Version May 2024
INTRODUCTION — Miliary tuberculosis (TB) refers to clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis. The term "miliary" was coined in 1700 by John Jacobus Manget, who likened the appearance of the involved lung with its surface covered with firm small white nodules to numerous millet seeds (picture 1).
Miliary TB can arise as a result of progressive primary infection or via reactivation of a contained, infected focus with subsequent spread. The term miliary TB was originally a pathologic and then a radiographic description; it is now used more broadly (and incorrectly) by some to denote all forms of progressive, widely disseminated TB, whether or not disease presents with the classic radiographic or pathologic nodular appearance characteristic of hematogenous spread.
Tuberculosis may be classified according to site of disease as pulmonary or extrapulmonary; miliary disease has been classified as both an extrapulmonary and a pulmonary form of TB.
The epidemiology and pathology of miliary TB will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of miliary TB are discussed separately. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)
TERMINOLOGY — TB terminology is inconsistent in the literature and in practice as discussed above [1]. Relevant terms are defined in the table (table 1).
EPIDEMIOLOGY — The epidemiology of miliary TB has been altered by use of chemotherapy for treatment of malignancy, use of biologic agents, the HIV epidemic, and immigration patterns. For reporting purposes, cases with both pulmonary and extrapulmonary disease are classified as pulmonary TB by the United States Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) [2,3].
Of 8331 TB cases reported in the United States in 2022, extrapulmonary TB (with no demonstrated pulmonary involvement) accounted for approximately 19 percent of cases. Disease with both pulmonary and extrapulmonary involvement was reported in 10.6 percent of cases [4]. Relative numbers are essentially unchanged since 2021, despite possible associations with COVID-19 and a 5.9 percent increase in the total number of reported cases of TB in the United States in 2022 versus 2021.
Generally, fewer than 2 percent of cases demonstrate miliary disease [5].
Worldwide, estimates of incidence are hampered by incomplete reporting and imprecise diagnostic criteria [6].
The epidemiology of miliary disease varies between case series:
●Prior to the availability of antituberculous therapy, 20 percent of TB autopsy cases at Boston City Hospital had evidence of miliary disease [7]. By the 1970s, with the availability of antituberculous therapy, the incidence had fallen to 0.7 percent [8].
●Data from the CDC in the early 1980s (after the availability of antituberculous therapy but prior to the HIV epidemic) reported 1.3 percent of TB cases had evidence of miliary disease [9].
●In the midst of the HIV epidemic during the mid-1980s, the percentage of miliary TB was higher among HIV-infected patients than HIV-uninfected patients (38 versus 8 percent) [10,11]. Risk for developing miliary TB appeared to be highest among patients with the lowest CD4 counts [12].
●In a public health clinic in Ireland in the 1990s, miliary disease accounted for 4 percent of TB cases [13].
Use of biologic agents such as tumor necrosis factor (TNF)-alpha inhibitors has been associated with a disproportionate increase in cases of extrapulmonary and miliary tuberculosis among individuals treated with these agents. In one study including 70 patients who developed tuberculosis in association with infliximab therapy, extrapulmonary disease was observed in 57 percent of cases, and "disseminated" disease was observed in 24 percent of cases [14]. In another study including 40 patients who developed TB in association with anti-TNF-alpha agents (etanercept, infliximab, or adalimumab), extrapulmonary TB (including miliary TB) was observed in 62 percent of cases [15].
The HIV epidemic has played a significant role in increasing the prevalence of miliary TB. Between 1999 and 2006 in England and Wales, an almost fivefold increase in the number of miliary cases was observed (38 to 180 cases); HIV coinfection was most strongly associated with miliary disease [16]. Other factors, such as the emergence of drug-resistant or multidrug-resistant strains, have also contributed [17].
While the early COVID-19 pandemic was associated with a decrease in the number of reported cases in the United States in 2020 and 2021, the relative number of extrapulmonary cases has not changed as case numbers appear to be rebounding [4].
Risk factors — Risk factors for the development of miliary TB include age and underlying medical conditions, especially HIV infection and other immunosuppression. However, a significant percentage of cases described in the literature have no demonstrable high-risk condition for dissemination; miliary TB should never be excluded as a clinical diagnosis because an underlying medical illness is absent.
Age — Infants and young children are highly susceptible to miliary TB, presumably due to their relatively immature immune systems [18-22]. In a study from Puerto Rico, miliary disease or meningitis occurred more frequently among children <6 years than among children >7 years of age (1 versus 0.4 percent, respectively) [19]. In another series from South Africa, miliary TB accounted for more hospital admissions among children than adults (8 versus 1 percent); 52 percent of cases occurred in children <1 year of age [20].
Miliary TB has been described more frequently among older adults in the post-antibiotic era than the pre-antibiotic era; this group is likely at increased risk due to relative waning of cellular immunity [8]. In addition, the rise of HIV has led to increased prevalence of miliary TB among young adults [23].
Medical conditions — The percentage of patients with miliary TB and some identifiable underlying medical condition in various studies ranged from 38 to 70 percent. The most common conditions include [24-30]:
●Alcohol abuse
●Malignancy
●HIV infection
●Corticosteroids or other iatrogenic immunosuppression (eg, TNF-alpha–blocking agents)
●Connective tissue disease (with or without iatrogenic immunosuppression)
●Renal failure
●Diabetes
●Pregnancy
Weight loss and/or malnutrition are important components of a number of these conditions but have not been addressed separately [24-28].
Other factors — Men outnumber women in most series of miliary TB (table 2); it is uncertain whether this reflects a greater prevalence of TB among men. It is also uncertain whether African-Americans are more likely to progress from infection to disseminated disease, since control for the relative contributions of socioeconomic factors, such as living conditions, nutrition, access to care, and comorbidities, is needed for proper data interpretation [31].
PATHOLOGY
Mechanisms of disease — Miliary or extrapulmonary TB can arise as a result of progressive primary infection or via reactivation of a contained (formerly termed latent) focus with subsequent lymphohematogenous spread. Rarely, iatrogenic infection can occur.
Progressive primary disease — After establishing a primary focus of infection in the lung, bacilli can disseminate via the lymphatics and hematogenously (algorithm 1). There is a predilection for spread to the most vascular organs, such as the liver, spleen, bone marrow, and brain. These distant foci usually heal by granulomatous containment over weeks to months as adaptive immunity develops; however, individual lesions harbor viable organisms. Failure of these foci to heal early during primary infection leads to progressive primary disease at these sites. Many adults with progressive TB have underlying medical or iatrogenic conditions that impair the development of effective cell-mediated immunity intended to contain the primary infection.
Reactivation of a viable focus — Miliary TB may result from reactivation of a contained focus of infection with subsequent erosion into adjoining lymphatics or blood vessels, leading to dissemination of viable organisms. Reactivation may occur at any time after the primary infection; commonly, it occurs years or decades later, in association with demonstrable waning of specific immune responses or in the presence of a high-risk condition associated with progressive TB. (See 'Risk factors' above.)
Iatrogenic infection — Rarely, miliary TB may occur as a result of iatrogenic exposure. Disseminated TB has been reported after extracorporeal shock wave lithotripsy [32,33], urethral catheterization [34], and cardiac valve homograft placement [35]. Tuberculosis also has been transmitted by solid organ transplantation [36,37] or insertion of contaminated single-donor bone allograft matrix material containing viable cells and growth factors in spinal/bone surgery [38].
Clinicopathologic patterns of disease — Classically, the clinical and pathologic patterns of miliary TB have been divided into three groups: acute miliary TB, late generalized TB, and anergic (nonreactive) TB. These terms can be confusing because there is considerable overlap among the categories and the terminology is no longer frequently used. Acute miliary TB is primarily a clinical term; this entity can be seen in the immediate post-primary period or in immunocompromised children or adults. It is usually observed within the first two to six months following exposure, although progression may be more rapid in neonates and children under the age of one year [39]. During one TB outbreak in an HIV housing facility in San Francisco, 11 of 30 HIV-infected residents (37 percent) who were exposed to an infectious pulmonary case of TB developed TB disease within 106 days; in one HIV-infected contact, TB was diagnosed within four weeks of exposure [40].
Acute miliary tuberculosis — Acute (generalized) miliary TB has a relatively rapid clinical course [7,41]. Prior to the availability of effective chemotherapy for TB, most cases of acute miliary TB resulted from progressive primary disease. The pathologic hallmark of acute miliary TB is a caseating granulomatous reaction (picture 2), with a smaller number of organisms than other forms of miliary disease [7,41].
Late generalized tuberculosis — Late generalized TB refers to hematogenous spread that occurs after the primary or post-primary period. In one autopsy series of 100 patients with late generalized TB from 1937 to 1959, patients had relatively chronic, clinically nonspecific presentations [42]. In this study, late generalized TB was frequently associated with chronic pulmonary TB. Since the availability of chemotherapy for TB, however, foci responsible for hematogenous spread are extrapulmonary in some cases and are thus more difficult to detect.
A subset of late generalized TB is labeled cryptic miliary TB. This term refers to patients in whom the illness is even more indolent and who may demonstrate an attenuated histologic response [42,43].
Anergic tuberculosis — Anergic TB is defined histologically by the absence of granulomata. In some cases, microabscesses containing large numbers of bacilli with a predominantly neutrophilic response are observed, although, in general, anergic TB is relatively difficult to establish based on histology [44]. Tissue stains and cultures are generally used for diagnosis.
Anergic (nonreactive) TB is a relatively uncommon form of miliary disease. The clinical spectrum ranges from overwhelming sepsis to nonspecific or typhoidal presentations. Most of the described cases are older patients with presumed reactivation TB. Granulomas in immunocompromised patients with TB may share similar characteristics [45].
Host and pathogen factors — The major determinants of TB dissemination include mycobacterial virulence factors and host immune defenses; these are not well defined [46]. The high susceptibility of infants to miliary TB has led some investigators to speculate that the developing immune system may lack critical elements for initiating protective cellular immune responses to M. tuberculosis [21,22]. After initial infection, the development of specific cell-mediated (Type IV) immunity appears to be critical in limiting disseminated disease. Cytokines, including tumor necrosis factor-alpha, interleukin 12 and interferon-gamma, are essential for granuloma development and protective immunity to M. tuberculosis [47,48]. (See "Tuberculosis: Natural history, microbiology, and pathogenesis" and "Immunology of tuberculosis".)
SUMMARY
●Miliary tuberculosis (TB) refers to clinical disease that results from the hematogenous dissemination of Mycobacterium tuberculosis; it affects multiple organs and systems. Miliary TB can arise as a result of progressive primary infection or via reactivation of a previously contained (formerly termed latent) focus with subsequent spread. Miliary TB accounts for approximately 2 percent of incident cases in the United States, with increased representation among infants and young children and in individuals with concomitant immunosuppression. Extrapulmonary TB accounts for approximately 19 percent of cases. (See 'Introduction' above and 'Epidemiology' above.)
●Risk factors for the development of miliary TB include extremes of age and underlying medical conditions. Infants are highly susceptible to miliary TB, presumably due to their relatively immature immune systems. Older adults are also at increased risk for miliary TB due to relative waning of cellular immunity. Underlying medical conditions conferring increased risk for miliary TB include alcohol abuse, malignancy, HIV infection, immunosuppression (including chronic corticosteroid use and biologic agents such as tumor necrosis factor-alpha inhibitors), connective tissue disease, renal failure, diabetes, and pregnancy. (See 'Risk factors' above.)
●After establishing a primary focus of infection in the lung, tuberculous bacilli can disseminate via the lymphatics and hematogenously to the most vascular organs, such as the liver, spleen, bone marrow, and brain. These distant foci usually heal by granulomatous encapsulation over weeks to months. Failure of these foci to heal within the first six months after primary infection leads to progressive primary disease. Healed, viable foci can reactivate at any time after the primary infection; most commonly, reactivation occurs years or decades after primary infection, in association with waning of cellular immune responses or other risk factors. (See 'Mechanisms of disease' above.)
●Acute (generalized) miliary TB has a relatively rapid clinical course. This entity can be seen in the immediate post-primary period or as a result of reactivation of a chronic focus; prior to the availability of anti-TB chemotherapy, most cases resulted from progressive primary disease. The pathologic hallmark of acute miliary TB is a caseating granulomatous reaction. (See 'Acute miliary tuberculosis' above.)
●Late generalized TB refers to hematogenous spread that occurs after the primary or post-primary period. Prior to the availability of effective TB chemotherapy, late generalized TB was frequently associated with chronic pulmonary TB. (See 'Late generalized tuberculosis' above.)
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