Clinical manifestations, diagnosis, and treatment of miliary tuberculosis

INTRODUCTION — Miliary tuberculosis (TB) refers to clinical disease resulting from hematogenous dissemination of Mycobacterium tuberculosis. The term "miliary" was coined in 1700 by John Jacobus Manget, who likened the appearance of the involved lung to millet seeds, with its surface covered with small, firm white nodules (picture 1). The term miliary TB was originally a pathologic and then a radiographic description; it is now used to denote all forms of progressive, widely disseminated hematogenous TB. The term also may be used more broadly (and incorrectly) by some to denote involvement at multiple sites, whether or not disease presents with the classic radiographic or pathologic nodular appearance characteristic of hematogenous spread. Miliary TB can arise as a result of progressive primary infection or via reactivation of a latent focus with subsequent spread via the bloodstream.

The clinical manifestations, diagnosis, treatment, and prevention of miliary TB will be reviewed here. The epidemiology and pathogenesis of miliary and extrapulmonary TB are discussed separately. (See "Epidemiology and pathology of miliary and extrapulmonary tuberculosis".)

CLINICAL MANIFESTATIONS — Clinical manifestations of miliary TB are most likely to be subacute or chronic; less commonly, acute presentations also occur. Patients with subacute or chronic disease may present with failure to thrive [1], fever of unknown origin [2,3], and/or dysfunction of one or more organ systems [4]. Night sweats are frequent; rigors are unusual [5,6]. In one series including 38 patients, the median duration of illness prior to clinical presentation was two months [2]. The most common extrapulmonary sites include the lymphatic system, bones and joints, liver, central nervous system (CNS), and adrenal glands.

Acute miliary TB may be fulminant, including multiorgan system failure [7], a syndrome of septic shock [8], and acute respiratory distress syndrome (ARDS) [9,10]. Miliary TB is a relatively rare cause of acute respiratory failure and ARDS [11-13]; one study in South Africa (where the prevalence of TB is very high) noted approximately 2 percent of cases of ARDS were associated with disseminated TB [14]. The diagnosis of TB is more likely to be delayed or missed in patients presenting with acute respiratory failure rather than more typical symptoms of pulmonary or pleural TB [15]. Patients who develop miliary TB during primary infection can present with relatively acute onset and rapid clinical course. (See "Pulmonary tuberculosis: Clinical manifestations and complications".)

Symptoms and signs of miliary TB are described in the tables (table 1 and table 2). Much of the data on clinical features of miliary TB comes from large retrospective series (table 3) [1,2,16-19]. These studies include a relatively large number of patients though differ markedly by year, inclusion criteria, country, and type of medical center; therefore, direct comparisons are difficult.

Pulmonary disease has been observed in more than 50 percent of patients with miliary TB in most series [16,17]. Patients with miliary TB that involves the lungs may have dyspnea or cough and rales or rhonchi on physical examination; hypoxemia is common. Pleuritic chest pain with accompanying pleural rub or other signs of a pleural effusion have also been well described.

Autopsy series of miliary TB describe seeding of every organ in the body [20]:

●Signs and symptoms of liver involvement in disseminated TB include diffuse abdominal pain or pain localizing to the right upper quadrant, nausea, vomiting, and diarrhea [21,22]. Cholestatic jaundice in miliary TB is also well described. Rarely, fulminant hepatic failure can occur [23]. Liver function test abnormalities are common; one series noted elevated alkaline phosphatase and transaminases in 83 and 42 percent of patients, respectively [16]. Histopathologic sections of involved liver demonstrate scattered granulomatous lesions that, on gross examination, have the appearance of millet seeds (picture 2) [24].

●Central nervous system lesions may occur diffusely throughout the brain and usually are not centered around the ventricles or basal cisterns (as seen in TB meningitis). In one series, meningeal involvement was evident postmortem in 54 percent of cases of miliary TB [20]. In another study including seven patients with radiographic pulmonary miliary TB and no clinical CNS findings, all had brain lesions on magnetic resonance imaging (MRI) [25]. (See "Central nervous system tuberculosis: An overview".)

●Adrenal involvement in disseminated TB has been described in as many as 40 percent of autopsies [18,26]. Overt adrenal insufficiency is less common, occurring in 1 percent of reported cases of miliary TB [16,26]. In a prospective study including 30 patients with miliary TB, adrenal function was abnormal in one case [27]. Another series including 55 patients with TB involvement of the adrenal gland noted 12 percent presented with clinical manifestations of Addison's disease [26]. (See "Clinical manifestations of adrenal insufficiency in adults".)

Mycobacteria can reach the liver by hematogenous dissemination (miliary) or by local spread from the gastrointestinal tract or the abdomen. A systematic review including 618 cases of hepatic TB noted miliary disease accounted for 79 percent of hepatic TB, usually accompanied by lung involvement; focal disease, including abscess formation or biliary tract TB, accounted for the remaining 21 percent [28]. Presenting findings described in 11 case series included hepatomegaly, fever, respiratory symptoms, abdominal pain, and weight loss. Imaging by computed tomography (CT) or ultrasound confirms liver involvement but is not specific for the diagnosis.

Tuberculous peritonitis usually develops following spread of infection from adjacent organs or by hematogenous spread in miliary disease. It should be suspected in patients at risk for TB who present with ascites. Symptoms of fever, fatigue, and abdominal pain are common. Ascites fluid usually demonstrates lymphocytosis, elevated protein, and elevated inflammatory markers. Culture of ascites fluid or of peritoneal tissue is required to confirm the diagnosis. The surface of the peritoneum may demonstrate focal granulomatous lesions on visual examination that may appear like miliary disease; biopsy of these lesions demonstrates caseating granulomas with or without acid-fast staining organisms. (See "Abdominal tuberculosis".)

Central nervous system disease, such as meningitis or tuberculoma, was observed in 15 to 20 percent of patients with TB in two large series [16,17]. Among patients with tuberculous meningitis, about one-third to one-half in one series had miliary TB [20]. In a study of seven patients with miliary pulmonary TB and no neurologic findings, all patients had evidence of CNS disease by MRI [25].

Other manifestations of miliary TB include laryngitis [29], otitis media [30], and thyroid involvement with clinical hyperthyroidism or hypothyroidism [31].

The diagnosis of miliary TB is often missed due to the nonspecific nature of the presentation. In one United States review, approximately 20 percent of miliary TB cases were diagnosed postmortem [32]. Among patients with human immunodeficiency virus (HIV) in Africa, previously unrecognized disseminated TB has been identified at autopsy in as many as 40 percent of hospital deaths [3].

LABORATORY FINDINGS — Many laboratory abnormalities may be observed in miliary TB (table 4). Hematologic abnormalities are prominent. Normocytic, normochromic anemia is seen in approximately one-half of the patients in most series. Most patients have a normal white blood cell count, but leukopenia and leukocytosis occur in a minority of patients with roughly equal frequency. Leukemoid reactions are also described and may be mistaken for leukemia [33,34]. Monocytosis occurs but is less common. Thrombocytopenia and thrombocytosis are also reported.

Pancytopenia, which should raise concern for miliary TB, may be due to marrow infiltration alone or may be a manifestation of an underlying hematologic disorder [35]. Cases of the histiocytic hemophagocytic syndrome associated with miliary TB have also been described [36].

Overt disseminated intravascular coagulation is rare; it has been described in acute, fulminant disease. Milder coagulation abnormalities have been described more frequently [16]. The erythrocyte sedimentation rate and other acute-phase reactants are elevated in the majority of patients with miliary TB. Polyclonal gammaglobulinemia is also common [2].

Hyponatremia may be observed; it is presumed to be due to the same problems with regulation of antidiuretic hormone seen in other pulmonary processes [2]. Hypercalcemia is rare but may be seen [37]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Sterile pyuria was found in 32 percent of patients with miliary TB in one series [2]. Urine cultures may also be positive for M. tuberculosis in miliary TB in the absence of an abnormal urine sediment.

RADIOGRAPHIC IMAGING — Two series of cases of miliary TB provide an excellent overview of pulmonary findings [2,16]. More than two-thirds of patients with the diagnosis of disseminated TB had a chest radiograph with a miliary pattern.

Chest radiography — The classic appearance in miliary disease is a faint, reticulonodular infiltrate distributed fairly uniformly throughout the lungs (image 1). This miliary pattern may become apparent days or weeks after presentation [16,17,19]. This finding is thought to reflect nodular interstitial spread without significant alveolar involvement, although it has been demonstrated that, by the time the miliary nodules are large enough to be appreciated on a plain chest radiograph, they typically involve the adjacent alveoli [38].

Conversely, pathologic conditions that initially involve alveoli, such as alveolar hemorrhage, pulmonary edema, or inhalational diseases, can appear initially as small nodules. These so-called "acinar nodules" are described as larger (5 to 10 mm) and more heterogeneous than classic miliary TB, but overlap occurs, making the appearance of many of these conditions indistinguishable [39]. The differential diagnosis of a miliary chest radiography pattern is summarized in the table (table 5).

Other chest radiograph abnormalities include pleural reactions, hilar or mediastinal adenopathy, and other evidence of active or healed parenchymal TB (interstitial or alveolar infiltrates or cavities). A miliary pattern can be seen in addition to non-miliary disease. Normal chest radiographs may be observed in up to one-half of patients with disseminated TB [40]. In some cases, abnormalities may be subtle and appreciated only after review with an experienced chest radiologist.

Computed tomography — High-resolution computed tomography (HRCT) of the chest is more sensitive for miliary TB than plain chest radiography [41]. Numerous 2 to 3 mm nodules can be visualized distributed throughout the lung (image 2). Septal thickening usually accompanies these nodules. These findings are sensitive but not necessarily specific for miliary TB. In series correlating clinical and pathologic findings with HRCT, disseminated nodules were found in many other infections (Haemophilus influenzae, Mycoplasma pneumoniae, Candida albicans) and noninfectious diseases (sarcoidosis, metastatic adenocarcinoma, lymphoma, amyloidosis, hypersensitivity pneumonitis, and pneumoconiosis) [42,43].

Other nonspecific findings on chest CT can be observed in miliary TB. As an example, in one study, ground-glass opacities covering >50 percent of the lung field were seen in 20 percent of patients with miliary TB [44].

Positron emission tomography CT — ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) computed tomography (CT) is becoming more widely used for the evaluation of malignancies [45]. Uptake of FDG is proportional to glycolysis within inflammatory cells such as neutrophils, activated macrophages, and lymphocytes as well as tumor cells, and regions of high uptake can be seen at sites of inflammation or infection such as in pulmonary and extrapulmonary sites of disease [46]. Findings are nonspecific for infection or neoplasm, and FDG-PET CT has not been systematically studied in miliary TB. Perhaps the most useful application of this technology will be to define sites of disease and monitor response to treatment [47].

Other imaging — Gallium scans can show diffuse pulmonary and extrapulmonary uptake in miliary TB [48]. However, sensitivity and specificity are limited; patients with miliary TB and evidence of miliary patterns on chest imaging may have negative gallium scans.

DIAGNOSIS — The diagnosis of miliary TB should be suspected in patients with relevant clinical manifestations such as fever, night sweats, and organ dysfunction in the context of relevant epidemiologic or exposure history. The diagnosis is established by identifying the organism obtained from a biopsy sample in culture.

The diagnosis can be challenging due to nonspecific clinical symptoms and signs and poor diagnostic tools [49]. Careful evaluation of extrapulmonary findings is warranted, whether systemic disease is suspected in the setting of known pulmonary TB or whether extrapulmonary disease is the initial presenting feature. The nature and scope of extrapulmonary findings identified on diagnostic evaluation may influence the approach to treatment.

Clinical approach — Clinical evaluation begins with a thorough history and physical examination, including a dilated funduscopic examination since choroidal tubercles are characteristic of miliary TB and, if present, strongly support the diagnosis of miliary TB [24]. One large autopsy series that included eye examinations found tubercles in 50 percent of eyes [20]. (See "Tuberculosis and the eye".)

In general, an evaluation for pulmonary disease is warranted in all patients in whom disseminated TB is suspected (table 6), including chest radiography (followed by computed tomography [CT] if warranted), sputum for acid-fast smear and culture, nucleic acid amplification (NAA) testing, and tuberculin skin test (TST) or interferon-gamma release assay (IGRA; see below). If sputum cannot be obtained (via expectoration or induction) or if sputum is acid-fast bacilli smear negative, evaluation via bronchoscopic sampling (including bronchial brushings and/or transbronchial biopsy) is warranted [50]. In addition, mycobacterial blood culture should be performed using a lysis centrifugation or automated broth system designed for mycobacterial culture [51-53]. (See 'Acid-fast smear and culture' below and 'Molecular tests' below and "Diagnosis of pulmonary tuberculosis in adults".)

The subsequent diagnostic approach should be tailored to localizing signs or symptoms of disease involvement:

●Patients with neurologic signs or symptoms should undergo neuroimaging and lumbar puncture (if feasible and if there is no indication of increased intracranial pressure). The most common radiographic findings in tuberculous meningitis are basal meningeal enhancement and/or hydrocephalus. Cerebrospinal fluid (CSF) should be analyzed for cell count, protein, and glucose concentrations as well as acid-fast staining and culture for bacterial and mycobacterial organisms. (See "Central nervous system tuberculosis: An overview".)

●In the setting of pleural effusion, pericardial effusion, or ascites, fluid should be obtained for evaluation of cell count, protein, glucose, and lactate dehydrogenase (LDH) concentrations as well as acid-fast staining and culture for bacterial and mycobacterial organisms [50]. Pleural biopsy is warranted in the setting of moderate to high suspicion for TB when pleural fluid evaluation is not diagnostic. (See "Tuberculous pleural effusion" and "Tuberculous pericarditis" and "Abdominal tuberculosis".)

●Patients with symptoms localizing to other extrapulmonary sites (lymph nodes, bones/joints, skin, and other sites) should undergo evaluation as warranted depending on the involved organ system. Radiographic imaging may be warranted. Tissue biopsy may be required to establish a definitive diagnosis. (See "Tuberculous lymphadenitis" and "Bone and joint tuberculosis" and "Cutaneous manifestations of tuberculosis".)

Biopsy specimens from the lung, bone marrow, pericardium, lymph nodes, bones, joints, bowel, liver, brain, or other tissues allow for both histopathologic examination and culture. Liver biopsies are generally associated with the highest yield for diagnosis of extrapulmonary TB. In two series, granulomas were demonstrated more frequently in liver biopsies (91 to 100 percent) than bone marrow biopsies (31 to 82 percent) or transbronchial biopsies (72 and 63 percent) [2,16]. Lymph nodes and serosal biopsies also had high yields in patients in these series. The biopsy yield is likely to be increased in the setting of associated clinical or laboratory abnormalities. Biopsy specimens should be collected with and without fixative; culture requires specimens without fixative. (See 'Histopathology' below.)

The tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are tools designed for diagnosis of TB infection; a positive result supports (but cannot be used to establish) a diagnosis of active TB disease, and a negative result does not rule out active TB disease. Anergy is observed more frequently among patients with miliary TB than those with pulmonary or isolated extrapulmonary involvement and may be as high as 68 percent [54]. Reports of IGRA sensitivity among patients with miliary TB have been inconsistent. One study including 44 patients with miliary TB noted positive results with the QuantiFERON-TB Gold in-tube assay in 68 percent of cases [55]. Another study including 43 patients with miliary TB tested with the ELISPOT assay noted sensitivity of 93 percent [56]. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

There is no role for serologic testing in the diagnosis of TB; such tests have very low specificity [57-60]. While large numbers of individuals worldwide have TB antibodies, only about 10 percent of them go on to develop active disease.

Diagnostic tools

Acid-fast smear and culture — Acid-fast smear and culture of tissue, fluid, or drainage from an infected locus is the standard tool for establishing the diagnosis of TB [50]. Acid-fast microscopy may support a diagnosis of TB, especially if organisms or caseating granulomas are seen. The frequency of positive smears or cultures is summarized in the table (table 7) [2,16]. These data make several important points:

●Smears for acid-fast bacilli were positive in a minority of patients when only a single site was sampled; the probability of a positive smear increased with the number of sites sampled. Thus, when possible, samples of multiple sites (sputum, gastric aspirate, pleural fluid, ascites, urine) should be examined for the presence of acid-fast bacilli.

●Gastric aspirate cultures were frequently positive in these series. However, it was not clear how often they were positive when sputum smears were negative. It may be reasonable to obtain gastric aspirates if sputum smears are not available or negative.

●Bronchoscopy may be warranted if acid-fast bacilli are not detected at multiple sites (sputum, gastric aspirate, pleural fluid, ascites, urine); bronchoscopy is most useful when there is evidence of pulmonary involvement on chest radiography [61,62]. In the setting of acute presentation or in the absence of rapid diagnostic tools, prompt bronchoscopy is warranted. (See 'Molecular tests' below.)

Smears should be stained with the acid-fast fluorochrome dye, auramine-O, which is more sensitive than the conventional Ziehl-Nielsen stain [63]. Where available and validated appropriately, rapid probes (not approved by the US Food and Drug Administration [FDA]) may be applied to smear-positive sputum specimens to confirm the diagnosis of M. tuberculosis [64]. Specimens also should be inoculated into a commercial liquid-medium automated detection system (eg, BACTEC MGIT 960), which is faster and more sensitive than standard techniques using solid medium for the isolation of M. tuberculosis [65]. M. tuberculosis can be differentiated from isolated nontuberculous mycobacteria by hybridization using FDA-approved nucleic acid probes where available or biochemical methods or by other non-FDA-approved methods that have been validated appropriately by the laboratory, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) [66].

Mycobacterial blood cultures (preferably using lysis centrifugation techniques) should be performed in all patients in whom hematogenous dissemination is suspected [51]. Positive blood cultures in disseminated TB are relatively rare, though they may be observed in immunocompromised patients, including those with HIV infection [53,67]. Species identification is important since positive mycobacterial blood cultures may also occur in the setting disseminated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection (eg, from patients receiving intravesical installation of BCG to treat bladder cancer) and disseminated Mycobacterium avium (eg, in untreated patients with advanced HIV infection).

Histopathology — Histopathology of tissue biopsy specimens in the setting of TB typically demonstrates granulomatous inflammation [50]. Granulomas of TB characteristically contain epithelioid macrophages, Langhans giant cells, and lymphocytes (picture 3). The centers of tuberculous granulomas often have characteristic caseation ("cheese-like") necrosis; organisms may or may not be seen with acid-fast staining. The demonstration of characteristic caseating granulomas on a tissue section in the appropriate clinical and epidemiologic circumstances strongly supports a diagnosis of active TB, but it is not pathognomonic; culture is required to establish a laboratory diagnosis.

Molecular tests — In regions where available, molecular tests can be useful rapid diagnostic tools.

Nucleic acid amplification — NAA assays are used to amplify the quantity of M. tuberculosis ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) in diagnostic specimens where organisms may be present in amounts too small to be seen by routine staining techniques. These techniques are sensitive for rapid detection of M. tuberculosis in a variety of specimens, including blood, sputum, and urine [50,68-74]. NAA tests available in the United States have been approved by the FDA only for use with sputum or respiratory secretions; use on other specimen types is off-label use. Sensitivity of these tests is better in smear-positive samples, and a positive test in the appropriate clinical setting likely represents pulmonary TB [50,75,76]. However, a negative NAA test result may not be used to exclude TB because false-negative results are common [50].

The primary advantage of NAA tests is that a positive result to establish a diagnosis may be available within 24 hours. The United States Centers for Disease Control and Prevention (CDC) has published recommendations for the use of these tests in the diagnosis of TB [77]. (See "Diagnosis of pulmonary tuberculosis in adults".)

Xpert MTB/RIF assay — The Xpert MTB/RIF assay is an automated nucleic acid amplification test that can simultaneously identify M. tuberculosis and rifampin resistance. The Xpert MTB/RIF assay is approved by the FDA only for testing sputum in adults, although it may be applied in a non-approved indication to non-sputum samples following a validation process for that indication by the laboratory performing the test [78]. (See "Diagnosis of pulmonary tuberculosis in adults".)

Other assays — Many hospital and clinical laboratories offer nucleic acid amplification testing for M. tuberculosis complex using molecular methods (eg, polymerase chain reaction) not approved by the FDA but validated internally within the testing laboratory according to a written protocol. These "in-house" tests generally offer high specificity and, if positive, may be useful in supporting a clinical diagnosis of TB. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Molecular testing'.)

Urine antigen test in HIV infection — Urine-based detection of mycobacterial cell wall glycolipid lipoarabinomannan (urine LAM assay) is an assay for diagnosis of TB [79-86]. The urine LAM test is an important adjunctive diagnostic tool for settings with high incidence of HIV and TB. Issues related to use of this assay are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Urine antigen test in HIV infection'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of miliary TB is broad and depends on the degree of dissemination and the involvement of specific tissues and organs. The anatomic distribution of granulomatous lesions within the lung on high-resolution computed tomography (CT) scanning can be helpful for distinguishing hematogenously disseminated processes like miliary TB (which exhibits a random distribution of lesions) from airway-centered disorders (such as inhalational diseases) and lymphatic-centered processes (such as sarcoidosis) [87].

A miliary pattern on chest imaging may be due to many conditions, including (table 5):

●Histoplasmosis – Clinical manifestations of histoplasmosis include fever, fatigue, hepatosplenomegaly, and pancytopenia. Pulmonary manifestations may include pneumonia, adenopathy, lung mass, lung nodule(s), and/or cavitary lung disease. The diagnosis is established via histopathology, culture, antigen detection, or serology. (See "Diagnosis and treatment of pulmonary histoplasmosis".)

●Sarcoidosis – Clinical manifestations of sarcoidosis include cough, dyspnea, chest pain, eye lesions, and/or skin lesions. Bilateral hilar adenopathy is a classic chest radiograph finding; it may be absent and/or occur in combination with parenchymal opacities. The diagnosis is based on compatible clinical and radiographic manifestations and histopathologic detection of noncaseating granulomas. (See "Clinical manifestations and diagnosis of sarcoidosis".)

●Hypersensitivity pneumonia – Subacute or chronic hypersensitivity pneumonitis is an inhalational lung disease characterized by productive cough, dyspnea, fatigue, anorexia, and weight loss. The diagnosis is based upon exposure history, clinical assessment, radiographic and physiologic findings, and the response to avoidance of the suspected etiologic agent. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

●Talc granulomatosis – Clinical manifestations of talc granulomatosis are usually nonspecific such as dyspnea, cough, or an increase in sputum production. Some patients are asymptomatic; night sweats, weight loss, and hemoptysis occur less commonly. Clinical history and radiographic findings are often highly suggestive; when the diagnosis is unclear, flexible bronchoscopy with bronchoalveolar lavage is warranted. (See "Foreign body granulomatosis".)

●Pulmonary hemosiderosis – The clinical presentation of pulmonary hemosiderosis varies from an acute-onset illness with hemoptysis and dyspnea to an insidious process characterized by fatigue, anemia, and slowly progressive exertional dyspnea. Radiography demonstrates bilateral ground-glass alveolar opacities. Hemosiderin-laden alveolar macrophages may be identified in sputum, bronchoalveolar lavage fluid, and lung biopsy. (See "Idiopathic pulmonary hemosiderosis".)

●Primary bronchoalveolar carcinoma – Radiographic findings of bronchioloalveolar carcinoma may be variable and range from a solitary or limited number of nodules to more extensive miliary disease or diffuse parenchymal infiltrates. The diagnosis is established via histopathology. (See "Pathology of lung malignancies", section on 'Adenocarcinoma'.)

●Tumor metastases – Metastatic disease from primary neoplasms such as thyroid or kidney may present with radiographic nodules or a miliary appearance. The diagnosis is established via histopathology. (See "Diagnostic evaluation of the incidental pulmonary nodule".)

●Spread of pyogenic infection from a remote site – Bacterial infection may reach the lung via hematogenous spread and/or via septic embolization. The diagnosis is established via bacterial culture. (See "Complications and outcome of infective endocarditis", section on 'Septic embolization'.)

TREATMENT — In general, the approach to antimicrobial therapy for treatment of miliary TB consists of the traditional regimen (≥6 months) for treatment of pulmonary TB [88]. While the data suggest that this approach is successful, individualization of regimens may be warranted. The rifapentine-moxifloxacin-based four-month regimen should not be used for treatment of extrapulmonary disease [89,90]. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Modifications to the standard drug regimen may be justified in the setting of drug-resistant TB. In addition, longer duration of therapy may be warranted for children, immunocompromised hosts, patients with a large organism burden, and patients with a slow microbiologic or clinical response. Longer duration of therapy is also warranted for patients with disease involving the central nervous system (CNS), some patients with bone or joint disease, and some cases of lymphadenitis (a site of early relapse in anecdotal reports) [91]. Depending on the site(s) and scope of disease, surgical intervention may be needed for diagnostic and/or therapeutic management.

Data on the role of corticosteroids in patients with miliary TB are limited; results of case reports and small clinical series using corticosteroids in miliary TB are conflicting [24]. In some circumstances, corticosteroids are warranted for treatment of TB involving the CNS [92] or pericardium [93]. (See "Central nervous system tuberculosis: Treatment and prognosis", section on 'Glucocorticoids'.)

OUTCOME — The clinical course and outcomes of miliary TB have improved markedly between the preantibiotic and postantibiotic eras [20,94]. In the United States Veteran's Administration study of miliary TB (excluding meningitis), the attributable mortality dropped successively (from nearly 100 percent) with the introduction of each new drug. Mortality dropped with the introduction of streptomycin (to 47 percent), with streptomycin plus para-aminosalicylic acid (to 18 percent), and with isoniazid-based combination therapy (to 5 percent) [94]. Subsequently, two large series noted mortality of approximately 20 percent [2,16]. These studies included patients with a broad range of underlying diseases and did not exclude meningeal TB. Since the introduction of isoniazid-based therapy, case series have documented shorter duration of fever and more rapid clinical and radiographic improvement. In one study, the median time to defervescence was 7 days (range 1 to 55 days); 76 percent of patients were afebrile within 14 days of the initiation of therapy [16]. Disseminated TB continues to be associated with a high mortality rate in patients with acquired immunodeficiency syndrome (AIDS) who are not on antiretroviral therapy [95].

The factors that contribute to survival in miliary TB are difficult to assess, since the literature is generally limited to retrospective case studies and includes patients with variable clinical and laboratory presentations. However, central nervous system disease appears to be an independent predictor of mortality in most studies [2,17,94]. Pancytopenia or lymphopenia were poor prognostic indicators in some studies [16,35]. Age, late presentation, serious underlying disease, and a nonreactive tuberculin skin test are cited in other studies as predictors of mortality [96].

PREVENTION — Miliary TB can be prevented by treatment of latent TB infection. In addition, childhood administration of Bacillus Calmette-Guérin in endemic areas reduces the incidence of miliary TB. A large meta-analysis found a 78 percent protective effect of the vaccine against miliary TB [97]. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection" and "Prevention of tuberculosis: BCG immunization and nutritional supplementation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY

●Definition – Miliary tuberculosis (TB) refers to clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis and is characterized by the presence of small, firm white nodules resembling millet seeds. Miliary TB can arise as a result of progressive primary infection or via reactivation of a latent focus with subsequent spread. The clinical presentation of miliary TB is highly variable; manifestations can be acute but are more likely to be subacute or chronic. (See 'Introduction' above.)

●Clinical manifestations – (see 'Clinical manifestations' above):

•Signs and symptoms – Acute disease may be fulminant, including multiorgan system failure, a syndrome of septic shock, and acute respiratory distress syndrome (ARDS). Patients with subacute or chronic disease may present with failure to thrive, fever of unknown origin, or dysfunction of one or more organ systems. Symptoms generally are related to the site(s) of disease involvement.

•Sites of involvement – The most common sites of involvement include the lungs, the lymphatic system, bones and joints, liver, central nervous system (CNS), and adrenal glands.

●Laboratory findings – The most common laboratory abnormalities include anemia and other hematologic findings. Other laboratory abnormalities may include elevated acute-phase reactants, hyponatremia, hypercalcemia, and sterile pyuria.

●Radiographic imaging – In miliary disease, the classic chest radiograph appearance is a faint, reticulonodular infiltrate distributed fairly uniformly throughout the lungs (image 1). Other chest radiograph abnormalities include pleural reactions, hilar or mediastinal adenopathy, interstitial or alveolar infiltrates, or cavities. Computed tomography of the chest is more sensitive for evaluation of miliary TB than plain chest radiography. (See 'Laboratory findings' above and 'Radiographic imaging' above.)

●Diagnosis

•Clinical approach – (see 'Clinical approach' above):

-Clinical evaluation for miliary TB begins with a thorough history and physical examination, including a dilated funduscopic examination. In general, evaluation for pulmonary disease and mycobacterial blood cultures are warranted in all patients in whom disseminated TB is being considered. In regions where available, molecular tests can be useful rapid diagnostic tools.

-The subsequent diagnostic evaluation should be tailored to localizing signs or symptoms of disease involvement. Patients with neurologic signs or symptoms should undergo neuroimaging and lumbar puncture (if feasible and not contraindicated). In the setting of pleural effusion, pericardial effusion, or ascites, fluid should be obtained for evaluation and a biopsy strongly considered. Radiographic imaging of the involved site(s) may be warranted for patients with symptoms referable to the CNS, gastrointestinal tract, genitourinary tract, bones/joints, or lymph nodes. Suspected genitourinary disease should prompt urine acid-fast bacillus culture. Depending on the involved site(s), tissue biopsy may be required to establish a definitive diagnosis.

•Histopathology - Biopsy specimens allow for both histopathologic examination and acid-fast culture. Biopsy sites with relatively good yield include the pleura, liver, bone marrow, lymph nodes, and lung via transbronchial biopsies; the yield is likely to be increased in the setting of associated clinical or laboratory abnormalities. Histopathology typically demonstrates granulomatous inflammation. Tuberculous granulomas characteristically contain epithelioid macrophages, Langhans giant cells, and lymphocytes, and the centers often have characteristic caseation ("cheese-like") necrosis. (See 'Histopathology' above.)

●Treatment - In general, the approach to antimicrobial therapy for treatment of miliary TB is the same as for pulmonary TB using a traditional multidrug regimen (≥6 months); modifications may be warranted in the setting of drug-resistant TB. In addition, longer duration of therapy may be warranted for children, immunocompromised hosts, patients with a large organism burden, and patients with a slow microbiologic or clinical response. Longer duration of therapy is also warranted for patients with disease involving the central nervous system, some patients with bone or joint disease, and some cases of lymphadenitis. Surgical intervention may be needed for diagnostic and/or therapeutic management in some cases. (See 'Treatment' above.)