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Miliary Tuberculosis: Surendra K. Sharma and Alladi Mohan
Miliary Tuberculosis: Surendra K. Sharma and Alladi Mohan
ABSTRACT Miliary tuberculosis (TB) results from a massive focus (1–5). The term “miliary TB” (derived from the
lymphohematogenous dissemination of Mycobacterium Latin word miliarius, meaning related to millet seed) was
tuberculosis bacilli and is characterized by tiny tubercles
coined by John Jacob Manget (6) in republishing the
evident on gross pathology resembling millet seeds in size and
appearance. The global HIV/AIDS pandemic and widespread use
work of Bonetus (7) in 1700 to describe the resemblance
of immunosuppressive drugs and biologicals have altered the of gross pathological findings to that of innumera-
epidemiology of miliary TB. Considered to be predominantly ble millet seeds in size and appearance (Fig. 1). Tradi-
a disease of infants and children in the pre-antibiotic era, tionally, the miliary pattern on a chest radiograph has
miliary TB is increasingly being encountered in adults as well. been defined as “a collection of tiny discrete pulmonary
The clinical manifestations of miliary TB are protean and opacities that are generally uniform in size and wide-
nonspecific. Atypical clinical presentation often delays the spread in distribution, each of which measures two mm
diagnosis. Clinicians, therefore, should have a low threshold for
or less in diameter” (8). In 10% of the cases, the nodules
suspecting miliary TB. Focused, systematic physical examination
helps in identifying the organ system(s) involved, particularly may be greater than 3 mm in diameter (9).
early in TB meningitis, as this has therapeutic significance. Previously, miliary TB was considered to be a disease
Fundus examination for detecting choroid tubercles offers of infants and children; however, during the last three
a valuable clinical clue for early diagnosis, as their presence decades, it has become increasingly recognized in adults
is pathognomonic of miliary TB. Imaging modalities help in as well. Several factors, such as the emergence of human
recognizing the miliary pattern, defining the extent of organ immunodeficiency virus (HIV) infection, the AIDS pan-
system involvement. Examination of sputum, body fluids,
demic, increasing use of immunosuppressive drugs, the
image-guided fine-needle aspiration cytology or biopsy from
various organ sites, needle biopsy of the liver, bone marrow
effect of bacillus Calmette-Guérin (BCG) vaccination
aspiration, and biopsy should be done to confirm the diagnosis. (resulting a substantial reduction in miliary TB among
Cytopathological, histopathological, and molecular testing young vaccines), increased awareness and use of com-
(e.g., Xpert MTB/RIF and line probe assay), mycobacterial culture, puted tomography (CT), and wider application of in-
and drug susceptibility testing must be carried out as appropriate vasive diagnostic methods, have been responsible for
and feasible. Miliary TB is uniformly fatal if untreated; therefore, this change in the epidemiology of miliary TB (2–5).
early initiation of specific anti-TB treatment can be lifesaving.
Diagnosis of miliary TB requires the presence of
Monitoring for complications, such as acute kidney injury,
air leak syndromes, acute respiratory distress syndrome, adverse
a diffuse miliary infiltrate on a chest radiograph or
drug reactions such as drug-induced liver injury, and drug-drug
interactions (especially in patients coinfected with HIV/AIDS), Received: 1 October 2016, Accepted: 9 January 2017,
is warranted. Published: 10 March 2017
Editor: David Schlossberg, Philadelphia Health Department,
Philadelphia, PA
Citation: Sharma SK, Mohan A. 2017. Miliary tuberculosis. Microbiol
INTRODUCTION Spectrum 5(2):TNMI7-0013-2016. doi:10.1128/microbiolspec
Miliary tuberculosis (TB) is a lethal form of disseminated .TNMI7-0013-2016.
Correspondence: Surendra K. Sharma, sksharma.aiims@gmail.com
TB that results from a massive lymphohematogenous
© 2017 American Society for Microbiology. All rights reserved.
dissemination from a Mycobacterium tuberculosis-laden
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Sharma and Mohan
FIGURE 1 Pearl millet (Pennisetum typhoides) seeds are small grains that have an average
diameter of <2 mm (A, B, and C). These grains (D and E) correspond to the approximate
size of lesions observed in miliary TB on HRCT of the chest.
high-resolution CT (HRCT) or histopathological evi- immunocompetent adults, miliary TB accounts for less
dence of miliary tubercles in tissue specimens obtained than 2% of all cases of TB and up to 20% of all ex-
from multiple organs. The myriad clinical manifesta- trapulmonary TB cases in various clinical studies (10–
tions and atypical radiographic findings often delay the 17). Among HIV-seropositive and immunosuppressed
diagnosis of miliary TB. Not surprisingly, mortality persons, extrapulmonary TB becomes increasingly com-
from miliary TB has remained high despite effective mon as immunosuppression progresses, and in late HIV
therapy being available. infection, extrapulmonary TB accounts for more than
50% of all cases of TB (Fig. 2) (18, 19). Autopsy studies
reveal a higher proportion of miliary TB among adult
EPIDEMIOLOGY TB cases (20–26) (Table 1). Per the U.S. Centers for
Community-based data on the prevalence of miliary TB Disease Control and Prevention (CDC) data (27), during
are lacking. Data derived from clinical series are ham- the period from 2012 to 2014, the prevalence of miliary
pered by factors such as lack of a gold standard for the TB was 349 to 357 cases/year among all reported cases
diagnosis and variation in the nature of invasive methods of TB; miliary TB accounted for 3.5% to 3.8% of all
used for securing tissue to confirm the diagnosis. Au- reported cases of TB and 11.2% to 12.2% of all reported
topsy studies contain few data regarding miliary TB in cases of extrapulmonary TB (Table 2) (27).
children and frequently include patients with advanced
disease or a missed diagnosis. These issues make mean- Age
ingful comparison of data difficult and should be kept In the pre-antibiotic era, miliary TB was predominantly
in mind while interpreting epidemiological data. Among a disease of infants and children (1–5). Currently, two
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Miliary Tuberculosis
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Sharma and Mohan
Value for:
Adults Children
peaks are evident: one involving adolescents and young an important role in the development of miliary TB. A
adults and another among elderly persons (2–5, 10–17, massive lymphohematogenous dissemination of Myco-
28–44). bacterium tuberculosis from a pulmonary or extrapul-
monary focus and embolization to the vascular beds
Gender of various organ systems result in miliary TB. Rarely,
Males seem to be more frequently affected by miliary TB simultaneous reactivation of multiple foci in various
in pediatric as well as adult series (2–5, 10–17, 28–44). organs can also result in miliary TB (Fig. 3) (2–5). When
A few recent adult series on miliary TB (14, 26, 34, 37) miliary TB develops during the course of primary dis-
describe a female preponderance, probably reflecting in- ease (early generalization), the disease has an acute onset
creased awareness and use of health services by women. and is rapidly progressive. During post-primary TB, late
generalization can be rapidly progressive (acute miliary
Ethnicity TB), episodic, or protracted (chronic miliary TB).
In the United States, a higher incidence of miliary TB Occasionally, discharge of caseous material from an
has been described for black Americans in some of the extrapulmonary site can result in miliary TB. If the ca-
earlier publications, though such a trend is not evident seous material is discharged into the portal circulation,
from recent data (2–5, 30, 38). Whether this is due to hepatic involvement occurs initially, with the classical
ethnic variation alone or is the consequence of host ge- pulmonary involvement becoming evident late (2–5). In
netic factors or because of other factors, such as socio- neonates, hematogenous spread from infected placenta
economic and nutritional status and comorbid illnesses, through the umbilical vein or aspiration of amniotic
needs further study. fluid in utero can cause congenital TB; miliary TB is a
common manifestation of congenital TB. Miliary TB
may also develop in neonates as a result of acquisition
PATHOGENESIS of infection during the perinatal period through aspira-
Miliary TB can develop either at the time of primary in- tion and ingestion of infected maternal genital tissues
fection or later, during reactivation of a dormant focus. and fluid and subsequent hematogenous dissemination.
In areas where TB is endemic, with increased transmis-
sion of Mycobacterium tuberculosis, reinfection also has Predisposing Conditions
Several predisposing or associated conditions that have
been described for patients with miliary TB are detailed
Q4 TABLE 2 Proportions of miliary TB cases among all in Table 3 (2–5).
reported TB cases and extrapulmonary TB cases in the
United States, 2012 to 2014a Iatrogenic Dissemination
No. of cases of No. of cases of miliary Use of certain drugs (45–48) and several procedures and
miliary TB/no. of TB/no. of all extrapulmonary interventions (49–53) have been implicated in facilitat-
Yr all TB cases (%) TB cases (%) ing hematogenous dissemination and the causation of
2012 349/9,945 (3.5) 349/3,116 (11.2) iatrogenic miliary TB (Table 4). Corticosteroids and im-
2013 353/9,582 (3.7) 353/2,889 (12.2) munosuppressive and cytotoxic drugs are increasingly
2014 357/9,421 (3.8) 357/2,916 (12.2) being used for the treatment of connective tissue dis-
Data are from reference 27.
a orders and in organ transplant recipients. Miliary TB
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Miliary Tuberculosis
FIGURE 3 The development of miliary TB. Small droplet nuclei (1 to 5 μm) containing Mycobacterium tuberculosis get deposited
in the alveoli (1), where host-pathogen interactions occur. Seventy percent of individuals exposed do not get infected (2), whereas
30% develop infection (3). Infection is contained in 90% of those infected (latent TB infection) (4). The remaining 10% develop
progressive primary TB (5). During this phase, extensive lymphohematogenous dissemination (6) to various organs can result in
miliary TB. People with latent TB infection have a 10% lifetime risk of reactivation of the infection, resulting in post-primary TB (7).
Fifty percent of reactivations occur during the first 2 years of primary infection. In contrast, in HIV-infected individuals with latent
TB infection, the risk of reactivation is enormously high (approximately 10%/year). Massive lymphohematogenous dissemination
during reactivation (8) can also result in miliary TB (progressive post-primary miliary TB). In areas with high transmission rates,
reinfection with a new strain of Mycobacterium tuberculosis (9) can occur and the cycle is repeated. *, important in areas of
endemicity; †, organ-restricted TB with adequate host immunity. MTB, miliary TB; TNF, tumor necrosis factor. Reproduced with
permission from reference 2.
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TABLE 3 Conditions predisposing to or associated with infection becomes latent or progressive (2, 55, 56). In-
miliary TB adequate T-cell response, particularly at the pathologic
Childhood infections
site(s), is believed to depend on the host immunoregu-
Malnutrition
latory mechanisms. Thus, Mycobacterium tuberculo-
HIV/AIDS sis can either fail to evoke the protective response or
Alcoholism drive the protective mechanisms and then deliberately
Tobacco smoking “sabotage” them, leading to progressive disease (2, 55–
Diabetes mellitus 58).
Chronic kidney disease, dialysis Regulatory T cells (Treg cells) are thought to play a
Postsurgery (e.g., gastrectomya) critical role in the immunopathogenesis of miliary TB
Organ transplantation by suppression of the effector immune response against
Connective tissue disorders
Mycobacterium tuberculosis at the pathologic site(s).
Pregnancy, postpartum
Increases in the frequency of Treg cells (CD4+ CD25+
Underlying malignancy
FoxP3+) and FoxP3 mRNA levels at the local disease site
Silicosis
in miliary TB have been described (58). Furthermore,
Predisposes to TB in general.
a
FoxP3+ Treg cells in bronchoalveolar lavage (BAL) fluid
from patients with miliary TB predominantly produced
interleukin-10 and suppressed the autologous T-cell
can develop as a consequence of their use (2–5). Fatal proliferation in response to Mycobacterium tuberculosis
TB, including miliary TB, has been described for patients antigen (57).
with rheumatoid arthritis who were treated with im- In miliary TB, the attempt by the host to selectively
munomodulator drugs, such as the anti-tumor necrosis recruit the Teff cells at the pathologic site fails to provide
factor agents infliximab (48, 54), etanercept (47), and an adequate level of effector immunity at the disease
adalimumab (46). A report from the British Society for site due to efficient and comparable homing of Treg
Rheumatology Biologics Register national prospective cells (FoxP3+), which inhibit the function of the Teff
observational study (45) among rheumatoid arthritis cells that have infiltrated at the pathologic disease site.
patients indicates a higher rate of development of TB This probably leads to a state of local immunosuppres-
with adalimumab (144 events/100,000 person years) and sion and dissemination of disease (2, 57, 58).
infliximab (136/100,000 person years) than etanercept
(39/100,000 person years). The median time to devel- Molecular Basis of Dissemination
opment of TB was lower for infliximab (5.5 months) Several molecular mechanisms have been implicated in
than for etanercept (13.4 months) and adalimumab the development of miliary TB. These include impaired
(18.5 months). Extrapulmonary TB constituted 25 of expansion of γ/δ T cells (59); failure to generate adequate
the 40 (62%) cases; 11 cases (27.5% of all TB cases and cell-mediated immunity (60); the presence of HLA-Bw15
44% of extrapulmonary TB cases) were disseminated (61), HLA-DRB1*15/16, DRB1*13, and DQB1*0602
and miliary TB (45).
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(62); the absence of HLA-Cw6, HLA-DRB1*10, and blood vessel is usually demonstrable, and the lesions
DQB1*0501 (62); impaired major histocompatibility often reveal acid-fast bacilli (AFB). When the dissemi-
complex class II-restricted target cell lysis; and over- nation is due to the discharge of bacilli into microscopic
exuberant lysis of target cell macrophages (63) and blood vessels within the caseous lesions, which, in turn,
LTA+368 G/A polymorphisms (64). seed large vessels, the acute soft lesions are found to be
admixed with “hard” tubercles. The AFB are seldom
demonstrable in these hard lesions (1–5). When acute
PATHOLOGY respiratory distress syndrome (ARDS) develops due to
The frequency of organ involvement at autopsy is shown miliary TB, hyaline membranes are present in addition
in Table 5 (21, 25, 28, 31–33, 40). Organs with a high to the cellular infiltrate. Occasionally, vasculitic lesions
blood flow, such as the spleen, liver, lungs, bone mar- can be discerned in miliary TB patients with TB men-
row, kidneys, and adrenals, are frequently affected. ingitis. Choroidal tubercles, when present, are patho-
On gross examination, small, punctate, gray to reddish gnomonic of miliary TB (see below). They are multiple in
brown, rounded lesions of more or less uniform size number and are usually evident in both eyes, mostly in
may be seen in the lungs and various other organs. The the posterior pole. As the acute infection resolves, the
“tubercle” constitutes the histopathological hallmark center of the choroidal tubercles may become white
of miliary TB. When miliary TB is the result of acute or yellow, with a surrounding peripheral rim of pig-
massive hematogenous dissemination, the lesions in all mentation; the margins become sharply delineated and
viscera appear similar (“soft” or “exudative” tubercles) distinct. Subsequently, an atrophic scar may develop.
(2–5, 65, 66); an obvious caseous focus invading the Rarely, infective endocarditis, pericarditis, intracardiac
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of miliary TB (1–5, 42). Thus, systematic ophthalmo- TABLE 9 Laboratory abnormalities in miliary TB
scopic examination after mydriatic administration must
Hematological Biochemical
be done in every suspected patient with miliary TB to
Anemia Hyponatremia
look for this valuable clue to the diagnosis (1–5, 42).
Leukocytosis Hypoalbuminemia
Neutrophilia Hyperbilirubinemia
Sputum, Body Fluid, and Tissue Examination Lymphocytosis Elevated transaminases
For patients with suspected miliary TB, attempts must be Monocytosis Elevated serum alkaline phosphatase
made to confirm histopathological microbiological di- Thrombocytosis Hypercalcemia
agnosis. Sputum, other body fluids (such as pleural fluid, Leukopenia Hypophosphatemia
pericardial fluid, ascitic fluid, cerebrospinal fluid, joint Lymphopenia Elevated serum ferritin levels
fluid, pus from cold abscess, and endometrial aspirate), Thrombocytopenia
urine, bronchoscopic secretions, blood, and tissue bi- Leukemoid reaction
opsy specimens have all been employed to confirm the Hemophagocytosis
Elevated ESRa and CRPb levels
diagnosis of disseminated and miliary TB, with various
results. For patients with miliary TB, relative diagnostic a ESR, erythrocyte sedimentation rate.
CRP, C-reactive protein.
yield with the conventional microbiological methods
b
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A positive IGRA result, however, does not distinguish proportion and absolute number of lymphocytes are
between latent TB infection and active disease, but a substantially increased in BAL fluid. Although a raised
negative IGRA result may be helpful in ruling out a di- CD4+ CD8+ T-lymphocyte ratio and B lymphocytes were
agnosis of TB (106). reported for BAL fluid in one study (108), a decrease in
CD4+ CD8+ T-lymphocyte ratio was reported in another
Pulmonary Function and Gas Exchange (110). The small number of patients studied could partly
Abnormalities be the reason for these differences. Polyclonal hyper-
Miliary TB is associated with abnormalities of pulmo- gammaglobulinemia with increases in immunoglobulin
nary function typical of interstitial lung disease, and G (IgG), IgA, and IgM was observed in peripheral blood
these may be of a greater magnitude than might be and BAL fluid in one study (108). These findings prob-
anticipated from the chest radiograph (107–109). Im- ably result from increased local synthesis by activated B
pairment of diffusion is the most common abnormality lymphocytes. Increased BAL fluid fibronectin and serum
and may sometimes be severe (109, 110). Other abnor- C3 levels as acute-phase response to ongoing inflam-
malities include a mild reduction in flow rates sugges- mation were observed (108, 114). Lymphocytic alveo-
tive of peripheral airway involvement (110). During the litis and increased IgG and IgA levels persisted following
acute stage, arterial hypoxemia due to widening of the anti-TB treatment (108).
alveolar-arterial oxygen gradient and hypocapnia due to
tachypnea are also observed (111). Imaging Studies
A miliary pattern on the chest radiograph is often the
Cardiopulmonary Exercise Testing first clue suggestive of miliary TB. Several other imaging
Patients with miliary TB have abnormal cardiopulmo- modalities, such as ultrasonography, CT, and magnetic
nary exercise performance with lower maximum oxygen resonance imaging (MRI), help to discern the extent of
consumption, maximal work rate, anaerobic threshold, organ involvement and are also useful in evaluation of
peak minute ventilation, breathing reserve, and low max- response to treatment.
imal heart rate (2–5, 98, 111, 112). Other abnormalities
include higher respiratory frequency, peak minute ven- Chest radiograph
tilation at submaximal work, and high physiological A miliary pattern on chest radiograph (1–5, 8) is the
dead space/tidal volume. A demonstrable fall in oxygen classical feature of miliary TB and is observed for a
saturation (to 4% or more) with exercise has been ob- majority of patients. Subtle miliary lesions are best de-
served. Following successful anti-TB treatment, these lineated in slightly underpenetrated films, especially
abnormalities had reversed in most of the patients, when the diamond-shaped areas of the lung in between
though they persisted in some of them (111, 112). the ribs are carefully scrutinized using bright light (9,
115). The chest radiographic abnormalities in miliary
Immunological Abnormalities and BAL Fluid TB are listed in Table 10 (2–5, 98). Some patients may
A few reports on the cellular characteristics of BAL fluid have normal chest radiographs initially and the classical
in patients with miliary TB have been published, and miliary pattern may evolve over the course of the disease
these have shown conflicting results (18, 110, 113). The (Fig. 5), emphasizing the importance of periodic repeat
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Miliary Tuberculosis
FIGURE 5 (A) Chest radiograph (postero-anterior view) for a 30-year-old woman who
presented with a 3-month history of fever with no other localizing clue. (B) HRCT of
the same patient showing a classical miliary pattern. Bone marrow biopsy confirmed
the diagnosis of miliary TB; Mycobacterium tuberculosis was grown on bronchoscopic
aspirate culture.
chest radiographic examination in patients with pyrexia times be loculated), focal hepatic and splenic lesions, and
of unknown origin (2–5, 42). cold abscess. Ultrasonography guidance also facilitates
When patients with miliary TB develop ARDS (Fig. 6), diagnostic thoracic or abdominal paracentesis to pro-
the chest radiograph findings may be identical to those cure pleural or peritoneal fluid for diagnostic testing,
seen in ARDS due to other causes (83, 85). The majority especially if the fluid is loculated.
of the patients (88%) in the study reported by Sharma
et al. (42) had chest radiographs consistent with miliary
TB; in some, these classical radiographic changes evolved
FIGURE 6 Chest radiograph (antero-posterior view, done
over the course of the disease. The diagnosis of miliary bedside with a portable machine) showing bilateral frontal
TB is easier when the patient presents with classical mil- opacities and airspace consolidation suggestive of ARDS
iary shadowing on chest radiograph in an appropriate in a HIV-seropositive patient with miliary TB. Tracheal aspi-
setting. However, the diagnosis may be difficult in situa- rate smear for AFB and bone marrow biopsy confirmed the
tions in which chest radiograph does not show classical diagnosis.
miliary shadows.
In the pre-CT scan era, for up to 50% of the patients,
the classical miliary pattern would not be discernible
on the chest radiograph, being evident only at the time
of autopsy (21, 24, 25, 30, 38, 115, 116). Steiner (115)
reasoned that when caseous material, collagen, or both
were present in the tubercles, they became visible on
the chest radiograph. The classical miliary pattern on the
chest radiograph represents a summation of densities
of the tubercles that are perfectly aligned; imperfectly
aligned tubercles result in curvilinear densities and a
reticulonodular pattern (117). Rarely, lymphatic ob-
struction or infiltration can result in a ground-glass ap-
pearance (118).
Ultrasonography
Ultrasonography helps in detecting associated lesions
such as ascites and pleural effusion (which may some-
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Sharma and Mohan
Computed tomography and magnetic and biopsy under CT or MRI guidance, are useful for
resonance imaging procuring tissue and body fluids for diagnostic testing.
HRCT and thin-section multidetector row CT have con-
siderably improved the antemortem diagnosis of mili- Echocardiography
ary pattern. HRCT reveals a mixture of both sharply Two-dimensional transthoracic echocardiography helps
and poorly defined, <2-mm nodules that are widely dis- to diagnose associated pericardial effusion.
seminated throughout the lungs, associated with diffuse
reticulation (119, 120). HRCT may reveal a classical Bronchoscopy
miliary pattern, even when the chest radiograph looks Fiberoptic bronchoscopy, BAL fluid, bronchoscopic as-
apparently normal (2–5, 42), and also facilitates iden- pirate, brushings, and transbronchial lung biopsy speci-
tification of intrathoracic lymphadenopathy, calcifica- mens are useful in confirming the diagnosis of miliary
tion, and pleural lesions. Air trapping has been described TB. The cumulative diagnostic yield for various bron-
on HRCT both at presentation and during follow- choscopic specimens by smear and culture methods in
up (120) and occurs due to endobronchial involvement published studies has been found to be 46.8% (Table 8)
of peripheral airways. The interlobular septal thicken- (29, 35, 36, 40, 42, 124, 125).
ing or intralobular fine network that is evident on
HRCT in miliary TB seems to be caused by the caseation Laparoscopy
necrosis in the alveolar walls and interlobular septa. When associated abdominal involvement is present,
Sometimes in subjects with active postprimary disease, laparoscopy provides an opportunity to visualize the
centrilobular nodules and branching linear structures lesions with the naked eye and facilitates biopsy from
giving a “tree-in-bud appearance” may be evident (119, the liver, peritoneum, omentum, and mesenteric lymph
120). nodes for diagnostic confirmation (126).
Pipavath et al. (121), in a recent publication, reported
the following changes on HRCT in patients with miliary Serodiagnostic, Molecular,
TB (n = 16): miliary pattern (n = 16); intrathoracic and Other Methods
lymphadenopathy (n = 8); alveolar lesions, such as Detection of mycobacterial antigens, antibodies, and
ground-glass attenuation and/or consolidation (n = 5); immune complexes in the blood and body fluids by en-
pleural and pericardial effusions (2 patients each); and zyme-linked immunosorbent assay has been used for di-
peribronchovascular interstitial thickening and emphy- agnosis of miliary TB; however, these methods are not
sema (1 patient each). In that study (121), nodules were being used currently (2–5). PCR of cerebrospinal fluid,
randomly distributed in both lung fields in miliary TB, tissue biopsy specimens, and blood (especially from HIV-
whereas in sarcoidosis, the findings included peribron- infected patients) may be useful for confirmation of di-
chovascular interstitial thickening and perilymphatic agnosis (18). The Xpert MTB/RIF (Cepheid, Sunnyvale,
distribution of the nodules (122). A higher prevalence CA), a cartridge-based nucleic acid amplification test,
of interlobular septal thickening, necrotic lymph nodes, has been found to be useful in the early diagnosis of
and extrathoracic involvement has also been observed in pulmonary (3–5) and extrapulmonary (127) TB and can
HIV-seropositive patients with miliary TB (122). detect the presence of Mycobacterium tuberculosis com-
MRI and CT have been useful in identifying miliary plex and provide information regarding rifampin re-
lesions at extrapulmonary sites. Abdominal CT has been sistance in 90 min. Line probe assays facilitate rapid
useful in identifying lesions in the liver and spleen, detection of Mycobacterium tuberculosis and mutations
lymphadenopathy, and cold abscesses (2–5). Unlike the associated with resistance to rifampin, isoniazid, and
CT of the chest, in which the classical <2-mm nodular second-line anti-TB drugs in under 24 h. Adenosine de-
lesions are evident, miliary lesions in the liver and spleen aminase and interferon gamma level estimations in as-
may appear as discrete hypodense lesions, a few of citic fluid and pleural fluid can be helpful in confirming
which may be confluent, sometimes with irregular pe- the diagnosis of TB (128–132).
ripheral rim enhancement (123). MRI of the brain and
spine is very useful in the initial evaluation and follow- Positron Emission Tomography
up of miliary TB patients with TBM or spinal TB and Positron emission tomography CT (PET-CT) using the
also protects from radiation exposure (2–5). radiopharmaceutical 18F-labeled 2-deoxy-D-glucose has
Image-guided radiological procedures, such as fine- been found to be useful to assess the activity of various
needle aspiration for cytological examination (FNAC) infectious lesions, including pulmonary TB (133, 134).
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Miliary Tuberculosis
FIGURE 7 Chest radiograph (poster-anterior view) (A) and chest CT (lung window) (B and
C) showing predominance of miliary lesions on the right side. (D) 18F-labeled 2-deoxy-
D-glucose PET-CT of the same patient showing increased activity in the coalesced pul-
monary lesions, which is evident more prominently on the right side. Reproduced with
permission from reference 4.
The utility of PET-CT in assessing the activity of lesions observed treatment using short-course chemotherapy
(Fig. 7) that might persist following anti-TB treatment in (135, 136). However, there are no published random-
miliary TB needs to be studied further. ized controlled trials assessing the efficacy of the stan-
The algorithm for the workup of a patient suspected dard World Health Organization (WHO) treatment
to have miliary TB is shown in Fig. 8. regimens (135, 136) that are widely used in national TB
control programs worldwide. Even less is known re-
garding the efficacy of standard treatment regimens in
TREATMENT the treatment of HIV and miliary TB coinfection.
Miliary TB is uniformly fatal if not treated (1–5). Stan- The American Thoracic Society, CDC, and Infectious
dard anti-TB treatment is the cornerstone of manage- Disease Society of America (137) guidelines, National
ment. There is no consensus regarding the optimum Institute for Health and Clinical Excellence (138) guide-
duration of treatment in patients with miliary TB. In lines, and the 2015 report of the Committee on Infec-
several parts of the world, patients with miliary TB get tious Diseases, American Academy of Pediatrics (AAP)
treated under national TB control program, with directly (139) from the United Kingdom recommend 6 months
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Sharma and Mohan
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Miliary Tuberculosis
of treatment (2-month intensive phase with isoniazid, ri- bility testing (DST) be obtained from all previously
fampin, pyrazinamide, and ethambutol or streptomycin, treated TB patients at or before at the start of treat-
followed by a 4-month continuation phase with isonia- ment. DST should be performed for at least isoniazid
zid and rifampin) for newly diagnosed cases of miliary TB and rifampin, and in settings where rapid molecular
without meningeal involvement. DSTs are available, the DST results should guide the
In the WHO guidelines for the treatment of TB (136), choice of regimen. Although this duration of treatment
patients are categorized as “new patients” or “previ- may be sufficient for many, each patient needs to be
ously treated patients.” In these guidelines (136), miliary assessed individually, and wherever indicated, treatment
TB is classified as pulmonary TB because there are le- duration may have to be extended.
sions in the lungs. New patients with miliary TB receive The evidence-based INDEX-TB guidelines (127) ad-
6 months of daily or intermittent treatment as described vocate treatment for at least 9 months when TBM is
above. The current WHO policy (140) suggests that present, and other guidelines (136–138) suggest that
HIV-coinfected patients with TB and all TB patients in treatment be extended for 12 months. When TB menin-
HIV-prevalent settings should receive daily treatment gitis is present, the recent AAP Committee on Infectious
during both the intensive and the continuation phases Diseases recommendations advocate an initial intensive
Q2 (strong recommendation, high-quality evidence). For phase with isoniazid, rifampin, pyrazinamide, and ethi-
previously treated patients, the WHO guidelines (136) onamide [or an aminoglycoside (in place of ethambu-
advocate that specimens for culture and drug suscepti- tol)] for 2 months, followed by a continuation phase
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Sharma and Mohan
< 30 g/liter), hypocholesterolemia (serum cholesterol < 2.33 mmol/liter), and severe lymphocytopenia (<7 × 105 cells/liter). Each risk factor was assigned a value of 1 if present or
0 if absent. Patients with 3 or 4 points were classified as having a high nutritional risk score.
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is not effective in individuals who have latent TB infec- 20. Ansari NA, Kombe AH, Kenyon TA, Hone NM, Tappero JW,
tion and should not be administered to immunosup- Nyirenda ST, Binkin NJ, Lucas SB. 2002. Pathology and causes of death
in a group of 128 predominantly HIV-positive patients in Botswana,
pressed hosts. Targeted tuberculin testing is practiced 1997–1998. Int J Tuberc Lung Dis 6:55–63.
in countries with a low prevalence of TB, such as the 21. Chapman CB, Whorton CM. 1946. Acute generalised miliary tuber-
United States (137, 147), but anti-TB drug-induced culosis in adults. A clinicopathological study based on sixty three cases
hepatotoxicity is a potential risk with the treatment of diagnosed at autopsy. N Engl J Med 235:239–248.
22. Jacques J, Sloan JM. 1970. The changing pattern of miliary tubercu-
latent TB infection. Ongoing research (148, 149) has yet losis. Thorax 25:237–240.
to provide a more effective vaccine than BCG. 23. Jagirdar J, Zagzag D. 2004. Pathology and insights into pathogenesis
of tuberculosis, p 323–344. In Rom WN, Garay SM (ed), Tuberculosis.
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