series of 18 patients with extensive destruction of one or both lungs, 8 died [83]. Causes of death were massive hemoptysis and respiratory failure, sometimes in the presence of active TB or superinfection. Radiographically patients had large cavities and fibrosis of remaining lung; in some cases, air-fluid levels at the base of the destroyed lung were observed [83,84]. Pulmonary gangrene refers to acute pulmonary destruction [85]. Patients with this form of TB progress rapidly from a homogeneous, extensive infiltrate to dense consolidation. Air-filled cysts develop and coalesce into cavities. Necrotic lung tissue attached to the wall of the cavity may be observed. Pulmonary gangrene may resemble an intracavitary clot, fungus ball, or Rasmussen's aneurysm. Pathology demonstrates arteritis and thrombosis of the vessels supplying the necrotic lung. Mortality usually is high; in one small series, 75 percent of patients died [85]. Resolution with effective therapy has also been reported [86],

Septic shock TB can cause septic shock; the manifestations are similar to bacterial septic shock. (See"Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis".) Compared to patients with septic shock due to other pathogens, patients with septic shock due to TB have lower mean BMIs (22 versus 27), lower mean white blood counts (10.4 versus 16.2), and are more often HIV infected (15 versus 3 percent). Extrapulmonary disease may be observed in more than 50 percent of cases. In one series, the mortality rate of TB septic shock was 79 percent; delayed initiation of appropriate therapy likely played an important role in clinical outcome [87]. Malignancy A study conducted by the National Cancer Institute found that pulmonary tuberculosis was associated with an increased risk of lung cancer, after adjustment for active smoking and socioeconomic status (odds ratio [OR] = 2.1, 95% CI: 1.4-3.1) [88]. Mycobacterial cell wall components may induce production of nitric oxide and reactive oxygen species, which have been implicated in DNA damage leading to carcinogenesis [89]. Chronic inflammation may also enhance mutagenesis. In addition, immune suppression and radiation therapy for lung cancer may be associated with an increased risk of tuberculosis. Clinical and radiographic similarities between TB and malignancy may mislead diagnosis. Chronic pulmonary aspergillosis Chronic pulmonary aspergillosis can be a sequela of pulmonary tuberculosis. This is discussed further separately. (See "Clinical manifestations and diagnosis of chronic pulmonary aspergillosis", section on 'Underlying diseases'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain th th language, at the 5 to 6 grade reading

level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the th th 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient information: Tuberculosis (The Basics)") Beyond the Basics topic (see "Patient information: Tuberculosis (Beyond the Basics)") SUMMARY Clinical manifestations of tuberculosis (TB) include primary TB, reactivation TB, endobronchial TB, lower lung field TB infection, and tuberculoma. (See 'Introduction' above.) Among patients with primary tuberculosis (TB), clinical manifestations have been observed in approximately one-third of cases. Symptoms include fever and chest pain. Retrosternal pain and dull interscapular pain have been ascribed to enlarged bronchial lymph nodes. The physical exam is generally normal. The most common chest radiograph abnormality in one large series was hilar adenopathy. Other manifestations include pleural effusions and pulmonary infiltrates. (See 'Primary tuberculosis' above.) Reactivation TB refers to reactivation of a previously dormant focus seeded

at the time of the primary infection. The apical posterior segments of the lung are frequently involved (image 1). Typically symptoms are insidious and may include cough, weight loss, fatigue, fever, night sweats, chest pain, dyspnea, and/orhemoptysis; these findings are observed less frequently among patients >60 years. (See 'Reactivation tuberculosis' above.) Endobronchial TB may develop via direct extension to the bronchi from an adjacent parenchymal focus (usually a cavity), or via spread of organisms to the bronchi via infected sputum. It can occur in patients with primary TB or reactivation TB, and was observed more frequently prior to the chemotherapy era. Symptoms may be acute or chronic; a barking cough has been described in approximately twothirds of patients. (See'Endobronchial tuberculosis' above.) Pulmonary complications of TB include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction (including pulmonary gangrene), malignancy, and chronic pulmonary aspergillosis. (See'Complications of tuberculosis' above.) ACKNOWLEDGMENT The editors of UpToDate, Inc. would like to acknowledge Nesli Basgoz, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15. 1. Stead WW, Kerby GR, Schlueter DP, Jordahl CW. The clinical spectrum of primary tuberculosis in adults. Confusion with reinfection in the pathogenesis of chronic tuberculosis. Ann Intern Med 1968; 68:731. Buckner CB, Walker CW. Radiologic manifestations of adult tuberculosis. J Thorac Imaging 1990; 5:28. POULSEN A. Some clinical features of tuberculosis. Acta Tuberc Scand 1957; 33:37.

16.

2.

17.

3.

18.

Choyke PL, Sostman HD, Curtis AM, et al. Adult-onset pulmonary tuberculosis. Radiology 1983; 148:357. Krysl J, Korzeniewska-Kosela M, Mller NL, FitzGerald JM. Radiologic features of pulmonary tuberculosis: an assessment of 188 cases. Can Assoc Radiol J 1994; 45:101. Khan MA, Kovnat DM, Bachus B, et al. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med 1977; 62:31. Barnes PF, Verdegem TD, Vachon LA, et al. Chest roentgenogram in pulmonary tuberculosis. New data on an old test. Chest 1988; 94:316. Arango L, Brewin AW, Murray JF. The spectrum of tuberculosis as currently seen in a metropolitan hospital. Am Rev Respir Dis 1973; 108:805. MacGregor RR. A year's experience with tuberculosis in a private urban teaching hospital in the postsanatorium era. Am J Med 1975; 58:221. Mayock RL, MacGregor RR. Diagnosis, prevention and early therapy of tuberculosis. Dis Mon 1976; 22:1. Verver S, Bwire R, Borgdorff MW. Screening for pulmonary tuberculosis among immigrants: estimated effect on severity of disease and duration of infectiousness. Int J Tuberc Lung Dis 2001; 5:419. Miller LG, Asch SM, Yu EI, et al. A population-based survey of tuberculosis symptoms: how atypical are atypical presentations? Clin Infect Dis 2000; 30:293. Oursler KK, Moore RD, Bishai WR, et al. Survival of patients with pulmonary tuberculosis: clinical and molecular epidemiologic factors. Clin Infect Dis 2002; 34:752. Wood R, Middelkoop K, Myer L, et al. Undiagnosed tuberculosis in a community with high HIV prevalence: implications for tuberculosis control. Am J Respir Crit Care Med 2007; 175:87. Prez-Guzmn C, Vargas MH, Torres-Cruz A, Villarreal-Velarde H. Does aging modify pulmonary tuberculosis?: A meta-analytical review. Chest 1999; 116:961. Mathur P, Sacks L, Auten G, et al. Delayed diagnosis of pulmonary tuberculosis in city hospitals. Arch Intern Med 1994; 154:306. Bobrowitz ID. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72:650. Breen RA, Leonard O, Perrin FM, et al. How good are systemic symptoms and blood inflammatory markers at detecting

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

individuals with tuberculosis? Int J Tuberc Lung Dis 2008; 12:44. Lee P, Ho KK. Hyponatremia in pulmonary TB: evidence of ectopic antidiuretic hormone production. Chest 2010; 137:207. Day JH, Charalambous S, Fielding KL, et al. Screening for tuberculosis prior to isoniazid preventive therapy among HIVinfected gold miners in South Africa. Int J Tuberc Lung Dis 2006; 10:523. POPPIUS H, THOMANDER K. Segmentary distribution of cavities; a radiologic study of 500 consecutive cases of cavernous pulmonary tuberculosis. Ann Med Intern Fenn 1957; 46:113. Farman DP, Speir WA Jr. Initial roentgenographic manifestations of bacteriologically proven Mycobacterium tuberculosis. Typical or atypical? Chest 1986; 89:75. LENTINO W, JACOBSON HG, POPPEL MH. Segmental localization of upper lobe tuberculosis; the rarity of anterior involvement. Am J Roentgenol Radium Ther Nucl Med 1957; 77:1042. Miller WT, MacGregor RR. Tuberculosis: frequency of unusual radiographic findings. AJR Am J Roentgenol 1978; 130:867. Woodring JH, Vandiviere HM, Fried AM, et al. Update: the radiographic features of pulmonary tuberculosis. AJR Am J Roentgenol 1986; 146:497. Marciniuk DD, McNab BD, Martin WT, Hoeppner VH. Detection of pulmonary tuberculosis in patients with a normal chest radiograph. Chest 1999; 115:445. Im JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings--early active disease and sequential change with antituberculous therapy. Radiology 1993; 186:653. Im JG, Itoh H, Han MC. CT of pulmonary tuberculosis. Semin Ultrasound CT MR 1995; 16:420. De Backer AI, Mortel KJ, De Keulenaer BL, Parizel PM. Tuberculosis: epidemiology, manifestations, and the value of medical imaging in diagnosis. JBR-BTR 2006; 89:243. Hara T, Kosaka N, Suzuki T, et al. Uptake rates of 18F-fluorodeoxyglucos e and 11Ccholine in lung cancer and pulmonary tuberculosis: a positron emission tomography study. Chest 2003; 124:893. Hoheisel G, Chan BK, Chan CH, et al. Endobronchial tuberculosis: diagnostic features and therapeutic outcome. Respir Med 1994; 88:593. Salkin D, Cadden AV, Edson RC. The natural history of tuberculous

33.

34.

35.

36. 37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

tracheobronchitis. Am Rev Tuberc 1943; 47:351. Wilson NJ. Bronchoscopic observations in tuberculosis tracheobronchitis: Clinical and pathological correlations. Dis Chest 1945; 11:36. MacRAE DM, HILTZ JE, QUINLAN JJ. Bronchoscopy in a sanatorium; a review of 522 consecutive bronchoscopies. Am Rev Tuberc 1950; 61:355. AUERBACH O. Tuberculosis of the trachea and major bronchi. Am Rev Tuberc 1949; 60:604. Shim YS. Endobronchial tuberculosis. Respirology 1996; 1:95. Kashyap S, Mohapatra PR, Saini V. Endobronchial tuberculosis. Indian J Chest Dis Allied Sci 2003; 45:247. LINCOLN EM, HARRIS LC, BOVORNKITTI S, CARRETERO R. The course and prognosis of endobronchial tuberculosis in children. Am Rev Tuberc 1956; 74:246. Frostad S. Lymph node perforation through the bronchial tree in children with primary tuberculosis. Acta Tuberc Scand 1959; 47:104. Lee JH, Park SS, Lee DH, et al. Endobronchial tuberculosis. Clinical and bronchoscopic features in 121 cases. Chest 1992; 102:990. Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986; 89:727. Seiden HS, Thomas P. Endobronchial tuberculosis and its sequelae. Can Med Assoc J 1981; 124:165. Caglayan S, Coteli I, Acar U, Erkin S. Endobronchial tuberculosis simulating foreign body aspiration. Chest 1989; 95:1164. Matthews JI, Matarese SL, Carpenter JL. Endobronchial tuberculosis simulating lung cancer. Chest 1984; 86:642. Van den Brande PM, Van de Mierop F, Verbeken EK, Demedts M. Clinical spectrum of endobronchial tuberculosis in elderly patients. Arch Intern Med 1990; 150:2105. So SY, Lam WK, Sham MK. Bronchorrhea. A presenting feature of active endobronchial tuberculosis. Chest 1983; 84:635. Williams DJ, York EL, Nobert EJ, Sproule BJ. Endobronchial tuberculosis presenting as asthma. Chest 1988; 93:836. Albert RK, Petty TL. Endobronchial tuberculosis progressing to bronchial stenosis. Fiberoptic bronchoscopic manifestations. Chest 1976; 70:537.

49. NEMIR RL, CARDONA J, LACOIUS A, DAVID M. PREDNISONE THERAPY AS AN ADJUNCT IN THE TREATMENT OF LYMPH NODE-BRONCHIAL TUBERCULOSIS IN CHILDHOOD. A DOUBLE-BLIND STUDY. Am Rev Respir Dis 1963; 88:189. 50. Chan HS, Sun A, Hoheisel GB. Endobronchial tuberculosis--is corticosteroid treatment useful? A report of 8 cases and review of the literature. Postgrad Med J 1990; 66:822. 51. Low SY, Hsu A, Eng P. Interventional bronchoscopy for tuberculous tracheobronchial stenosis. Eur Respir J 2004; 24:345. 52. Caligiuri PA, Banner AS, Jensik RJ. Tuberculous main-stem bronchial stenosis treated with sleeve resection. Arch Intern Med 1984; 144:1302. 53. Sawada S, Fujiwara Y, Furui S, et al. Treatment of tuberculous bronchial stenosis with expandable metallic stents. Acta Radiol 1993; 34:263. 54. Yencha MW, Linfesty R, Blackmon A. Laryngeal tuberculosis. Am J Otolaryngol 2000; 21:122. 55. SEGARRA F, SHERMAN DS, RODRIGUEZ-A GUE RO J. Lower lung field tuberculosis. Am Rev Respir Dis 1963; 87:37. 56. Chang SC, Lee PY, Perng RP. Lower lung field tuberculosis. Chest 1987; 91:230. 57. Parmar MS. Lower lung field tuberculosis. Am Rev Respir Dis 1967; 96:310. 58. STEELE JD. THE SOLITARY PULMONARY NODULE. REPORT OF A COOPERATIVE STUDY OF RESECTED ASYMPTOMATIC SOLITARY PULMONARY NODULES IN MALES. J Thorac Cardiovasc Surg 1963; 46:21. 59. Stead WW. Tuberculosis among elderly persons: an outbreak in a nursing home. Ann Intern Med 1981; 94:606. 60. Johnston H, Reisz G. Changing spectrum of hemoptysis. Underlying causes in 148 patients undergoing diagnostic flexible fiberoptic bronchoscopy. Arch Intern Med 1989; 149:1666. 61. McGuinness G, Beacher JR, Harkin TJ, et al. Hemoptysis: prospective high-resolution CT/bronchoscopic correlation. Chest 1994; 105:1155. 62. Conlan AA, Hurwitz SS, Krige L, et al. Massive hemoptysis. Review of 123 cases. J Thorac Cardiovasc Surg 1983; 85:120. 63. Rasmussen V, Moore WD. Continued observations on hemoptysis. Edinburgh Med J 1869; 15:97.

64. THOMPSON JR. Mechanisms of fatal pulmonary hemorrhage in tuberculosis. Am J Surg 1955; 89:637. 65. Corey R, Hla KM. Major and massive hemoptysis: reassessment of conservative management. Am J Med Sci 1987; 294:301. 66. Muthuswamy PP, Akbik F, Franklin C, et al. Management of major or massive hemoptysis in active pulmonary tuberculosis by bronchial arterial embolization. Chest 1987; 92:77. 67. Bobrowitz ID, Ramakrishna S, Shim YS. Comparison of medical v surgical treatment of major hemoptysis. Arch Intern Med 1983; 143:1343. 68. Yeoh CB, Hubaytar RT, Ford JM, Wylie RH. Treatment of massive hemorrhage in pulmonary tuberculosis. J Thorac Cardiovasc Surg 1967; 54:503. 69. Amirana M, Frater R, Tirschwell P, et al. An aggressive surgical approach to significant hemoptysis in patients with pulmonary tuberculosis. Am Rev Respir Dis 1968; 97:187. 70. Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results. Radiology 1985; 157:637. 71. Berry FB. Tuberculous pyopneumothorax with pyogenic infection. J Thorac Surg 1932; 2:139. 72. WILDER RJ, BEACHAM EG, RAVITCH MM. Spontaneous pneumothorax complicating cavitary tuberculosis. J Thorac Cardiovasc Surg 1962; 43:561. 73. Ihm HJ, Hankins JR, Miller JE, McLaughlin JS. Pneumothorax associated with pulmonary tuberculosis. J Thorac Cardiovasc Surg 1972; 64:211. 74. Aktou S, Yorgancioglu A, Cirak K, et al. Clinical spectrum of pulmonary and pleural tuberculosis: a report of 5,480 cases. Eur Respir J 1996; 9:2031. 75. Hussain SF, Aziz A, Fatima H. Pneumothorax: a review of 146 adult cases admitted at a university teaching hospital in Pakistan. J Pak Med Assoc 1999; 49:243. 76. Auerbach O, Lipstein S. Bronchopleural fistulas complication pulmonary tuberculosis. J Thorac Surg 1939; 8:384. 77. Rilance AB, Gerstl B. Bronchiectasis secondary to puomonary tuberculosis. Am Rev Tuberc 1943; 48:8. 78. Roberts JC, Blair LG. Bronchiectasis in primary tuberculosis. Lancet 1950; 1:386. 79. Rosenzweig DY, Stead WW. The role of tuberculosis and other forms of bronchopulmonary necrosis in the

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

pathogenesis of bronchiectasis. Am Rev Respir Dis 1966; 93:769. COHEN AG. Atelectasis of the right middle lobe resulting from perforation of tuberculous lymph nodes into bronchi in adults. Ann Intern Med 1951; 35:820. CURTIS JK. The significance of bronchiectasis associated with pulmonary tuberculosis. Am J Med 1957; 22:894. Brock RC. Post-tuberculous bronchostenosis and bronchiectasis of the middle lobe. Thorax 1950; 5:5. Bobrowitz ID, Rodescu D, Marcus H, Abeles H. The destroyed tuberculous lung. Scand J Respir Dis 1974; 55:82. Palmer PE. Pulmonary tuberculosis--usual and unusual radiographic presentations. Semin Roentgenol 1979; 14:204. Khan FA, Rehman M, Marcus P, Azueta V. Pulmonary gangrene occurring as a complication of pulmonary tuberculosis. Chest 1980; 77:76. Lorenz R, Kraman SS. Intracavitary mass in a patient with far-advanced tuberculosis. Chest 1982; 82:91. Kethireddy S, Light RB, Mirzanejad Y, et al. Mycobacterium tuberculosis Septic Shock. Chest 2013; 144:474. Brenner AV, Wang Z, Kleinerman RA, et al. Previous pulmonary diseases and risk of lung cancer in Gansu Province, China. Int J Epidemiol 2001; 30:118. Falagas ME, Kouranos VD, Athanassa Z, Kopterides P. Tuberculosis and malignancy. QJM 2010; 103:461. Topic 7026 Version 13.0

Tuberculosis disease in children

Authors Lisa V Adams, MD Jeffrey R Starke, MD Section Editors C Fordham von Reyn, MD Morven S Edwards, MD Deputy Editor Elinor L Baron, MD, DTMH Disclosures

Progressive primary TB Cavitary TB TB pulmonary lesion Left upper lobe TB infiltrate Partially calcified primary TB TB pleural effusion x-ray Extensive primary TB x-ray TABLES Worldwide TB burden Definition positive TST in children Causes of false negative TST Treatment of TB in children Pediatric dosing TB drugs Second line TB drugs for children

INTRODUCTION EPIDEMIOLOGY Global epidemiology United States epidemiology CLINICAL MANIFESTATIONS Pulmonary tuberculosis Extrapulmonary tuberculosis Perinatal infection Adolescent infection DIAGNOSIS Screening tests - Tuberculin skin test - Interferon gamma release assays Imaging - Chest radiography - Computed Tomography scan Laboratory studies - Acid-fast bacilli smear and culture Sputum Gastric aspirate Other specimens - Rapid testing Drug resistance TREATMENT Susceptible disease Drug-resistant TB PREVENTION SUMMARY AND RECOMMENDATIONS REFERENCES
GRAPHICSView All

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2013. | This topic last updated: sep 23, 2013. INTRODUCTION Formal policies and control efforts addressing tuberculosis (TB) in children have been limited, in part due to lack of a standardized case definition and difficulties associated with establishing a definitive diagnosis [1]. However, since diagnostic and treatment tools for TB in children have begun to improve

DIAGNOSTIC IMAGES TB Ghon complex TB pneumonia Miliary TB pulmonary lesions Extensive pulmonary TB

significantly, TB in children has received increasing attention by researchers, clinicians, and policy makers. Issues related to TB disease in children will be reviewed here. Issues related to diagnosis and treatment of latent TB (LTBI) in children are discussed in detail separately. (See "Latent tuberculosis infection in children".) EPIDEMIOLOGY Global epidemiology Estimating the global burden of tuberculosis (TB) disease in children is challenging due to the lack of a standard case definition, the difficulty in establishing a definitive diagnosis, the frequency of extrapulmonary disease in young children, and the relatively low public health priority given to TB in children relative to adults [2]. The World Health Organizations (WHO) global TB data include age breakdowns only for smear-positive TB cases; among children, such cases represent only a small subset of the burden of disease due to TB (about 8 percent) [3]. The WHO estimates that of the 8.7 million incident cases of TB in 2011, approximately 500,000 occurred among children under age 15 [4]. Additionally, it is estimated there were 64,000 pediatric deaths due to TB (among HIV-negative children) [4]. Approximately 75 percent of these cases occurred in the 22 highest TB-burden countries (table 1) [5]. In many developing countries, children comprise more than one-half of the population, suggesting that the reported cases of childhood TB are likely underestimated. Children under age five represent an important demographic group for understanding TB epidemiology, since TB frequently progresses rapidly from latent infection to disease and severe disease manifestations, such as miliary TB and meningitis, are more common in this age group. Therefore, these children serve as sentinel cases, indicating recent and/or ongoing transmission in the community.

Most children are infected by household contacts with TB disease, particularly parents or other caretakers. Even in circumstances when adult index cases are sputum smear-negative, transmission to children has been documented in 30 to 40 percent of households [6]. United States epidemiology Risk factors for pediatric TB in the United States include being foreign-born, having a parent who is foreign-born, or having lived outside the United States for more than two months [7]. In the United States, TB among children is relatively rare. In 2010, there were 818 cases of TB in children and adolescents under 18 years of age reported by the United States Centers for Disease Control and Prevention (CDC); this number represented 7 percent of the total 11,181 cases reported that year [7,8]. However, TB in children and adolescents is prone to both under- and over-reporting due to the difficulties related to diagnosis. Nonetheless, in the United States, TB in children and adolescents appears to be declining. Between 2007 and 2010, TB annual case notifications in those under age 18 years decreased from 997 (2007) to 818 cases (2010) [7]. Between 2008 and 2010, most children and adolescents with TB were born in the United States (69 percent). In contrast, most adults with TB in the United States are born in areas where the disease is endemic. Roughly half of all non-US-born patients under age 18 diagnosed with TB in this time period were adolescents between the ages of 13 and 17 [7]. Among the child and adolescent TB patients who were born in the United States, 66 percent had at least one non-US-born parent [7]. One-quarter (25 percent) of pediatric TB patients diagnosed in the United States had no known international connection through family or residence history [7]. A small proportion of non-US-born pediatric TB patients (4 percent) had parents who were both born in the United States; these cases may arise from international adoptions, but

this could not be confirmed with available data [7]. Between 2008 and 2010, among the 2628 children and adolescents with TB with known race/ethnicity, 45 percent were Hispanic, 27 percent were black, 20 percent were Asian, 7 percent were white, and 1 percent American Indian or Native Alaskan [7]. HIV status was only known for approximately half of the pediatric patients reported; of these, only 1 percent was HIVinfected [7]. The isolates from 19 percent of the 918 children and adolescents with positive cultures and drug susceptibility testing had detectable resistance to one or more drugs, and 2 percent were multidrugresistant TB [7]. CLINICAL MANIFESTATIONS Pulmonary tuberculosis Pulmonary disease and associated intrathoracic adenopathy are the most frequent presentations of tuberculosis (TB) in children [9,10]. Common symptoms of pulmonary TB in children include [5]: Chronic, unremitting cough that is not improving and has been present for more than three weeks Fever of more than 38C for at least two weeks, other common causes having been excluded Weight loss or failure to thrive (based on child's growth chart) However, these symptoms are fairly nonspecific. In one study comparing symptoms of children with culture-proven TB with children with other lung diseases, there was no difference between the two groups with respect to weight loss, chronic cough, and duration of symptoms [11]. The only factors differentiating the groups were history of contact with an infectious TB case and a positive tuberculin skin test (TST). Physical exam findings may suggest the presence of a lower respiratory infection, but there are no specific clinical signs or findings to confirm that pulmonary TB is the cause. Children ages 5 to 10 may present with clinically silent (but radiographically

apparent) disease, particularly in the setting of contact investigation [9]. In contrast, infants are more likely to present with signs and symptoms of lung disease. Common radiographic findings are discussed below. (See 'Chest radiography' below.) Extrapulmonary tuberculosis The clinical presentation of extrapulmonary TB depends on the site of disease. The most common forms of extrapulmonary disease in children are TB of the superficial lymph nodes and of the central nervous system (CNS) [12]. Neonates have the highest risk of progression to TB disease with miliary and meningeal involvement [12]. Some forms of TB and their common physical signs are as follows [13]: Tuberculous meningitis meningitis not responding to antibiotic treatment, with a subacute onset, communicating hydrocephalus, stroke, and/or elevated intracranial pressure (see "Central nervous system tuberculosis") Pleural TB pleural effusion (see "Tuberculous pleural effusions in HIV-negative patients") Pericardial TB pericardial effusion (see "Tuberculous pericarditis") Abdominal TB distended abdomen with ascites, abdominal pain, jaundice, or unexplained chronic diarrhea (see "Tuberculous enteritis" and "Tuberculous peritonitis") TB adenitis painless, fixed, enlarged lymph nodes, especially in the cervical region, with or without fistula formation (see "Tuberculous lymphadenitis") TB of the joint nontender joint effusion (see "Skeletal tuberculosis") Vertebral TB back pain, gibbus deformity, especially of recent onset (rarely seen) (see "Skeletal tuberculosis") Skin warty lesion(s), papulonecrotic lesions, lupus vulgaris.

Erythema nodosum may be a sign of tuberculin hypersensitivity Renal sterile pyuria, hematuria (see "Renal disease in tuberculosis") Eye iritis, optic neuritis, phlyctenular conjunctivitis (see "Tuberculosis and the eye") In the context of exposure to TB, presence of these signs should prompt further investigation of extrapulmonary TB. Perinatal infection Perinatal TB can be a life-threatening infection; the mortality in the setting of congenital and neonatal TB is about 50 percent [14-16]: Congenital TB is rare and most often is associated with tuberculous endometritis or disseminated TB in the mother. It can be acquired hematogenously via the placenta and umbilical vein or by fetal aspiration (or ingestion) of infected amniotic fluid [14,16]. Clinical manifestations of congenital TB include respiratory distress, fever, hepatomegaly, splenomegaly, poor feeding, lethargy, irritability, and low birth weight [15]. Clinical evaluation of the infant in the setting of suspected congenital TB should include TST, HIV testing, chest radiograph, lumbar puncture, cultures (blood and respiratory specimens), and evaluation of the placenta with histologic examination (including AFB staining culture). The TST in newborns is usually negative, but an IGRA test may be positive in some cases. Neonatal TB develops following exposure of an infant to his or her mother's aerosolized respiratory secretions. This is more common than congenital TB, and diagnosis of neonatal TB can lead to identification of previously unrecognized diagnosis of TB in the mother [17]. In the setting of congenital or neonatal TB, the mother should be evaluated as outlined

in detail separately. (See"Diagnosis of pulmonary tuberculosis in HIV-negative patients".) Adolescent infection Adolescents with TB can present with features common in children or adults. In one review including 145 cases of adolescent TB, the following features were noted [18]: Most adolescents presented with clinical symptoms. Rates of extrathoracic TB were high, including six immunocompetent adolescents with TB meningitis. Most cases were AFB sputum smear-negative. Only half of patients with intrathoracic TB had positive cultures. Antituberculous medications were generally well tolerated. DIAGNOSIS Tuberculosis (TB) in children is often diagnosed clinically. Because pulmonary TB in children typically presents with paucibacillary, non-cavitary pulmonary disease, bacteriologic confirmation is achievable in only about 30 to 40 percent of cases. Obtaining sputum samples from young children is challenging because they lack sufficient tussive force to produce adequate sputum samples by expectoration alone [19]. For these reasons, gastric aspiration is the principal means of obtaining material for culture from young children; induced sputum may also be collected if feasible. For diagnosis of extrapulmonary TB, specimens for culture should be collected from any site where infection is suspected. The most common extrapulmonary specimens include whole blood, bone marrow, tissue specimens (such as lymph node or bone), cerebrospinal fluid, urine, and pleural fluid. Diagnostic yield is variable. In pleural TB, adenosine deaminase (ADA) levels over 40 units/L in the pleural fluid are observed in the majority of patients [9]. (See "Tuberculous pleural effusions in HIV-negative patients".) A diagnosis of TB (pulmonary or extrapulmonary) in a child is often based on

the presence of the classic triad: (1) recent close contact with an infectious case, (2) a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and (3) suggestive findings on chest radiograph or physical examination [13]. The approach outlined by the World Health Organization (WHO) for evaluation of a child suspected of having TB includes [5]: Careful history (including history of TB contact and symptoms consistent with TB) Clinical examination (including growth assessment) TST and/or IGRA (both tests, if available, to increase sensitivity) Bacteriological confirmation whenever possible Investigations relevant for suspected pulmonary and extrapulmonary TB HIV testing (eg, in high HIV prevalence areas) All data, including thorough history, physical exam, and diagnostic testing, must be considered carefully. A history of recent close contact with an infectious (sputumsmear positive) case of TB is a critical factor in making the diagnosis of TB in children, especially for those under the age of five years. However, the ill adult may have not yet been diagnosed, so asking about ill contacts and facilitating evaluation for ill adults can also expedite diagnosis for children. In many cases of TB in children, laboratory confirmation is never established (particularly among children under five years of age). In such cases, a presumptive diagnosis may be made based on clinical and radiographic response to empiric treatment. Treatment is often guided by the culture and drug susceptibility results from the index case (eg, the adults TB contact). Screening tests Tuberculin skin test A positive TST may be present in both contained latent TB infection (LTBI) and in active TB disease.

Thus, although a positive TST may help support a diagnosis of active disease, this finding alone is not diagnostic of active disease; it must be considered together with other diagnostic criteria. The TST is helpful for diagnosis of TB in children only in circumstances when it is positive. Criteria for positive TST are outlined in the Table (table 2) [13]. A positive TST may be falsely positive due to prior vaccination with Bacille Calmette-Gurin (BCG), infection with nontuberculous mycobacteria, and improper administration or interpretation (table 3). A negative TST does NOT rule out TB disease, since false negative results can occur in a variety of circumstances (eg, incorrect administration or interpretation of the TST, age less than six months, immunosuppression by HIV, other disease or medication, certain viral illnesses or recent live-virus immunization, overwhelming TB infection) [13,20]. (See "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIVnegative adults", section on 'False negative tests'.) Because the TST cannot distinguish between TB disease, latent M. tuberculosis infection, and infection due to nontuberculous mycobacteria, the result must be interpreted in the context of the clinical features and history of TB exposure [21]. Overall, up to 40 percent of immunocompetent children with cultureconfirmed TB disease may have a negative TST [22,23]. TST positivity rates vary by form of disease; in pulmonary and extrapulmonary TB, the TST is typically positive (90 and 80 percent respectively), while in miliary TB and TB meningitis, the TST is usually positive in only 50 percent of cases [24-26]. Interferon gamma release assays IGRAs are in vitro blood tests of cellmediated immune response. These assays have greater specificity than TST for diagnosis of LTBI in adults and are most useful for evaluation of LTBI in BCGvaccinated individuals. As with the TST, IGRAs cannot distinguish LTBI from active

disease. IGRAs may prove a useful tool to improve the diagnosis of TB, although evidence for use of IGRAs in children is limited [27-31]. Use of both TST and IGRA may increase sensitivity for evaluation of children with suspected TB. Additional issues related to use of IGRAs are discussed further separately. (See "Interferon-gamma release assays for diagnosis of latent tuberculosis infection".) Imaging Chest radiography Frontal and lateral chest radiography can be a very useful tool for diagnosis of TB in children (image 1A-K) [32,33]. The most common chest radiograph finding in a child with TB disease is a primary complex, which consists of opacification with hilar or subcarinal lymphadenopathy, in the absence of notable parenchymal involvement [5]. When adenopathy advances, consolidation or a segmental lesion may occur, leading to collapse in the setting of infiltrate and atelectasis. In a study of 326 traced contacts under five years of age, 9 percent of children diagnosed with intrathoracic TB were asymptomatic and had radiographic findings only of the primary complex [34]. A miliary pattern of opacification is highly suspicious for TB, as is opacification that does not improve or resolve following a course of antibiotics [5]. Adolescents with TB generally present with typical adult disease findings of upper lobe infiltrates, pleural effusions and cavitations on chest radiograph [5]. (See "Diagnosis of pulmonary tuberculosis in HIV-negative patients".) Computed Tomography scan Computed tomography (CT) scan of the chest may be used to further delineate the anatomy for cases in which radiographic findings are equivocal. Endobronchial involvement, bronchiectasis, and cavitations may be more readily visualized on CT scans than chest radiographs [35]. However, there is no role for routine use of CT scans in the evaluation of an

asymptomatic child since treatment regimens are based on chest radiography findings [9]. In the setting of tuberculous meningitis, CT scan of the head is useful. Hydrocephalus and basilar meningeal enhancement are observed in 80 and 90 percent of cases, respectively; chest radiography may be normal in up to 90 percent of these patients [9]. Laboratory studies The likelihood of achieving bacteriological confirmation depends on the extent of disease and the type of specimen. The initial approach for diagnosis of TB in children consists of sputum examination: expectorated (for adolescents), swallowed and collected as gastric contents (young children), or induced. Gastric aspiration is the primary method of obtaining material for acid-fast bacilli (AFB) smear and culture from young children. Sputum specimens should be sent for examination by smear microscopy and mycobacterial culture. Nucleic acid amplification (NAA) testing can be used for rapid diagnosis of an organism belonging to the M. tuberculosis complex (24 to 48 hours) in patients for whom the suspicion for TB is moderate to high [36]. (See "Diagnosis of pulmonary tuberculosis in HIV-negative patients", section on 'Diagnostic microbiology'.) Acid-fast bacilli smear and culture Sputum Obtaining expectorated sputum from children for detection of AFB is difficult and its examination of low yield (15 percent or less for microscopic examination and 30 percent or less for culture) [37,38]. However, most adolescents can produce expectorated sputum spontaneously. Sputum induction has higher yield than expectorated sputum in children, and the use of sputum induction for obtaining TB diagnostic specimens in children is increasing. Sputum induction is performed via administration of aerosolized heated saline combined with salbuterol (or similar

drug to minimize wheezing), followed by suctioning to capture the expectorated sputum. In a study of 250 children (median age 13 months), sputum induction was found to be a safe and effective procedure in children as young as one month of age [37]. In two studies, outpatient sputum induction yielded culture results comparable to or better than inpatient gastric aspiration [22,37]. Minimal adverse effects associated with the procedure included coughing, epistaxis, vomiting, and wheezing. Children with underlying reactive airways disease should receive pretreatment with a bronchodilator to prevent bronchospasm during or following the procedure [37]. Gastric aspirate Early morning gastric contents collected from a fasting child contain sputum swallowed during the night. Children are typically hospitalized for two to three days for obtaining gastric aspiration specimens, although one retrospective study comparing inpatient and outpatient specimen collection demonstrated comparable bacteriologic yield [39]. Ideally, three early morning samples collected on different days before the child eats or ambulates optimize specimen yield [40]. Gastric aspiration remains the most common method for obtaining respiratory samples from children (in facilities where this procedure may be performed). In general, cultures of gastric aspirate specimens are positive for TB in only 30 to 40 percent of cases [41]. Smears are even less reliable with positive results in fewer than 10 percent of cases [41]; in addition, false-positive smear results caused by the presence of nontuberculous mycobacteria can occur [23]. Similar yields have been reported with nasopharyngeal aspiration, a less invasive technique that can be performed in the outpatient setting [42]. Other specimens Other body fluid and/or tissue samples may be necessary in some circumstances, depending on suspicion for extrapulmonary TB. The approach to these diagnostic tools is outlined separately. (See "Diagnosis of pulmonary tuberculosis in HIV-negative

patients", section on 'Body fluids' and "Diagnosis of pulmonary tuberculosis in HIV-negative patients", section on 'Tissue biopsy'.) Diagnosis of TB should prompt HIV testing. (See "Serologic screening for HIV infection".) Rapid testing The GeneXpert MTB/RIF assay is an automated nucleic acid amplification test that can simultaneously identify M. tuberculosis and detect rifampin resistance. This test performs substantially better than smear microscopy [43,44]. In a randomized trial including 452 children in South Africa with suspected pulmonary TB, 6 percent had a positive sputum smear, 16 percent had a positive sputum culture, and 13 percent had a positive sputum GeneXpert MTB/RIF result [43]. The initial GeneXpert MTB/RIF test detected 100 percent of culture-positive cases that were smear positive but only 33 percent of those that were smear negative; a second GeneXpert MTB/RIF test improved the detection of smear-negative cases to 61 percent. Overall, with induced sputum specimens, the sensitivity and specificity were 59 and 99 percent, respectively for one GeneXpert MTB/RIF test, and 76 and 99 percent for two GeneXpert MTB/RIF tests. Test performance was unaffected by patient HIV status. Results for GeneXpert MTB/RIF were available within a median of one day (versus 12 days for culture). Detection of rifampin resistance was less promising: 1 of 3 rifampin-resistant isolates was not detected, and 4 of 74 rifampin-sensitive isolates had an indeterminate result. While the GeneXpert MTB/RIF test appears to be highly specific, its sensitivity for sputum smear-negative TB in children remains low. Since culture was used as the gold standard in the study described above, the sensitivity of GeneXpert MTB/RIF is expected to be even lower in sputum culture-negative, clinically confirmed cases. Therefore, it cannot replace current

methods used to suspect and diagnose TB in infants and children. Most children in the study presented with symptomatic pulmonary TB and extensive disease. The GeneXpert MTB/RIFtest is meant to be a rapid diagnostic test that may take the place of sputum microscopy but not mycobacterial culture. A negative GeneXpert MTB/RIF test should be interpreted in the context of the childs clinical and radiolographic findings. Sputum culture remains a more sensitive test and is required to detect the full drug susceptibility profile of the infecting organism. Further study of the assay is needed, in areas with high and low prevalence of TB. (See "Diagnosis of pulmonary tuberculosis in HIV-negative patients", section on 'Xpert MTB/RIF assay'.) Use of the GeneXpert MTB/RIF test on gastric lavage and nasopharyngeal specimens may be beneficial in settings where induced sputum and mycobacterial culture are not feasible. In one study in Zambia, sensitivity and specificity were found to be similar for sputum and gastric lavage aspirates (sensitivity 90 and 69 percent respectively; specificity 99 percent for both) [45]. Among over 900 children in South Africa, the sensitivity of GeneXpert MTB/RIF was similar for induced sputum and nasopharyngeal aspirate specimens (71 and 65 percent, respectively); specificity was >98 percent [46]. Molecular line probe assays are rapid tests that can be used to detect the presence of M. tuberculosis as well as genetic mutations that confer rifampin resistance alone or in combination with isoniazid resistance. These assays have high sensitivity (90 to 97 percent) and specificity (99 percent) compared with drug susceptibility testing [47]. (See "Microbiology and pathogenesis of tuberculosis", section on 'Drug susceptibility tests'.) Drug resistance New technologies including GeneXpert MTB/RIF and line probe assays will likely facilitate diagnosis

of drug-resistant TB among children, since these assays do not require culture. For most children, the diagnosis of drugresistant TB is established based on clinical criteria including signs and symptoms, radiographic findings, history of contact with a presumed or confirmed source case with drug-resistant TB, and failure to respond to first-line TB drugs [48]. To avoid unnecessary exposure to toxic second-line agents, extensive effort should be made to obtain multiple high quality specimens from the most accessible site(s) of disease [48]. All isolates with resistance to rifampinshould undergo complete second-line drug susceptibility testing and genotyping [48]. Issues related to diagnosis of drug resistance are discussed further separately. (See "Diagnosis, treatment, and prevention of drug-resistant tuberculosis".) TREATMENT Susceptible disease Guidelines endorsed by the United States Centers for Disease Control (CDC) and World Health Organization (WHO) for the treatment of tuberculosis (TB) in children emphasize the use of short-course multi-drug regimens under directly observed therapy [13]. In general, the pediatric treatment regimens outlined by the WHO are comparable to the adult regimens (table 4) [23,49]. Because TB in young children can rapidly disseminate with serious sequelae, prompt initiation of therapy is critical. Appropriate dosing is outlined in the Table (table 5). (See "Treatment of pulmonary tuberculosis in HIV-negative patients".) Pyridoxine supplementation is not routinely recommended for children receiving INH, but should be considered for exclusively breastfed infants, malnourished children or those with diets poor in pyridoxine, and HIV-infected children [23,50]. In many cases of TB in children, laboratory confirmation is never established (particularly among children under five years of age). In such cases, a presumptive

diagnosis may be made based on clinical and radiographic response to empiric treatment. If the cultures are negative, the isolates of contacts (if known/available) should guide decisions about treatment with respect to susceptibility. Drug susceptibility testing should be performed on initial isolates from each site of disease. Susceptibility testing should be repeated if the patient remains culturepositive after three months of therapy or positive cultures are detected after negative cultures have been documented. In HIV-positive children are not on antiretroviral therapy (ART), ART should be initiated within eight weeks of starting antituberculous therapy, or within two to four weeks if the CD4 count is 3 <50 cells/mm . Children with TB meningitis may be the only exception. Emerging evidence suggests that there is no survival benefit to starting ART before two months of antituberculous therapy, and in fact, delaying ART until that time may reduce adverse events [51]. Selection of an optimal ART regimen should be made in consultation with a pediatric HIV specialist. Unexplained deterioration among immunocompetent children receiving appropriate therapy for pulmonary and/orextrapulmonary TB has been described [52,53]. In one study of 110 children, clinical or radiographic deterioration was observed in 14 percent of cases after initiating therapy (range 10 to 181 days; mean 80 days) [52]. The most common complication was enlarging intrathoracic lymphadenopathy, often causing airway compromise. Deterioration was more likely among children with weight-for-age 25th percentile and multiple sites of disease. All children achieved clinical or radiographic cure; corticosteroids were administered in 60 percent of cases. In another study of 115 immunocompetent children, 12 developed paradoxical worsening within 15 to 75 days (median 39 days) of starting TB therapy; children with paradoxical reactions tended to be younger

(median age at diagnosis of 26 months versus 66 months) and had never received BCG vaccination [53]. The most common manifestation was worsening of preexisting pulmonary lesions, observed in 75 percent, while 25 percent had new disease present in new anatomic locations. Drug-resistant TB Expert consultation is important for management of drugresistant TB. Ensuring treatment adherence and support through a multidisciplinary care team are critical components of care. Selection of drugs for treatment of drugresistant TB in children should be guided by the drug susceptibility testing (DST) results of the childs isolate; in the absence of such data, treatment should be guided by the DST results of the presumed source case. Ideally, the regimen for treatment of drugresistant TB should include at least four drugs to which the isolate is known to be, or presumed to be, susceptible [48]. The number of drugs and duration of therapy should be determined by the extent of disease, site of disease (and correlating drug penetration) and treatment response [48]. Children with cavitary or extensive disease with resistance to only rifampin and isoniazid can achieve a favorable outcome when treated for 18 months from the time the first negative culture is obtained [48]. Whenever possible, first-line TB drugs should be used since they have the most favorable efficacy and toxicity profiles. In general, treatment of multi-drug resistant TB should include a fluoroquinolone and an injectable agent (although there is no role for use of more than one fluoroquinolone or injectable agent) (table 6). Subsequently, if needed, ethionamide, cycloserine, and aminosalicylic acid may be added to complete the regimen such that it consists of at least four active drugs. Alternative agents should be added only when the preceding drugs are not sufficient. Treatment of children with second-line agents is complicated by the absence of pediatric formulations for most of these

drugs, which can lead to under- or overdosing. In a retrospective case series including 38 children under 15 years of age in Peru, all children had a supervised individualized treatment regimen (five to seven drugs) based on susceptibility results of their M. tuberculosis isolate or the source case's isolate (usually a household contact) [54]. Adverse effects occurred in 42 percent of cases, although no events required suspension of therapy for >5 days. Cure or probable cure occurred in 95 percent of cases. Drug toxicity is common; in one metaanalysis of children treated for multidrugresistant TB, it was reported in 39 percent of cases [55]. Children on treatment for drug-resistant TB should be monitored at least monthly for adherence, response to treatment (eg, sputum analysis for those with pulmonary TB), and potential adverse events. PREVENTION Measures for prevention of tuberculosis (TB) include infection control interventions and prompt identification and treatment of latent TB infection (LTBI). Suspicion of TB disease in a child should be reported to the health department, so an investigation can be started right away. (See "Tuberculosis transmission and control", section on 'Contact investigation' and "Latent tuberculosis infection in children".) In countries where TB is endemic, routine childhood Bacille Calmette-Gurin (BCG) immunization is also an important preventive measure. (See "BCG vaccination".) SUMMARY AND RECOMMENDATIONS Estimating the global burden of tuberculosis (TB) disease in children is challenging due to the lack of a standard case definition, the difficulty in establishing a definitive diagnosis, the frequency of extrapulmonary disease in young children, and the relatively low public health priority

given to TB in children relative to adults. As a result, there is likely significant under-reporting of childhood TB from high-prevalence countries. (See 'Epidemiology' above.) Children under the age of five years represent an important demographic group for understanding TB epidemiology; in this group, TB frequently progresses rapidly from latent infection to TB disease. Therefore, these children serve as sentinel cases, indicating recent and/or ongoing transmission in the community. (See 'Epidemiology' above.) Common symptoms of pulmonary TB in children include cough (chronic, without improvement for more than three weeks), fever (more than 38C for more than two weeks), and weight loss or failure to thrive. Physical exam findings may suggest the presence of a lower respiratory infection but there are no specific findings to confirm that pulmonary TB is the cause. (See 'Pulmonary tuberculosis' above.) The clinical presentation of extrapulmonary TB depends on the site of disease. The most common forms of extrapulmonary disease in children are TB of the superficial lymph nodes and of the central nervous system (CNS). Infants have the highest risk of progression to TB disease with dissemination (miliary TB) and meningeal involvement. (See 'Extrapulmonary tuberculosis' above.) Forms of perinatal TB include congenital and neonatal disease. Congenital TB is very rare and most often is associated with maternal tuberculous endometritis or miliary TB. Neonatal TB is more common and develops following exposure of an infant to his or her mother's aerosolized respiratory secretions. (See'Perinatal infection' above.) TB in children is often diagnosed clinically; in many cases, laboratory

confirmation is never established (particularly among children under five years of age). Diagnosis is often based on the presence of the classic triad: (1) recent close contact with an infectious case, (2) a positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and (3) suggestive findings on chest radiograph or physical examination. (See 'Diagnosis' above.) In children, the TST or IGRA may be used as a tool for diagnosis of TB disease or latent TB (LTBI) (although in adults the TST or IGRA may be used only for diagnosis of LTBI, not TB disease). The TST or IGRA is helpful for diagnosis of TB in children only in circumstances when it is positive (table 2). (See 'Tuberculin skin test' above.) The most common chest radiograph finding in a child with TB disease is a primary complex, which consists of opacification with hilar or subcarinal lymphadenopathy, in the absence of notable parenchymal involvement. (See 'Imaging' above.) Gastric aspiration is the primary method of obtaining material for acidfast bacilli (AFB) smear and culture from young children, since these patients lack sufficient tussive force to produce adequate sputum samples by expectoration alone. Alternative approaches include sputum induction or expectoration (for older children). For diagnosis of extrapulmonary TB, specimens for culture should be collected from any site where infection is suspected. Diagnosis of TB should also prompt HIV testing. (See 'Laboratory studies'above.) The pediatric treatment regimens for TB are outlined in the Tables (table 4 and table 5). Because TB in young children can rapidly disseminate with serious sequelae, prompt initiation of therapy is critical. Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES 1. Starke JR. New concepts in childhood tuberculosis. Curr Opin Pediatr 2007; 19:306. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis 2004; 8:636. Wells CD, Nelson LJ. New international efforts in childhood tuberculosis: proceedings from the 2002 Workshop on Childhood Tuberculosis, Montreal, Canada, 6-7 October 2002. Int J Tuberc Lung Dis 2004; 8:630. World Health Organization. Global tuberculosis control: WHO report 2012. Geneva: World Health Organization, 2012. WHO/HTM/TB/2012.16. Stop TB Partnership Childhood TB Subgroup World Health Organization. Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Chapter 1: introduction and diagnosis of tuberculosis in children. Int J Tuberc Lung Dis 2006; 10:1091. Marais BJ, Gie RP, Schaaf HS, et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004; 8:278. Winston CA, Menzies HJ. Pediatric and adolescent tuberculosis in the United States, 2008-2010. Pediatrics 2012; 130:e1425. Centers for Disease Control and Prevention (CDC). Trends in tuberculosis--United States, 2010. MMWR Morb Mortal Wkly Rep 2011; 60:333. Cruz AT, Starke JR. Clinical manifestations of tuberculosis in children. Paediatr Respir Rev 2007; 8:107. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med 2012; 367:348. Schaaf HS, Beyers N, Gie RP, et al. Respiratory tuberculosis in childhood: the diagnostic value of clinical features and special investigations. Pediatr Infect Dis J 1995; 14:189. Mandalakas AM, Starke JR. Current concepts of childhood tuberculosis. Semin Pediatr Infect Dis 2005; 16:93. World Health Organization, Childhood TB Subgroup. Guidance for national tuberculosis programmes on the management of tuberculosis in children, Geneva. WHO/HTM/ TB/2006.371WHO/FCH/CA H/2006.7. Starke JR. Tuberculosis in childhood and pregnancy. In: Tuberculosis: current

2.

3.

4.

5.

6.

7.

8.

9.

10. 11.

12.

13.

14.

15.

16.

17. 18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

concepts and treatment, 2nd ed, Friedman LN (Ed), CRC Press, Boca Raton 2000. Hageman J, Shulman S, Schreiber M, et al. Congenital tuberculosis: critical reappraisal of clinical findings and diagnostic procedures. Pediatrics 1980; 66:980. Manji KP, Msemo G, Tamim B, Thomas E. Tuberculosis (presumed congenital) in a neonatal unit in Dar-es-Salaam, Tanzania. J Trop Pediatr 2001; 47:153. Laibl VR, Sheffield JS. Tuberculosis in pregnancy. Clin Perinatol 2005; 32:739. Cruz AT, Hwang KM, Birnbaum GD, Starke JR. Adolescents with tuberculosis: a review of 145 cases. Pediatr Infect Dis J 2013; 32:937. Pereira L. Tuberculosis: role of etiologic diagnosis and tuberculin skin test. Pediatr Pulmonol Suppl 2004; 26:240. Drobac PC, Shin SS, Huamani P, et al. Risk factors for in-hospital mortality among children with tuberculosis: the 25-year experience in Peru. Pediatrics 2012; 130:e373. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000; 49:1. Hatherill M, Hawkridge T, Zar HJ, et al. Induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis? Arch Dis Child 2009; 94:195. American Academy of Pediatrics. Tuberculosis. In: Red Book: 2012 Report of the Committee on Infectious Diseases, 29th ed, Pickering LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2012. Steiner P, Rao M, Victoria MS, et al. Persistently negative tuberculin reactions: their presence among children with culture positive for Mycobacterium tuberculosis (tuberculin-negative tuberculosis). Am J Dis Child 1980; 134:747. van den Bos F, Terken M, Ypma L, et al. Tuberculous meningitis and miliary tuberculosis in young children. Trop Med Int Health 2004; 9:309. van der Weert EM, Hartgers NM, Schaaf HS, et al. Comparison of diagnostic criteria of tuberculous meningitis in human immunodeficiency virus-infected and uninfected children. Pediatr Infect Dis J 2006; 25:65. Menzies D, Pai M, Comstock G. Metaanalysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007; 146:340.

28. Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149:177. 29. Connell TG, Curtis N, Ranganathan SC, Buttery JP. Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children. Thorax 2006; 61:616. 30. Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR Recomm Rep 2005; 54:49. 31. Starke, J. Use of the new TB test in children should be limited. AAP News 2006; 27:14. 32. Gie RP, Beyers N, Schaaf HS, Goussard P. The challenge of diagnosing tuberculosis in children: a perspective from a high incidence area. Paediatr Respir Rev 2004; 5 Suppl A:S147. 33. Gwee A, Pantazidou A, Ritz N, et al. To xray or not to x-ray? Screening asymptomatic children for pulmonary TB: a retrospective audit. Arch Dis Child 2013; 98:401. 34. Marais BJ, Gie RP, Hesseling AC, et al. Radiographic signs and symptoms in children treated for tuberculosis: possible implications for symptom-based screening in resource-limited settings. Pediatr Infect Dis J 2006; 25:237. 35. Lighter J, Rigaud M. Diagnosing childhood tuberculosis: traditional and innovative modalities. Curr Probl Pediatr Adolesc Health Care 2009; 39:61. 36. Centers for Disease Control and Prevention (CDC). Updated guidelines for the use of nucleic acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep 2009; 58:7. 37. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005; 365:130. 38. Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Respir Crit Care Med 2006; 173:1078. 39. Lobato MN, Loeffler AM, Furst K, et al. Detection of Mycobacterium tuberculosis in gastric aspirates collected from children: hospitalization is not necessary. Pediatrics 1998; 102:E40. 40. Cruz A, Revell P, Starke J. Gastric Aspirate Yield For Children With Suspected Pulmonary Tuberculosis. J Ped Infect Dis 2013; 2:171.

41. Starke JR. Pediatric tuberculosis: time for a new approach. Tuberculosis (Edinb) 2003; 83:208. 42. Owens S, Abdel-Rahman IE, Balyejusa S, et al. Nasopharyngeal aspiration for diagnosis of pulmonary tuberculosis. Arch Dis Child 2007; 92:693. 43. Nicol MP, Workman L, Isaacs W, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infect Dis 2011; 11:819. 44. Smith MS, Williams DE, Worley SD. Potential uses of combined halogen disinfectants in poultry processing. Poult Sci 1990; 69:1590. 45. Bates M, O'Grady J, Maeurer M, et al. Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study. Lancet Infect Dis 2013; 13:36. 46. Zar HJ, Workman L, Isaacs W, et al. Rapid molecular diagnosis of pulmonary tuberculosis in children using nasopharyngeal specimens. Clin Infect Dis 2012; 55:1088. 47. Perez-Velez CM. Pediatric tuberculosis: new guidelines and recommendations. Curr Opin Pediatr 2012; 24:319. 48. Seddon JA, Furin JJ, Gale M, et al. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am J Respir Crit Care Med 2012; 186:953. 49. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendations. Int J Tuberc Lung Dis 2006; 10:1318. 50. Cruz AT, Starke JR. Treatment of tuberculosis in children. Expert Rev Anti Infect Ther 2008; 6:939. 51. Trk ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis 2011; 52:1374. 52. Thampi N, Stephens D, Rea E, Kitai I. Unexplained deterioration during antituberculous therapy in children and adolescents: clinical presentation and risk factors. Pediatr Infect Dis J 2012; 31:129. 53. Olive C, Mouchet F, Toppet V, et al. Paradoxical reaction during tuberculosis treatment in immunocompetent children: clinical spectrum and risk factors. Pediatr Infect Dis J 2013; 32:446. 54. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children

with multidrug-resistant tuberculosis. Pediatrics 2006; 117:2022. 55. Ettehad D, Schaaf HS, Seddon JA, et al. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:449. Topic 8007 Version 23.0