Miliary Tuberculosis
SURENDRA K. SHARMA1 and ALLADI MOHAN2
1
Division of Infectious Diseases, Department of Medicine, All India Institute of Medical Sciences,
New Delhi 110 029, India; 2Division of Pulmonary and Critical Care Medicine,
Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati 517 507, India
ABSTRACT Miliary tuberculosis (TB) results from a massive
lymphohematogenous dissemination of Mycobacterium
tuberculosis bacilli and is characterized by tiny tubercles
evident on gross pathology resembling millet seeds in size and
appearance. The global HIV/AIDS pandemic and widespread use
of immunosuppressive drugs and biologicals have altered the
epidemiology of miliary TB. Considered to be predominantly
a disease of infants and children in the pre-antibiotic era,
miliary TB is increasingly being encountered in adults as well.
The clinical manifestations of miliary TB are protean and
nonspecific. Atypical clinical presentation often delays the
diagnosis. Clinicians, therefore, should have a low threshold for
suspecting miliary TB. Focused, systematic physical examination
helps in identifying the organ system(s) involved, particularly
early in TB meningitis, as this has therapeutic significance.
Fundus examination for detecting choroid tubercles offers
a valuable clinical clue for early diagnosis, as their presence
is pathognomonic of miliary TB. Imaging modalities help in
recognizing the miliary pattern, defining the extent of organ
system involvement. Examination of sputum, body fluids,
image-guided fine-needle aspiration cytology or biopsy from
various organ sites, needle biopsy of the liver, bone marrow
aspiration, and biopsy should be done to confirm the diagnosis.
Cytopathological, histopathological, and molecular testing
(e.g., Xpert MTB/RIF and line probe assay), mycobacterial culture,
and drug susceptibility testing must be carried out as appropriate
and feasible. Miliary TB is uniformly fatal if untreated; therefore,
early initiation of specific anti-TB treatment can be lifesaving.
Monitoring for complications, such as acute kidney injury,
air leak syndromes, acute respiratory distress syndrome, adverse
drug reactions such as drug-induced liver injury, and drug-drug
interactions (especially in patients coinfected with HIV/AIDS),
is warranted.
INTRODUCTION
Miliary tuberculosis (TB) is a lethal form of disseminated
TB that results from a massive lymphohematogenous
dissemination from a Mycobacterium tuberculosis-laden
ASMscience.org/MicrobiolSpectrum
focus (1–5). The term “miliary TB” (derived from the
Latin word miliarius, meaning related to millet seed) was
coined by John Jacob Manget (6) in republishing the
work of Bonetus (7) in 1700 to describe the resemblance
of gross pathological findings to that of innumera-
ble millet seeds in size and appearance (Fig. 1). Tradi-
tionally, the miliary pattern on a chest radiograph has
been defined as “a collection of tiny discrete pulmonary
opacities that are generally uniform in size and wide-
spread in distribution, each of which measures two mm
or less in diameter” (8). In 10% of the cases, the nodules
may be greater than 3 mm in diameter (9).
Previously, miliary TB was considered to be a disease
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of infants and children; however, during the last three
decades, it has become increasingly recognized in adults
as well. Several factors, such as the emergence of human
immunodeficiency virus (HIV) infection, the AIDS pan-
demic, increasing use of immunosuppressive drugs, the
effect of bacillus Calmette-Guérin (BCG) vaccination
(resulting a substantial reduction in miliary TB among
young vaccines), increased awareness and use of com-
puted tomography (CT), and wider application of in-
vasive diagnostic methods, have been responsible for
this change in the epidemiology of miliary TB (2–5).
Diagnosis of miliary TB requires the presence of
a diffuse miliary infiltrate on a chest radiograph or
Received: 1 October 2016, Accepted: 9 January 2017,
Published: 10 March 2017
Editor: David Schlossberg, Philadelphia Health Department,
Philadelphia, PA
Citation: Sharma SK, Mohan A. 2017. Miliary tuberculosis. Microbiol
Spectrum 5(2):TNMI7-0013-2016. doi:10.1128/microbiolspec
.TNMI7-0013-2016.
Correspondence: Surendra K. Sharma, sksharma.aiims@gmail.com
© 2017 American Society for Microbiology. All rights reserved.
1
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.

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high-resolution CT (HRCT) or histopathological evi-
dence of miliary tubercles in tissue specimens obtained
from multiple organs. The myriad clinical manifesta-
tions and atypical radiographic findings often delay the
diagnosis of miliary TB. Not surprisingly, mortality
from miliary TB has remained high despite effective
therapy being available.
EPIDEMIOLOGY
Community-based data on the prevalence of miliary TB
are lacking. Data derived from clinical series are ham-
pered by factors such as lack of a gold standard for the
diagnosis and variation in the nature of invasive methods
used for securing tissue to confirm the diagnosis. Au-
topsy studies contain few data regarding miliary TB in
children and frequently include patients with advanced
disease or a missed diagnosis. These issues make mean-
ingful comparison of data difficult and should be kept
in mind while interpreting epidemiological data. Among
immunocompetent adults, miliary TB accounts for less
than 2% of all cases of TB and up to 20% of all ex-
trapulmonary TB cases in various clinical studies (10–
17). Among HIV-seropositive and immunosuppressed
persons, extrapulmonary TB becomes increasingly com-
mon as immunosuppression progresses, and in late HIV
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
TB cases (20–26) (Table 1). Per the U.S. Centers for
Disease Control and Prevention (CDC) data (27), during
the period from 2012 to 2014, the prevalence of miliary
TB was 349 to 357 cases/year among all reported cases
of TB; miliary TB accounted for 3.5% to 3.8% of all
reported cases of TB and 11.2% to 12.2% of all reported
cases of extrapulmonary TB (Table 2) (27).
Age
In the pre-antibiotic era, miliary TB was predominantly
a disease of infants and children (1–5). Currently, two

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FIGURE 2 Distribution of tuberculosis cases by anatomical site in immunocompetent

(A) and immunosuppressed (B) adults. PTB, pulmonary TB; EPTB, extrapulmonary TB;
GUTB, genitourinary TB; DTB, disseminated TB; MTB, miliary TB; ABD, abdominal TB;
LNTB, lymph node TB. Reproduced with permission from reference 18.

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 Sharma and Mohan

TABLE 1 Epidemiology of miliary TB

Value for:

Adults Children

Frequency of miliary TB Autopsy studiesa Clinical studiesb Clinical studiesc

Overall (%) 0.3–13.3 1.3–2.0 0.7–41.3
Among TB cases (%) 11.9–40.5 0.64–6.0 1.3–3.2
Among EPTBd cases (%) 2.9–20
aData from references 20 to 26.
bData from references 10, 12, 14, and 15.
cData from references 11 to 13, 16, and 17.

dEPTB, extrapulmonary TB.

peaks are evident: one involving adolescents and young
adults and another among elderly persons (2–5, 10–17,
28–44).
Gender
Males seem to be more frequently affected by miliary TB
in pediatric as well as adult series (2–5, 10–17, 28–44).
A few recent adult series on miliary TB (14, 26, 34, 37)
describe a female preponderance, probably reflecting in-
creased awareness and use of health services by women.
Ethnicity
In the United States, a higher incidence of miliary TB
has been described for black Americans in some of the
earlier publications, though such a trend is not evident
from recent data (2–5, 30, 38). Whether this is due to
ethnic variation alone or is the consequence of host ge-
an important role in the development of miliary TB. A
massive lymphohematogenous dissemination of Myco-
bacterium tuberculosis from a pulmonary or extrapul-
monary focus and embolization to the vascular beds
of various organ systems result in miliary TB. Rarely,
simultaneous reactivation of multiple foci in various
organs can also result in miliary TB (Fig. 3) (2–5). When
miliary TB develops during the course of primary dis-
ease (early generalization), the disease has an acute onset
and is rapidly progressive. During post-primary TB, late
generalization can be rapidly progressive (acute miliary
TB), episodic, or protracted (chronic miliary TB).
Occasionally, discharge of caseous material from an
extrapulmonary site can result in miliary TB. If the ca-
seous material is discharged into the portal circulation,
hepatic involvement occurs initially, with the classical
pulmonary involvement becoming evident late (2–5). In

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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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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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Sharma and Mohan
TABLE 3 Conditions predisposing to or associated with
miliary TB
Childhood infections
Malnutrition
HIV/AIDS
Alcoholism
Tobacco smoking
Diabetes mellitus
Chronic kidney disease, dialysis
Postsurgery (e.g., gastrectomya)
Organ transplantation
Connective tissue disorders
Pregnancy, postpartum
Underlying malignancy
Silicosis
Predisposes to TB in general.
a
can develop as a consequence of their use (2–5). Fatal
TB, including miliary TB, has been described for patients
with rheumatoid arthritis who were treated with im-
munomodulator drugs, such as the anti-tumor necrosis
factor agents infliximab (48, 54), etanercept (47), and
adalimumab (46). A report from the British Society for
Rheumatology Biologics Register national prospective
observational study (45) among rheumatoid arthritis
patients indicates a higher rate of development of TB
with adalimumab (144 events/100,000 person years) and
infliximab (136/100,000 person years) than etanercept
(39/100,000 person years). The median time to devel-
opment of TB was lower for infliximab (5.5 months)
than for etanercept (13.4 months) and adalimumab
(18.5 months). Extrapulmonary TB constituted 25 of
the 40 (62%) cases; 11 cases (27.5% of all TB cases and
44% of extrapulmonary TB cases) were disseminated
and miliary TB (45).
Immunopathogenesis
The inadequacy of effector T-cell (Teff cell) response in
containment of Mycobacterium tuberculosis is thought
to be responsible for the development of miliary TB (55–
58). Although both Th1 and Th2 responses are inflam-
matory reactions, Th1 reactions characterize protective
immunity and Th2 reactions seem to have a counter-
regulatory effect. Miliary TB probably represents the
Th2 end of the spectrum. The abundance of Th1 and
Th2 polarized Teff cells in the peripheral blood and local
disease site(s) among patients with miliary TB has been
described (57, 58). Interleukin-4, with its ability to
downregulate inducible nitric oxide synthase, Toll-like
receptor 2, and macrophage activation, may play an
important role in the events that determine whether the
6 ASMscience.org/MicrobiolSpectrum
infection becomes latent or progressive (2, 55, 56). In-
adequate T-cell response, particularly at the pathologic
site(s), is believed to depend on the host immunoregu-
latory mechanisms. Thus, Mycobacterium tuberculo-
sis can either fail to evoke the protective response or
drive the protective mechanisms and then deliberately
“sabotage” them, leading to progressive disease (2, 55–
58).
Regulatory T cells (Treg cells) are thought to play a
critical role in the immunopathogenesis of miliary TB
by suppression of the effector immune response against
Mycobacterium tuberculosis at the pathologic site(s).
Increases in the frequency of Treg cells (CD4+ CD25+
FoxP3+) and FoxP3 mRNA levels at the local disease site
in miliary TB have been described (58). Furthermore,
FoxP3+ Treg cells in bronchoalveolar lavage (BAL) fluid
from patients with miliary TB predominantly produced
interleukin-10 and suppressed the autologous T-cell
proliferation in response to Mycobacterium tuberculosis
antigen (57).
In miliary TB, the attempt by the host to selectively
recruit the Teff cells at the pathologic site fails to provide
an adequate level of effector immunity at the disease
site due to efficient and comparable homing of Treg
cells (FoxP3+), which inhibit the function of the Teff
cells that have infiltrated at the pathologic disease site.
This probably leads to a state of local immunosuppres-
sion and dissemination of disease (2, 57, 58).
Molecular Basis of Dissemination
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Several molecular mechanisms have been implicated in
the development of miliary TB. These include impaired
expansion of γ/δ T cells (59); failure to generate adequate
cell-mediated immunity (60); the presence of HLA-Bw15
(61), HLA-DRB1*15/16, DRB1*13, and DQB1*0602
TABLE 4 Iatrogenic causes of miliary TBa
Drugs
Corticosteroids
Immunosuppressive and cytotoxic drugs
Immunomodulator drugs (e.g., infliximab, etanercept, and
adalimumab)
Procedures and interventions
Ureteral catheterizationb
Extracorporeal shockwave lithotripsyc
Laser lithotripsyc
Cardiac valve homograft replacementd
Intravesical BCG therapy for urinary bladder carcinoma
aData are from references 45 to 53.
bPredisposes to TB in general.
cPatient had undiagnosed genitourinary TB.
dContamination of homografts probably occurred at the time of harvest from
cadavers.
 Miliary Tuberculosis

(62); the absence of HLA-Cw6, HLA-DRB1*10, and
DQB1*0501 (62); impaired major histocompatibility
complex class II-restricted target cell lysis; and over-
exuberant lysis of target cell macrophages (63) and
LTA+368 G/A polymorphisms (64).
PATHOLOGY
The frequency of organ involvement at autopsy is shown
in Table 5 (21, 25, 28, 31–33, 40). Organs with a high
blood flow, such as the spleen, liver, lungs, bone mar-
row, kidneys, and adrenals, are frequently affected.
On gross examination, small, punctate, gray to reddish
brown, rounded lesions of more or less uniform size
may be seen in the lungs and various other organs. The
“tubercle” constitutes the histopathological hallmark
of miliary TB. When miliary TB is the result of acute
massive hematogenous dissemination, the lesions in all
viscera appear similar (“soft” or “exudative” tubercles)
(2–5, 65, 66); an obvious caseous focus invading the
blood vessel is usually demonstrable, and the lesions
often reveal acid-fast bacilli (AFB). When the dissemi-
nation is due to the discharge of bacilli into microscopic
blood vessels within the caseous lesions, which, in turn,
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
respiratory distress syndrome (ARDS) develops due to
miliary TB, hyaline membranes are present in addition
to the cellular infiltrate. Occasionally, vasculitic lesions
can be discerned in miliary TB patients with TB men-
ingitis. Choroidal tubercles, when present, are patho-
gnomonic of miliary TB (see below). They are multiple in
number and are usually evident in both eyes, mostly in
the posterior pole. As the acute infection resolves, the
center of the choroidal tubercles may become white
or yellow, with a surrounding peripheral rim of pig-
mentation; the margins become sharply delineated and
distinct. Subsequently, an atrophic scar may develop.
Rarely, infective endocarditis, pericarditis, intracardiac

TABLE 5 Organ system involvement in miliary TBa

Chapman and Gelb et al. Grieco and Prout and Slavin

Variable Whorton (21)b (32)b,c Campbell (31)b,c Chmel (33)b,c Aderele (28)b,c Benatar (40)b,c (25)b
Yr of publication 1946 1973 1973 1974 1978 1980 1980
No. of autopsies 63 21d 23e 10f 11g 34h 100
Organ system
involvement (%)
Spleen 100 86 70 80 82 79 100
Liver 100 91 61 60 55 85 97

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Lungs 63 100 100 100 100 77 86
Lymph nodes 33 38i 39 80 73 79 ND
Bone marrow 84 24 ND ND ND 47 77
Kidneys 53 62 43 30 55 56 64
Adrenals 42 14 22 30 ND 29 53
Ocular choroid ND ND ND ND ND ND 50j
Thyroid ND 19 ND ND ND 06 14
Breast ND ND ND ND ND ND 13
Pancreas 20 14 ND ND ND ND 12
Heart 10 ND ND ND 36 06 10
Prostate ND ND ND ND ND ND 07
Testis 41 ND ND ND ND ND 05
Pituitary ND ND ND ND ND ND 04
Central nervous 41 ND 22 ND 36 26 ND
system
aAll values are expressed as a percentage corrected to the nearest round figure. ND, not described.
bAutopsy data.
cClinical data.

dAutopsy was performed in 21 of the 30 patients who died.

eAutopsy was performed in 23 of the 25 patients who died.

fAutopsy was performed in 10 patients who died.

gPediatric series. Autopsy was performed in 11 of the 44 children.

hAutopsy was performed in 34 of the 40 patients who died.

iMediastinal lymph nodes.

jFourteen eyes were available for histological examination.

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Sharma and Mohan

mass, or mycotic aneurysm may also be evident at au- Constitutional symptoms

topsy. Patients with miliary TB classically present with fever of
When patients with advanced HIV infection develop several weeks’ duration, anorexia, weight loss, weak-
miliary TB, the salient pathological features include poor ness, and cough (1–5). Recently, the occurrence of daily
granuloma formation with minimal cellular reaction, morning temperature spikes (67) was reported to be
severe necrosis, and presence of abundant AFB. Foci of characteristic of miliary TB. Occasionally, fever may be
acute TB pneumonia involving airspaces rather than the absent and the patients may present with progressive
interstitium are also common in HIV-coinfected patients wasting strongly mimicking a metastatic carcinoma.
with miliary TB (18, 19). Proudfoot et al. (68) suggested “cryptic miliary TB” for
this presentation in the pre-CT era. Since its initial
description, cryptic miliary TB is increasingly being
CLINICAL MANIFESTATIONS reported for the elderly (69, 70). Previously, cryptic
Adults miliary TB could be diagnosed only at autopsy. How-
The clinical manifestations of miliary TB in adults are ever, with the availability of HRCT, affected patients
protean and nonspecific and can be obscured until late in can now be diagnosed during their lifetime (2–5, 42).
the disease (Table 6). Chills and rigors, usually seen in patients with ma-
laria or sepsis and bacteremia, have often been de-
scribed for adult patients with miliary TB (1–5). The
TABLE 6 Presenting symptoms and signs in miliary TBa
utility of a damp shadow sign (where sweat engraves
Variable Adult series (%)b Pediatric series (%)c the patient’s silhouette on the bed, closely resembling a
Symptoms body’s shadow) in raising the suspicion of miliary TB
Fever 35–100 61–98 has been noted (71).
Chills 15–28 ND
Anorexia 24–100 4–81 Systemic involvement
Weight loss 20–100 4–60 Since miliary TB can involve many organs, patients
Night sweats 8–100 8–75
present with symptoms and signs referable to various
Weakness/fatigue 25–100 14–54
organ systems (Table 6). Dry cough and dyspnea are
Cough/sputum 27–82 17–90
Chest pain 3–49 1–3
often present. Sometimes, cutaneous lesions are the only
Dyspnea 8–100 7–25 discernible clues to miliary TB (Fig. 4). These include
erythematous macules and papules (tuberculosis miliaria

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Hemoptysis 3–15 1
Headache 2–18 2–8 cutis) (1–5). Choroidal tubercles, when present, offer a
Altered sensorium 5–26 2–8 valuable clue to miliary TB as the diagnosis (1–5, 42). TB
Seizures ND 7–30 meningitis (TBM) has been described for 10% to 30%
Nausea 1–19 ND adult patients with miliary TB (14, 25, 28–44); about
Abdominal pain 5–19 3–15 one-third of patients presenting with TBM have under-
Diarrhea 2–3 ND lying miliary TB (72). In a study published from India
Urinary symptoms 2–6 ND
(73), the spectrum of neurological involvement in adult
Signs
patients with miliary TB (n = 60) included TBM with
Fever 35–100 39–75
Pallor 36–59 31
(45%) and without (35%) tuberculoma and included
Cyanosis 1–2 ND
thoracic transverse myelopathy (15%). These observations
Icterus 5–9 3 warrant a careful clinical examination and appropriate
Lymphadenopathy 2–30 5 investigations to ascertain neurological involvement.
Chest signs 29–84 34–72 Clinically evident cardiac or renal involvement is
Hepatomegaly 14–62 39–82 uncommon in patients with miliary TB. Overt adrenal
Splenomegaly 2–32 24–54 insufficiency manifesting as Addison’s disease at initial
Ascites 4–38 6–9 presentation or during anti-TB treatment has also been
Choroidal tubercles 2–12 2–5 described to occur in miliary TB (74, 75).
Neurological signs 3–26 19–35
aAll values are expressed as percentages corrected to the nearest round figures.
Children
ND, not described.
bData are from references 30 to 33 and 35 to 40. Comparatively fewer published series on miliary TB in
cData are from references 11 to 13, 28, and 41.
children (11–13, 28, 41) than in adults (14, 25, 28–44)

8 ASMscience.org/MicrobiolSpectrum

FIGURE 4 Papulonodular skin lesions in a patient with miliary
TB. Skin biopsy confirmed the diagnosis.
are available. Clinical presentation of miliary TB in
children (Table 6) is similar to that observed in adults,
with some important differences. Miliary TB develops
less often in children who have received the BCG vac-
cination (2–5). Chills and night sweats, hemoptysis, and
productive cough are less common than in adults; pe-
ripheral lymphadenopathy and hepatosplenomegaly are
more frequent in children with miliary TB (Table 6). A
larger proportion of children with miliary TB (20% to
40%) (11–13, 28, 41) than adults (15% to 30%) (14,
25, 28–44) suffer from TBM.
Immunosuppressed Individuals
The prevalence of miliary TB in persons with early
HIV infection (CD4+ cell counts of >200/mm3) is simi-
lar to that observed in immunocompetent individuals.
With progression of immunosuppression, in late, ad-
vanced stages of HIV infection (CD4+ cell counts of
<200/mm3), miliary TB is seen more often (2–5, 18, 19).
Cutaneous involvement, a rare clinical manifestation
in HIV-seronegative patients with miliary TB, is more
commonly seen in HIV-infected patients with CD4+
cell counts below 100/mm3 (2–5, 18, 19, 76–78), in
whom these lesions (1–5) appear as tiny papules or
vesiculopapules, described as tuberculosis cutis miliaris
ASMscience.org/MicrobiolSpectrum
Miliary Tuberculosis
disseminata, tuberculosis cutis acuta generalisita, and
disseminated tuberculosis of the skin (Fig. 4). Some-
times, macular, pustular, or purpuric lesions, indurated
ulcerating plaques, and subcutaneous abscesses have
been reported (79). In miliary TB patients coinfected
with HIV, especially in those with profound immuno-
suppression, intrathoracic lymphadenopathy and tuber-
culin anergy are more common; sputum smears are
seldom positive, and blood culture may grow Myco-
bacterium tuberculosis (2–5, 18, 19, 76–78). These ob-
servations seem to be applicable to other causes of
immunosuppression as well. In a study from China (80),
miliary TB was present in 31% of immunocompromised
patients (n = 39), compared to 2.6% of immunocom-
petent persons (n = 79).
ATYPICAL CLINICAL MANIFESTATIONS
Several atypical clinical manifestations have been ob-
served in adult and pediatric patients with miliary TB
(Table 7) (2, 4, 5). Atypical clinical presentations often
result in a delay in the diagnosis, and miliary TB is often
a “missed diagnosis.”
Acute Respiratory Distress Syndrome
Miliary TB is a rare but an important treatable cause of
ARDS. Although ARDS may develop anytime during
the course of miliary TB, it is usually seen at the time
of initial presentation (81–85). Sometimes, ARDS may
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TABLE 7 Atypical clinical manifestations and
complications in miliary TB
Cryptic miliary TB
Presentation as pyrexia of unknown origin
Incidental diagnosis
ARDS
Air leak syndrome (pneumothorax, pneumomediastinum)
Myelophthisic anemia, myelofibrosis, pancytopenia,
immune hemolytic anemia
Acute empyema
Septic shock, MODS
Thyrotoxicosis
Renal failure
Immune complex glomerulonephritis
Sudden cardiac death
Mycotic aneurysm of aorta
Native valve and prosthetic valve endocarditis
Myocarditis, congestive heart failure, intracardiac masses
Cholestatic jaundice
Presentation as focal extrapulmonary TB (e.g., hepatic miliary TB)
Syndrome of inappropriate antidiuretic hormone secretion
Deep vein thrombosis
9
Sharma and Mohan
develop as a component of the multiorgan dysfunction
syndrome (MODS) due to TB or as a manifestation of
immune reconstitution inflammatory syndrome (IRIS)
(81–85). In a study from two large teaching hospitals at
New Delhi and Tirupati in India (85), among patients
with TB, prolonged illness, miliary TB, absolute lympho-
cytopenia, and elevated alanine aminotransferase were
found to be independently associated with the develop-
ment of ARDS. In another study (86) from Korea, higher
C-reactive protein levels and an increasing nutritional
risk score were found to be independent risk factors for
the development of ARDS in patients with miliary TB.
Air Leak Syndromes
Pneumothorax, which may sometimes be bilateral, may
be the presenting feature or may sometimes develop
while the patient is receiving treatment (1–5, 87, 88).
Typical miliary shadows may not be evident initially and
may become apparent once the lung expands. Intrapul-
monary rupture of alveoli and consequent air leak that
traverses into the mediastinum after spreading along the
vascular sheath can result in pneumomediastinum with
subcutaneous emphysema, which may be fatal (89).
Renal Failure
In patients with miliary TB, apart from being a part
of MODS, acute kidney injury (AKI) may occur due to
direct renal parenchymal involvement (2–5, 90). AKI
can also develop as a manifestation of IRIS in HIV-
infected patients (91). Rarely, renal failure can develop
as a consequence of obstructive uropathy caused by the
disease process (18).
Hepatic and Gastrointestinal Complications
Asymptomatic rise in hepatic transaminases is common
in patients with miliary TB, and anti-TB treatment
should not be withheld on this evidence alone. In this
scenario, liver functions should be periodically moni-
tored. Fulminant hepatic failure due to widespread liver
cell necrosis may rarely be the presenting manifesta-
tion in miliary TB (92, 93). In some of these patients
the characteristic pulmonary lesions that constitute the
hallmark of miliary TB are absent, resulting in a delay in
diagnosis (92, 93). This could probably be the result of
an extrapulmonary focus discharging the tubercle bacilli
into the portal circulation, resulting in hepatic miliary
TB. Anti-TB drug-induced hepatotoxicity is also com-
mon; standard guidelines (94) should be followed in its
management. Small intestinal perforations at the site
of granulomatous involvement have been described for
some patients on treatment (95).
10
Cardiovascular Complications
For patients with miliary TB, life-threatening compli-
cations such as myocarditis, congestive heart failure,
infective endocarditis, pericarditis, intracardiac mass,
mycotic aneurysm, and sudden cardiac death have been
described (2–5).
Immune Reconstitution
Inflammatory Syndrome
IRIS, occasionally described to occur in HIV-negative
individuals with TB, has been reported to occur in 32%
to 36% of patients coinfected with HIV and TB within
days to weeks of the initiation of antiretroviral ther-
apy (96). Manifestations range from isolated instances
of fever to increased or initial appearance of lymph-
adenopathy, new or worsening pulmonary infiltrates,
serositis, cutaneous lesions, and new or expanding
central nervous system mass lesions (19, 96). IRIS can
be brief or prolonged with multiple recurrences. AKI
(91, 97) or ARDS (81) can develop during the course
of IRIS.
APPROACH TO DIAGNOSIS
Even in an area where TB is endemic, the diagnosis
of miliary TB can be difficult, as the clinical symptoms
can be nonspecific, the chest radiographs do not always
reveal the classical miliary changes and atypical presen-
tations such as ARDS, and shadows larger than miliary
on chest radiograph commonly occur. Therefore, a high
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index of clinical suspicion and a focused diagnostic test-
ing to establish the diagnosis of miliary TB can facilitate
early institution of anti-TB treatment that can be life-
saving.
The following criteria have been suggested for the
diagnosis of miliary TB: (i) clinical presentation consis-
tent with a diagnosis of TB, such as pyrexia with evening
rise of temperature, weight loss, anorexia, tachycardia,
and night sweats of greater than 6 weeks’ duration
responding to anti-TB treatment; (ii) classical miliary
pattern on chest radiograph; (iii) bilateral diffuse re-
ticulonodular lung lesions on a background of miliary
shadows demonstrable either on plain chest radiograph
or HRCT; and (iv) microbiological, cytopathological,
histopathological, or molecular evidence of TB (2–5,
42).
Fundus Examination
Choroidal tubercles are bilateral, pale, grayish white,
and oblong patches that are pathognomonic of miliary
TB. Though rare (Table 6), their presence is diagnostic
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 Miliary Tuberculosis

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.
b CRP, C-reactive protein.
yield with the conventional microbiological methods
from various body fluids and tissues that are commonly
tested are listed in Table 8 (14, 16, 17, 28–44, 54, 98). Hyponatremia in patients with miliary TB may indi-
cate the presence of TBM (38) and may also be a pre-
Laboratory Abnormalities dictor of mortality (42). Hyponatremia in miliary TB has
A number of hematological and biochemical abnor- been thought to be due to an acquired disturbance of
malities are known to occur in miliary TB (Table 9) (14, neurohypophyseal function resulting in unregulated an-
16, 17, 28–44, 98), but their significance is controver- tidiuretic hormone release due to an antidiuretic prin-
sial. Disseminated intravascular coagulation (83, 85) has ciple in the lung tissue affected by TB that may either
been described for patients with miliary TB in the setting produce antidiuretic hormone or absorb an inappro-
of ARDS and MODS and is associated with a high priately released hormone from the posterior pituitary
mortality rate. Miliary TB has also been implicated as (101–103). Rifampin-induced adrenal crisis in a patient
a cause of pancytopenia and hypoplastic anemia (99). with miliary TB and Addison’s disease who developed
Immune mechanisms have been implicated in causing generalized malaise and hyponatremia while she was
bone marrow suppression in patients with miliary TB initiated on anti-TB treatment has also been described

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(2–5). Hypercalcemia has been documented in miliary (75).
TB but is uncommon (100).
Tuberculin Skin Test
TABLE 8 Method of confirmation of diagnosis in adults Tuberculin anergy is more common in miliary TB than
with miliary TBa
in pulmonary TB and extrapulmonary TB; tuberculin
Variable Cumulative yield (%) skin test conversion may occur following successful
Sputumb 41.4 treatment. In various published pediatric series, tuber-
Bronchoscopyb,c 46.8 culin anergy has ranged from 35% to 74% (11–13, 28,
Gastric lavageb 61.1 41); in published adult series, the corresponding figures
CSFb,e 21.2 have been 20% to 70% (30–33, 35–40, 98). However, a
Urine 32.7 positive tuberculin skin test only indicates infection with
Bone marrowb,d 66.7 Mycobacterium tuberculosis and does not always indi-
Liver biopsy 88.9 cate active disease.
Lymph node biopsy 90.9
aData are from references 14, 16, 17, 28 to 44, 54, and 98. Criteria for subjecting Interferon Gamma Release Assays
the patients to these tests were not clearly defined in any of the studies. Often, more
than one test was performed for confirming the diagnosis. For histopathological The in vitro T-cell-based interferon gamma release as-
diagnosis, the presence of granulomas and caseation and demonstration of AFB have says (IGRAs), available in enzyme-linked immuno-
been variously used to define a positive test.
bYield from smear and culture. sorbent assay and enzyme-linked immunospot assay
cIncludes yield from bronchoscopic aspiration, washings, brushings, BAL, and
formats, may be useful for patients with miliary TB,
transbronchial lung biopsy.
dYield from aspiration and/or trephine biopsy. especially children, BCG-vaccinated individuals, and
eCSF, cerebrospinal fluid. persons living with HIV infection and AIDS (104, 105).

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Sharma and Mohan
A positive IGRA result, however, does not distinguish
between latent TB infection and active disease, but a
negative IGRA result may be helpful in ruling out a di-
agnosis of TB (106).
Pulmonary Function and Gas Exchange
Abnormalities
Miliary TB is associated with abnormalities of pulmo-
nary function typical of interstitial lung disease, and
these may be of a greater magnitude than might be
anticipated from the chest radiograph (107–109). Im-
pairment of diffusion is the most common abnormality
and may sometimes be severe (109, 110). Other abnor-
malities include a mild reduction in flow rates sugges-
tive of peripheral airway involvement (110). During the
acute stage, arterial hypoxemia due to widening of the
alveolar-arterial oxygen gradient and hypocapnia due to
tachypnea are also observed (111).
Cardiopulmonary Exercise Testing
Patients with miliary TB have abnormal cardiopulmo-
nary exercise performance with lower maximum oxygen
consumption, maximal work rate, anaerobic threshold,
peak minute ventilation, breathing reserve, and low max-
imal heart rate (2–5, 98, 111, 112). Other abnormalities
include higher respiratory frequency, peak minute ven-
tilation at submaximal work, and high physiological
dead space/tidal volume. A demonstrable fall in oxygen
saturation (to 4% or more) with exercise has been ob-
served. Following successful anti-TB treatment, these
abnormalities had reversed in most of the patients,
though they persisted in some of them (111, 112).
Immunological Abnormalities and BAL Fluid
A few reports on the cellular characteristics of BAL fluid
in patients with miliary TB have been published, and
these have shown conflicting results (18, 110, 113). The
TABLE 10 Chest radiographic abnormalities in miliary TB
Common Uncommon
Classical miliary pattern (50%) a a
Nonmiliary patterns (10%–30%)
Asymmetrical nodular pattern
Coalescence of nodules
Mottled appearance
“Snow storm” appearance
Airspace consolidation
a Data are from references 2 to 5, 10 to 17, 28 to 44, and 98.
12
proportion and absolute number of lymphocytes are
substantially increased in BAL fluid. Although a raised
CD4+ CD8+ T-lymphocyte ratio and B lymphocytes were
reported for BAL fluid in one study (108), a decrease in
CD4+ CD8+ T-lymphocyte ratio was reported in another
(110). The small number of patients studied could partly
be the reason for these differences. Polyclonal hyper-
gammaglobulinemia with increases in immunoglobulin
G (IgG), IgA, and IgM was observed in peripheral blood
and BAL fluid in one study (108). These findings prob-
ably result from increased local synthesis by activated B
lymphocytes. Increased BAL fluid fibronectin and serum
C3 levels as acute-phase response to ongoing inflam-
mation were observed (108, 114). Lymphocytic alveo-
litis and increased IgG and IgA levels persisted following
anti-TB treatment (108).
Imaging Studies
A miliary pattern on the chest radiograph is often the
first clue suggestive of miliary TB. Several other imaging
modalities, such as ultrasonography, CT, and magnetic
resonance imaging (MRI), help to discern the extent of
organ involvement and are also useful in evaluation of
response to treatment.
Chest radiograph
A miliary pattern on chest radiograph (1–5, 8) is the
classical feature of miliary TB and is observed for a
majority of patients. Subtle miliary lesions are best de-
lineated in slightly underpenetrated films, especially
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when the diamond-shaped areas of the lung in between
the ribs are carefully scrutinized using bright light (9,
115). The chest radiographic abnormalities in miliary
TB are listed in Table 10 (2–5, 98). Some patients may
have normal chest radiographs initially and the classical
miliary pattern may evolve over the course of the disease
(Fig. 5), emphasizing the importance of periodic repeat
Rare
Other associated findings (<5%)a
Intrathoracic lymphadenopathy
Pleural effusion
Empyema
Pulmonary parenchymal lesions and cavitation
Segmental consolidation
Thickening of interlobular septa
Pneumothorax
Pneumomediastinum
Pericardial effusion
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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
of unknown origin (2–5, 42).
When patients with miliary TB develop ARDS (Fig. 6),
the chest radiograph findings may be identical to those
seen in ARDS due to other causes (83, 85). The majority
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
over the course of the disease. The diagnosis of miliary
TB is easier when the patient presents with classical mil-
times be loculated), focal hepatic and splenic lesions, and
cold abscess. Ultrasonography guidance also facilitates
diagnostic thoracic or abdominal paracentesis to pro-
cure pleural or peritoneal fluid for diagnostic testing,
especially if the fluid is loculated.
FIGURE 6 Chest radiograph (antero-posterior view, done
bedside with a portable machine) showing bilateral frontal

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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
resonance imaging
HRCT and thin-section multidetector row CT have con-
siderably improved the antemortem diagnosis of mili-
ary pattern. HRCT reveals a mixture of both sharply
and poorly defined, <2-mm nodules that are widely dis-
seminated throughout the lungs, associated with diffuse
reticulation (119, 120). HRCT may reveal a classical
miliary pattern, even when the chest radiograph looks
apparently normal (2–5, 42), and also facilitates iden-
tification of intrathoracic lymphadenopathy, calcifica-
tion, and pleural lesions. Air trapping has been described
on HRCT both at presentation and during follow-
up (120) and occurs due to endobronchial involvement
of peripheral airways. The interlobular septal thicken-
ing or intralobular fine network that is evident on
HRCT in miliary TB seems to be caused by the caseation
necrosis in the alveolar walls and interlobular septa.
Sometimes in subjects with active postprimary disease,
centrilobular nodules and branching linear structures
giving a “tree-in-bud appearance” may be evident (119,
120).
Pipavath et al. (121), in a recent publication, reported
the following changes on HRCT in patients with miliary
TB (n = 16): miliary pattern (n = 16); intrathoracic
lymphadenopathy (n = 8); alveolar lesions, such as
ground-glass attenuation and/or consolidation (n = 5);
pleural and pericardial effusions (2 patients each); and
peribronchovascular interstitial thickening and emphy-
sema (1 patient each). In that study (121), nodules were
randomly distributed in both lung fields in miliary TB,
whereas in sarcoidosis, the findings included peribron-
chovascular interstitial thickening and perilymphatic
distribution of the nodules (122). A higher prevalence
of interlobular septal thickening, necrotic lymph nodes,
and extrathoracic involvement has also been observed in
HIV-seropositive patients with miliary TB (122).
MRI and CT have been useful in identifying miliary
lesions at extrapulmonary sites. Abdominal CT has been
useful in identifying lesions in the liver and spleen,
lymphadenopathy, and cold abscesses (2–5). Unlike the
CT of the chest, in which the classical <2-mm nodular
lesions are evident, miliary lesions in the liver and spleen
may appear as discrete hypodense lesions, a few of
which may be confluent, sometimes with irregular pe-
ripheral rim enhancement (123). MRI of the brain and
spine is very useful in the initial evaluation and follow-
up of miliary TB patients with TBM or spinal TB and
also protects from radiation exposure (2–5).
Image-guided radiological procedures, such as fine-
needle aspiration for cytological examination (FNAC)
14
and biopsy under CT or MRI guidance, are useful for
procuring tissue and body fluids for diagnostic testing.
Echocardiography
Two-dimensional transthoracic echocardiography helps
to diagnose associated pericardial effusion.
Bronchoscopy
Fiberoptic bronchoscopy, BAL fluid, bronchoscopic as-
pirate, brushings, and transbronchial lung biopsy speci-
mens are useful in confirming the diagnosis of miliary
TB. The cumulative diagnostic yield for various bron-
choscopic specimens by smear and culture methods in
published studies has been found to be 46.8% (Table 8)
(29, 35, 36, 40, 42, 124, 125).
Laparoscopy
When associated abdominal involvement is present,
laparoscopy provides an opportunity to visualize the
lesions with the naked eye and facilitates biopsy from
the liver, peritoneum, omentum, and mesenteric lymph
nodes for diagnostic confirmation (126).
Serodiagnostic, Molecular,
and Other Methods
Detection of mycobacterial antigens, antibodies, and
immune complexes in the blood and body fluids by en-
zyme-linked immunosorbent assay has been used for di-
agnosis of miliary TB; however, these methods are not
being used currently (2–5). PCR of cerebrospinal fluid,
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tissue biopsy specimens, and blood (especially from HIV-
infected patients) may be useful for confirmation of di-
agnosis (18). The Xpert MTB/RIF (Cepheid, Sunnyvale,
CA), a cartridge-based nucleic acid amplification test,
has been found to be useful in the early diagnosis of
pulmonary (3–5) and extrapulmonary (127) TB and can
detect the presence of Mycobacterium tuberculosis com-
plex and provide information regarding rifampin re-
sistance in 90 min. Line probe assays facilitate rapid
detection of Mycobacterium tuberculosis and mutations
associated with resistance to rifampin, isoniazid, and
second-line anti-TB drugs in under 24 h. Adenosine de-
aminase and interferon gamma level estimations in as-
citic fluid and pleural fluid can be helpful in confirming
the diagnosis of TB (128–132).
Positron Emission Tomography
Positron emission tomography CT (PET-CT) using the
radiopharmaceutical 18F-labeled 2-deoxy-D-glucose has
been found to be useful to assess the activity of various
infectious lesions, including pulmonary TB (133, 134).
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 Miliary Tuberculosis

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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
(Fig. 7) that might persist following anti-TB treatment in
miliary TB needs to be studied further.
The algorithm for the workup of a patient suspected
to have miliary TB is shown in Fig. 8.
TREATMENT
Miliary TB is uniformly fatal if not treated (1–5). Stan-
dard anti-TB treatment is the cornerstone of manage-
ment. There is no consensus regarding the optimum
duration of treatment in patients with miliary TB. In
several parts of the world, patients with miliary TB get
treated under national TB control program, with directly
observed treatment using short-course chemotherapy
(135, 136). However, there are no published random-
ized controlled trials assessing the efficacy of the stan-
dard World Health Organization (WHO) treatment
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
the treatment of HIV and miliary TB coinfection.
The American Thoracic Society, CDC, and Infectious
Disease Society of America (137) guidelines, National
Institute for Health and Clinical Excellence (138) guide-
lines, and the 2015 report of the Committee on Infec-
tious Diseases, American Academy of Pediatrics (AAP)
(139) from the United Kingdom recommend 6 months

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Sharma and Mohan

FIGURE 8 Algorithm for the diagnostic workup of a pa-

tient with suspected miliary TB. The clinical and imaging
diagnostic workup should also aim at accurately assessing
the extent of extrapulmonary involvement to facilitate
monitoring and ensure adequate duration of treatment.
All laboratory testing, especially anti-TB DST, must be
carried out in quality-assured, periodically accredited
laboratories. *, often used in children; †, FNAC/excision
biopsy; ‡, radiologically guided FNAC/biopsy; §, media-
stinoscopic/video-assisted thoracoscopic surgery, bi-
opsy; ||, laparoscopic biopsy; ¶, useful in advanced HIV
infection. TST, tuberculin skin test; CECT, contrast-
enhanced CT; L-J, Lowenstein-Jensen medium; MGIT,
mycobacterial growth inhibitor tube; BACTEC, radio-
metric culture method; Xpert MTB/RIF, GeneXpert MTB/
RIF assay (Cepheid, Sunnyvale, CA); LPA, line probe assay.
Reproduced with permission from reference 4.

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16 ASMscience.org/MicrobiolSpectrum
 Miliary Tuberculosis

of treatment (2-month intensive phase with isoniazid, ri-
fampin, pyrazinamide, and ethambutol or streptomycin,
followed by a 4-month continuation phase with isonia-
zid and rifampin) for newly diagnosed cases of miliary TB
without meningeal involvement.
In the WHO guidelines for the treatment of TB (136),
patients are categorized as “new patients” or “previ-
ously treated patients.” In these guidelines (136), miliary
TB is classified as pulmonary TB because there are le-
sions in the lungs. New patients with miliary TB receive
6 months of daily or intermittent treatment as described
above. The current WHO policy (140) suggests that
HIV-coinfected patients with TB and all TB patients in
HIV-prevalent settings should receive daily treatment
during both the intensive and the continuation phases
Q2 (strong recommendation, high-quality evidence). For
previously treated patients, the WHO guidelines (136)
advocate that specimens for culture and drug suscepti-
bility testing (DST) be obtained from all previously
treated TB patients at or before at the start of treat-
ment. DST should be performed for at least isoniazid
and rifampin, and in settings where rapid molecular
DSTs are available, the DST results should guide the
choice of regimen. Although this duration of treatment
may be sufficient for many, each patient needs to be
assessed individually, and wherever indicated, treatment
duration may have to be extended.
The evidence-based INDEX-TB guidelines (127) ad-
vocate treatment for at least 9 months when TBM is
present, and other guidelines (136–138) suggest that
treatment be extended for 12 months. When TB menin-
gitis is present, the recent AAP Committee on Infectious
Diseases recommendations advocate an initial intensive
phase with isoniazid, rifampin, pyrazinamide, and ethi-
onamide [or an aminoglycoside (in place of ethambu-
tol)] for 2 months, followed by a continuation phase

Q3 FIGURE 9 Guidelines on timing of antiretroviral treatment in patients with HIV and TB

coinfection. *, although the data suggest a cutoff of 50 cells/μl, because of the daily
variability in CD4, a cutoff of 100 cells/μl may be more appropriate. ART, antiretroviral
treatment; BHIVA, British HIV Association; EFV, efavirenz; HAART, highly active antiretro-
viral treatment; NNRTI, nonnucleoside reverse transcriptase inhibitor; INSTI, integrase
strand transfer inhibitor; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine; FTC,
emtricitabine. Data are from references 144 and 145.

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ASMscience.org/MicrobiolSpectrum 17
Sharma and Mohan

TABLE 11 Predictors of poor outcome in patients with disseminated or miliary TB

Study (year) (reference) Predictors of poor outcome

Gelb et al. (1973) (32)a Stupor, meningismus, increasing age, cirrhosis of liver, leukopenia, leukocytosis
Grieco and Chmel (1974) (33) Increasing age, presence of underlying disease, history of cough, night sweats
Kim et al. (1990) (35) Female gender, altered mental status
Maartens et al. (1990) (36) Age greater than 60 yrs, lymphopenia, thrombocytopenia, hypoalbuminemia, elevated transaminase levels,
treatment delay
Sharma et al. (1995) (42) Dyspnea, chills, temp of >39.3°C, icterus, hepatomegaly, hypoalbuminemia, hyponatremia, elevated serum
alkaline phosphatase
Long et al. (1997) (14) Presence of one or more predisposing conditionsb
Mert et al. (2001) (37) Male sex, presence of atypical chest radiographic pattern, delay in instituting anti-TB treatment
Hussain et al. (2004) (34) Presence of altered mental status, lung crackles, leukocytosis, thrombocytopenia, and the need for ventilation
Kim et al. (2008) (86) High nutritional risk scorec
a No statistical analysis was performed.
b Listed in Table 3.
cA four-point nutritional risk score was defined according to the presence of four nutritional factors: low body mass index (<18.5 kg/m2), hypoalbuminemia (serum albumin

< 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.

of 7–10 months with isoniazid and rifampin (139). Mechanical Ventilation

The WHO guidelines (136) indicate 9 months of treat-
ment when bone and joint TB is also present. The
evidence-based INDEX-TB guidelines (127) suggest that
when spinal TB and other forms of bone and joint TB
are present, a total treatment duration of 12 months
(extendable to 18 months on a case-by-case basis) is in-
dicated.
Corticosteroids
No study has specifically evaluated the role of ad-
junct corticosteroid treatment in patients with miliary
Assisted mechanical ventilation and other interventions
may be required for the management of patients with
miliary TB who develop ARDS (83, 85).
Surgery
Surgery is often required to procure specimens for di-
agnostic testing and to ameliorate complications, such as
small bowel perforation, for which it may be lifesaving.
Mortality
The mortality rate related to miliary TB is about 15% to

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TB; only limited evidence is available, showing con-
flicting results. A beneficial response was observed in
some studies (141), although such benefit could not
be documented in others (142). While associated ad-
renal insufficiency is an absolute indication for their
administration, adjunctive corticosteroid treatment may
be beneficial in miliary TB with TB meningitis, large
pericardial or pleural effusion, dyspnea, and/or dis-
abling chest pain, IRIS, ARDS, immune complex ne-
phritis, and histiocytic phagocytosis syndrome (2–5, 81,
143).
Antiretroviral Drugs
Coadministration of rifampin may result in dangerously
low levels of antiretroviral agents by inducing the he-
patic cytochrome P450 pathway. The current WHO
recommendations (144) and the British HIV Association
guidelines regarding the timing of starting antiretroviral
drugs, the choice of drugs, and the timing of initiation
in relation to institution of anti-TB treatment (145) are
shown in Fig. 9.
20% in children (11–13, 28, 41) and is slightly higher in
adults (25% to 30%) (30–33, 35–40). Delay in diagnosis
and initiation of specific anti-TB treatment appears to be
responsible for a higher mortality rate in miliary TB.
Prognostic Factors
Several factors have been identified as predictors of
poor outcome in patients with miliary TB (Table 11).
In patients with ARDS due to miliary TB (85), an acute
physiological and chronic health evaluation (APACHE
II) score greater than 18 or a score less than or equal to
18 in the presence of hyponatremia and ratio of arterial
oxygen tension (PaO2) to fraction of inspired oxygen
(FIO2) less than or equal to 108.5 have been identified to
be predictors of death. Identification of these factors can
alert the clinicians managing patients with miliary TB.
PREVENTION
BCG vaccination is effective in reducing the incidence
of miliary TB, especially in children (146). However, it

18 ASMscience.org/MicrobiolSpectrum

is not effective in individuals who have latent TB infec-
tion and should not be administered to immunosup-
pressed hosts. Targeted tuberculin testing is practiced
in countries with a low prevalence of TB, such as the
United States (137, 147), but anti-TB drug-induced
hepatotoxicity is a potential risk with the treatment of
latent TB infection. Ongoing research (148, 149) has yet
to provide a more effective vaccine than BCG.
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